WO2019017964A1 - Bioassay carrier and preparation thereof - Google Patents
Bioassay carrier and preparation thereof Download PDFInfo
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- WO2019017964A1 WO2019017964A1 PCT/US2017/043264 US2017043264W WO2019017964A1 WO 2019017964 A1 WO2019017964 A1 WO 2019017964A1 US 2017043264 W US2017043264 W US 2017043264W WO 2019017964 A1 WO2019017964 A1 WO 2019017964A1
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- WIPO (PCT)
- Prior art keywords
- test
- pathogen
- mixture
- dispenser
- pathogen mixture
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/26—Accessories or devices or components used for biocidal treatment
- A61L2/28—Devices for testing the effectiveness or completeness of sterilisation, e.g. indicators which change colour
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L9/00—Supporting devices; Holding devices
- B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00378—Piezoelectric or ink jet dispensers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00497—Features relating to the solid phase supports
- B01J2219/00527—Sheets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00686—Automatic
- B01J2219/00689—Automatic using computers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0822—Slides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/089—Virtual walls for guiding liquids
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/16—Surface properties and coatings
- B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/02—Burettes; Pipettes
- B01L3/0241—Drop counters; Drop formers
- B01L3/0268—Drop counters; Drop formers using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
Definitions
- the present disclosure generally relates to systems and methods of depositing a pathogen on a test article, and more particularly, but not exclusively, to utilization of an automated system for depositing the pathogen uniformly across a test article in a distributed pattern.
- Disinfecting processes which may also be referred to as sterilizing processes if performed to a high level of pathogen removal and/or deactivation, are used to render medical equipment to a biologically "safe" state. These cleaning procedures are important to the medical community and to patients that rely on re-used medical equipment. To reduce the risk of infection to patients, the re-used equipment must have a low presence of pathogen, or "bioburden.” Some medical equipment is manufactured aseptically (i.e., in a sterile environment) or sterilized during the manufacturing process and used only once on a given patient. Because it is discarded, this type of medical equipment does not require disinfection or sterilization after use. Other medical equipment, however, is intended for re-use and is returned to a condition suitable for use with the same or another patient. This re-used medical equipment may be disinfected by soaking in a chemical solution between uses or by some other means.
- disinfection/sterilization methods are imaging probes, such as optical, ultrasonography, and other internal and external imaging probes.
- Exposure to X-rays, gamma rays, and other wavelengths of electromagnetic radiation has been found to be useful in sterilizing some types of medical equipment.
- the efficiency and efficacy of sterilization using electromagnetic radiation can vary depending on the amount and type(s) of pathogen on the medical equipment, the distribution of pathogen on the medical equipment, the surface material of the medical equipment, and the surface contours, structures, and condition of the medical equipment.
- the type of energy used which is often defined by wavelength
- the power level which is how much energy is being delivered per unit time
- the total energy dosage delivered during the electromagnetic radiation process and other variables will determine whether the medical equipment has been disinfected or sterilized to the appropriate level.
- Disinfectants and systems designed to deliver disinfectants are approved for sale in the United States and other markets subject to testing in accordance with various standards, including the Association of Official
- AOAC Analytical Chemists
- the standard carriers that evolved and are now in common use are conventionally made of porcelain, glass, stainless steel, or some combination thereof.
- the standard carriers may be simple discs or rectangular coupons.
- the standard carriers may be arranged in a "standard” form called a "penicylinder,” which is a small cylindrical carrier whose use arose from the perceived need for a compact, small reference surface that could be easily inoculated in a moderately sized test tube containing inoculating suspension.
- these penicylinders are exposed to liquid disinfectants by complete immersion, soaking, and often some agitation, for a range of exposure intervals. Following disinfection, the carriers are subsequently washed to recover remaining viable pathogen and bioassays performed to quantitate the results.
- hand tied "suture loops" of DACRON, silk thread, or another suitable material also became commonplace for tests directed at evaluating disinfection efficacy of liquid disinfectants used on medical products or devices that are compatible with soaking in liquids.
- testing is performed on actual medical devices in so-called "simulated use” tests.
- the standard approach employed in a biological test lab is to hand-pipette droplets of a pathogen-laced, water- based suspension onto the test article or, if appropriate, to fully immerse the test article in a suspension of pathogen.
- test area While a specifically defined test area is supposed to be inoculated, simply placing a small volume of suspension containing a known number (i.e., count, concentration) of pathogen on the target surface does not result in the subsequent distribution of said pathogen across the target surface. Unlike fully immersing a penicylinder or suture loop where the pathogen tends to distribute uniformly across the entire surface, an unrealistically high concentration of pathogen results at the site where the droplet was deposited.
- the production of a suitable test article should seek to create a biologically relevant and representative population density in "counts" or “colony forming units” (CFUs) per unit area, and the production of test articles should be reproducible, but this does not happen because these hand pipetting
- Producing test articles by hand pipetting has shown steady improvement in results as the size of the droplets is reduced, the number of droplets is increased, and the droplets are distributed over the entire test area defined by the AOAC standard.
- a practical limit for conducting this process by hand deposits 100 or so droplets of approximately the same volume.
- the hand pipetting process still tends to overly concentrate the pathogen in small areas of the test article because a relatively large amount of pathogen is still deposited at one time in one spot. Further, due to surface tension of the suspensions and related non-wetting of many surfaces commonly used, the deposited droplets typically do not "spread out," and instead remain as a spherical or hemispherical drop, which then dries, again leaving an unrealistically high concentration of pathogen "residue" in a very small area.
- Hand pipetting large numbers of droplets is also limited by human capabilities. It is difficult for a human to position and dispense the drops accurately, and a human's ability to focus and concentrate so as to perform this task repeatedly across many sample carriers is limited. What is more, humans cannot reasonably be expected to accurately and reproducibly deposit the very small volumes typically dispensed by hand pipettes.
- Hand pipetting procedures to produce test articles also have other shortcomings.
- the hand pipetting methods may also lead to cross contamination, where material may be transferred from one location to another.
- some surfaces may be substantially more wetted than others, which leads to some "dot areas" being larger than others, and hence the resulting distribution of pathogen is less homogenous across the entire treated area.
- Another factor that may lead to unpredictable results derives from commonly used "half-hemisphere” approximations. In these cases, a half- hemisphere assumes that the volume of a spherical droplet is constrained within a half sphere once the liquid is deposited on a surface, and the diameter that results is thereby greater than that of the original full sphere.
- the inventive concepts now disclosed provide a significant improvement over the standard biological lab approach of hand-pipetting a pathogen-laced suspension onto test articles.
- the hand pipetting test preparation has practical limitations of 100 or so droplets of approximately a microliter ( ⁇ ) or half-microliter volume, and even under these conditions the area distribution of pathogen (CFUs/area) in these limited samples are often not accurately or consistently reproducible. It has been recognized that volume resolution and accuracy of hand pipettes are increasingly less accurate as dispensed volumes drop below about 0.5 ⁇ per dispensed sample.
- an automated, acceptably precise, liquid dispensing system for creating test articles treated with biological suspensions.
- the automated system is arranged to produce test articles for performance verification and for validation of medical device disinfection systems.
- a micro-drop delivery valve is mounted to an XYZ dispensing robot table that provides significant improvement in reproducibility of artificially contaminated test articles.
- the test articles produced by the automated system are more representative of the surface of a "dirty" probe, where the pathogen is well distributed and not overly concentrated in certain locations, as is the case when depositing a relatively large amount of pathogen at one time, in one spot, by a hand pipetting method.
- the envisioned automated system can in essence achieve uniform "coating" of desired areas of test articles by depositing discrete micro-droplets in close proximity to each other.
- the micro-droplets are on the order of 50-200 droplets per square centimeter (cm 2 ), and in some
- a desirable target is 100 droplets/1.0 cm 2 .
- a continuous bead, spray, or sheet of pathogen-laced liquid suspension is deposited on the test article.
- Embodiments are directed towards methods and systems of depositing a uniform test-pathogen mixture onto a test article for testing the sterilization efficacy of a particular process such as an electromagnetic radiation process on the test article.
- the system includes a holding mechanism configured to removably secure the test article to the system.
- the system also includes a test-pathogen dispenser, also referred to as a pathogen distribution mechanism, configured to uniformly deposit the test-pathogen mixture onto a reference surface of the test article.
- the system is structured so that either the test article or the test-pathogen dispenser, or both, traverse relative to one another to allow for the uniform deposition of the test-pathogen mixture.
- a plurality of test-pathogen mixture droplets or lines are deposited onto the reference surface in a predetermined test-pathogen pattern, such as, for example, a plurality of rows and columns of droplets.
- a distance from a dispenser tip of the test-pathogen dispenser to the reference surface of the test article is determined using contact sensors (e.g., force-feedback sensors when the dispenser tip touches the test article, a secondary probing element to touch the surface, or the like) or non-contact sensors (e.g., light-based sensors, acoustic-based sensors, detectors based on electromagnetic fields, or the like). This distance is utilized, for example, to maintain consistency between test-pathogen mixture droplets or lines.
- an apparatus in a first embodiment, includes a holding mechanism configured to removably secure a test article such that at least one reference surface of the test article is exposed and a pathogen distribution mechanism configured to uniformly distribute a test-pathogen mixture across a reference area of the exposed test article.
- the reference area is treated to improve its surface wetting properties, and in some, the reference area is treated to improve adhesion of the test-pathogen mixture. In some
- the test-pathogen mixture includes at least one type of virus, bacteria, fungus, yeast-mold, spore, or chemotherapeutic agent.
- uniform distribution of the test-pathogen mixture includes a substantially homogeneous distribution of the test-pathogen mixture across the reference area.
- uniform distribution of the test-pathogen mixture includes distribution of the test- pathogen mixture as a continuous film across a determined length and a determined width of the reference area.
- uniform distribution of the test-pathogen mixture includes distribution of the test- pathogen mixture as a deposition of one or more continuous lines, each of the one or more continuous lines having a determined length and a determined width.
- Uniform distribution of the test-pathogen mixture may include distribution of the test-pathogen mixture as a deposition of a plurality of individual droplets in some embodiments, and in others, uniform distribution of the test-pathogen mixture includes distribution of the test-pathogen mixture in a plurality of layers. Sometimes, distribution of the test-pathogen mixture includes a determined time-to-dry between applications of a plurality of portions of the test-pathogen mixture.
- uniform distribution of the test- pathogen mixture includes distribution of the test-pathogen mixture in a determined pattern.
- the determined pattern may include a plurality of rows and a plurality of columns of droplets the test-pathogen mixture, or the determined pattern may include distribution of the test-pathogen mixture in a plurality of non-touching arrays.
- distribution of the test-pathogen mixture in the plurality of non-touching arrays includes a first array deposited and allowed to dry before a second array is deposited. Drying time between deposition of a first droplet in an array and deposition of a second droplet in an array may in some cases be at least 100 milliseconds. Selected ones of the plurality of rows may be offset from adjacent rows, and selected ones of the plurality of columns may be offset from adjacent columns.
- An apparatus includes an automated positioning system to repeatably move a dispensing mechanism to a plurality of determined locations in proximity to the reference area and an automated dispensing system to direct the dispensing mechanism to repeatably introduce portions of the test-pathogen mixture about a surface of the reference area.
- the automated positioning system controls movement of the dispensing mechanism in at least two dimensions, and in these and other cases, the automated positioning system controls movement of the dispensing mechanism in at least three dimensions.
- the automated positioning system is configured to repeatably position at least one orifice of the dispensing mechanism at a pre-determined distance from the reference area.
- the automated positioning system may include at least one distance sensor to determine a distance between the dispensing
- the at least one range sensor of the automated positioning system may in some cases be used to confirm distribution of at least some of the test pathogen.
- the at least one range sensor of the automated positioning system may include at least one force-feedback sensor.
- the automated positioning system includes a control system to generate at least one data structure representing a plurality of contours of the reference area of the exposed test article.
- the dispensing mechanism is arranged to form a defined volume of the test-pathogen mixture as a droplet at an opening of a dispensing orifice and the automated positioning system is arranged to permit the droplet to contact the surface of the reference area.
- the dispensing mechanism may include a dispenser tip, and the dispenser tip may be arranged to induce separation of the droplet when the droplet contacts the surface of the reference area.
- the dispenser tip may have a substantially cylindrical shape or a substantially cannular shape.
- the dispenser tip may be one of a plurality of dispenser tips. In these cases, the plurality of dispenser tips may be formed as an array of dispenser tips.
- the dispensing mechanism includes a separation mechanism to induce separation of the droplet from the dispensing mechanism.
- the separation mechanism includes at least one of a vibration device (e.g. , an acoustic vibration device, a mechanical vibration device, or another vibration device), an electrostatic charge generation device, a pump, a heater, and an aerator.
- the dispensing mechanism may be arranged to reciprocate with respect to the reference area. In addition, or in the alternative, the dispensing mechanism may be arranged to rotate with respect to the reference area.
- the dispensing mechanism includes a micro-droplet dispenser configured to introduce a substantially accurate volume of the test-pathogen mixture about the surface of the reference area.
- the micro-droplet dispenser may in some cases be configured to release the substantially accurate volume of the test-pathogen mixture based on a control signal provided by the automated dispensing system.
- the dispensing mechanism includes a pressure control device. The pressure control device may be arranged to supply positive pressure and negative pressure, wherein the positive pressure and negative pressure are arranged to form and hold the substantially accurate volume of the test pathogen at an orifice of the dispensing mechanism.
- the droplet has a volume of between about between 0.001 ⁇ and about 0.1 ml.
- a method of manufacturing a test article for disinfection device testing includes removably securing a test article with a holding mechanism such that at least one reference surface of the test article is exposed, and uniformly distributing a test-pathogen mixture across a reference area of the exposed test article with a pathogen distribution mechanism.
- uniform distribution of the test-pathogen mixture includes a substantially homogeneous distribution of the test-pathogen mixture across the reference area and the test-pathogen mixture includes at least one type of virus, bacteria, fungus, yeast-mold, spore, or chemotherapeutic agent.
- uniform distribution of the test-pathogen mixture includes distribution of the test-pathogen mixture in a determined pattern.
- Uniformly distributing the test-pathogen mixture across the reference area of the exposed test article in some of the second embodiments includes repeatably moving a dispensing mechanism to a plurality of determined locations in proximity to the reference area via an automated positioning system and directing the dispensing mechanism to repeatably introduce portions of the test-pathogen mixture to a surface of the reference area with an automated dispensing system.
- directing the dispensing mechanism to repeatably introduce portions of the test-pathogen mixture includes forming a defined volume of the test-pathogen mixture as a droplet at an opening of a dispensing orifice of the dispensing mechanism and permitting the droplet to contact the surface of the reference area.
- a test article production device in a third embodiment, includes a base and a holding mechanism coupled to the base. The holding mechanism is configured to support a test article.
- the test article production device includes a gantry structure fixed relative to the base and a test-pathogen dispenser movably secured relative to the gantry structure.
- the test article production device also includes at least one dispenser tip in fluid communication with the test-pathogen dispenser.
- the at least one dispenser tip is arranged to deliver portions of test-pathogen from the test-pathogen dispenser to the test article via the at least one dispenser tip, and each portion of test pathogen has a determined volume.
- the test article production device includes a controller arranged direct movement of one of the test article and the at least one dispenser tip relative to each other.
- the controller is further arranged to direct formation of each portion of test-pathogen. In some of these cases, the controller is arranged to deliver the portions of test-pathogen to the test article in a determined pattern. In some cases of the third embodiment, the test-pathogen dispenser is arranged to store a test-pathogen mixture constituted with least one type of virus, bacteria, fungus, yeast-mold, spore, or chemotherapeutic agent.
- FIGS. 1 A-1 D show various views of an illustrative example of an automated test-pathogen deposition system
- FIGS. 2A-2B show different illustrative examples of a test- pathogen pattern on a test article
- FIGS. 3A-3B show an illustrative example of the sequence of depositing test-pathogen mixture droplets into the test-pathogen pattern
- FIGS. 4A-4B show an illustrative example of another sequence of depositing test-pathogen mixture droplets into the test-pathogen pattern
- FIG. 5A illustrates a test-pathogen pattern on a test article with distance measurement positions
- FIG. 5B illustrates a fixture embodiment arranged to removably receive a plurality of test articles
- FIG. 6 is a system diagram of a computing system that controls the test-pathogen system to deposit test pathogens onto a test article
- FIG. 7 is a logical flow diagram generally showing one embodiment of a process for depositing the test pathogens onto a test article in test-pathogen pattern.
- embodiments may be methods, systems, media, devices, or some other single or combination of such mechanisms. Accordingly, the various embodiments may be entirely hardware embodiments, entirely software embodiments, or embodiments combining software and hardware aspects.
- logarithm, or "LOG" as the term may be used herein, of a given number is the exponent to which the fixed base number 10 must be raised to produce the given number.
- the number "10" raised to the power of "7” i.e., 10 7
- 7 LOG the number “10” raised to the power of "7” (i.e., 10 7 ) may also be referred to as 7 LOG.
- Disinfection processes lower the presence of one or more viable pathogens in a target area down to or below an acceptably minimum allowable load, wherein a "viable" pathogen is one considered able to reproduce.
- an unviable pathogen is one that is physically removed, killed, destroyed, rendered unable to reproduce, or rendered into a state that is considered safe in some other way.
- Sterilization processes lower the presence of one or more pathogens in a target area to a point where no colony forming units (CFU) of the given pathogen are detectable, so it is accepted that none of the pathogen is present. Sterilization may thus be described as the limiting condition of continually greater disinfection, which is to the point where no viable pathogen remains.
- Disinfecting processes which may also be referred to as sterilizing processes if performed to a high level of pathogen removal and/or deactivation, are used to render medical equipment to a biologically "safe" state.
- sterilizing processes which may also be referred to as sterilizing processes if performed to a high level of pathogen removal and/or deactivation, are used to render medical equipment to a biologically "safe" state.
- disinfect and sterilize in all of their syntactic contexts, may be used interchangeably herein where such use is not inconsistent with the inventive teachings of the present disclosure.
- test article refers to the item that includes at least one reference surface on which to test the sterilization efficacy of electromagnetic radiation or one or more other sterilization processes.
- the test article, or at least a reference surface of the test article can be made of one or more different types of materials, such as, but not limited to steel, ceramic, glass, petroleum-based materials, plant-based materials, mammalian tissue, thread or woven material, or other materials.
- the test article may be substantially planar (e.g. , flat) and generally two-dimensional, and in some embodiments, the reference area is about eight square centimeters (8 cm 2 ).
- the test article may be three-dimensional having corners, curves, contours, valleys, protuberances, patterns, convex surfaces, concave surfaces, or the like.
- One non-limiting, non- exhaustive example of a test article is an ultrasound probe.
- Another non- limiting, non-exhaustive example of a test article has at least one substantially cylindrical surface.
- Yet one more non-limiting, non-exhaustive example of a test article is substantially devoid of fissures, cracks, and occlusions.
- test pathogen refers to an agent, such as a disease- producing agent, that is to be deposited onto a test article; said test article for testing against the disinfection or sterilization efficacy of electromagnetic radiation or one or more other disinfection or sterilization processes.
- test pathogens include, but are not limited to, viruses, bacteria, fungi, yeast- molds, spores, chemotherapeutic agents, chemo-toxic agents, chemicals, other toxic material, or other substances that are expected to have some sort of bioactivity.
- the test pathogen may in some cases be suspended in a liquid, a gel, or some other suspension agent or concoction to form a test-pathogen mixture.
- the suspension agent is a water based suspension agent, which may be 90-95% by mass of the test-pathogen mixture.
- the bacteria, virus, fungal spores, mold/yeasts, or other pathogens are less than or about equal to one percent (1 %) by mass of the test-pathogen mixture's mass.
- the test pathogen may have a different concentration.
- test-pathogen mixture such as pH controlling or buffering agents, dispersants, stabilizers, or other elements that provide benefit to the test-pathogen mixture.
- elements are included in the test-pathogen mixture to increase its stability, dispersion, suspension, homogeneity, or other physical or chemical properties.
- interfering elements may be included in the test-pathogen mixture to simulate potential effects of native biological materials on the efficacy of the disinfecting agent or process.
- a non-limiting, non-exhaustive list of these elements includes Bovine/Human Serum Albumin (BSA/HSA), Fetal Calf Serum (FCS), and metal salts (e.g., potassium, sodium, calcium, magnesium salts, and the like). The inclusion or exclusion of any of these other non-pathogen elements is not discussed in detail in the present disclosure.
- test-pathogen mixture refers to a sample that is to be deposited onto at least one reference surface of a test article.
- the test- pathogen mixture may include the test pathogen itself or a combination of the test pathogen along with other liquids or matter as described herein.
- the test-pathogen mixture may be a suspension, solution, concoction, or other combination of the test pathogen with other liquids, solids, gasses, gels, or other materials.
- test pathogen and test-pathogen mixture may be used interchangeably, unless the context clearly dictates otherwise.
- spiking connotes adding one or more specified elements to an existing mixture, which is in many cases a liquid.
- test pathogen per eight square centimeters (8 cm 2 ) of treated area of a test article.
- treated areas (i.e. , reference areas) of one or more test articles range from about four square centimeters (4 cm 2 ) to about 12 square centimeters (12 cm 2 ) or more.
- concentration of the test pathogen can be adjusted depending on total volume of suspension material to be deposited. For example, a micro-droplet size of a selected volume can be mathematically combined (e.g. , multiplied) by a number of micro-droplets to be deposited.
- test-pathogen mixture a 75 to 100 microliter ( ⁇ ) volume of test-pathogen mixture is deposited onto an 8 cm 2 reference area as about 100 drops; each drop having a volume of 0.75 to 1 .0 ⁇ .
- the test-pathogen mixture may have a test pathogen concentration of between 1 .5e8 and 5.0e8 colony forming units per milliliter (CFU/ml).
- CFU/ml colony forming units per milliliter
- HLD High Level Disinfection
- an acceptably produced test article will be formed with about 1 .5 times to 10 times that amount of pathogen.
- 840 droplets, or "dots” were dispensed over a test area of 8 cm 2 .
- each dot was formed to a volume of about 0.075 ⁇ (i.e. , 75 nanoliters (nl)) for a total dispensed volume of 63 ⁇ of suspension, distributed evenly in a staggered pattern over the 8 cm 2 test area.
- the starting suspension had about 1 .0e8 CFU/ml, which included about 6.3e6 viable pathogens that were distributed over the 8 cm 2 test area, thereby resulting in about 8.5e7 per cm 2 of pathogen distributed over the 8 cm 2 test area.
- Other test pathogen concentrations are of course contemplated.
- Test pathogen droplets are distributed evenly across a majority of, or even the entire reference area of, the test article surface such that the reference area of the test article surface is substantially wetted by the test-mixture.
- Concentrating pathogen is small areas and not making use of a substantial portion of, or in a limiting case the entirety of, the reference area is often not desirable. Such concentration does not emulate in vivo conditions where a medical device might have been contaminated while in use, because a medical device contaminated in actual use typically does not exhibit extraordinarily high or grossly discontinuous local area concentrations of pathogen. Instead, when a medical device contaminated in actual use, the pathogen tends to be more smoothly distributed or "smeared" across a surface, and generally not so highly locally concentrated. Accordingly, it is undesirable to create test articles that do not reflect contact of a medical device with a contaminated surface. In some cases, it is desired that test pathogen concentration be reasonably uniform .
- test pathogen concentration be reasonably low so that the total pathogen loading or area count density (ACD) across the treated surface is reduced and is reasonably spatially homogenous.
- ACD area count density
- adjacent droplets of test-pathogen mixture are preferably not touching or joined together.
- the penicylinders described herein have an approximate surface area of about five square centimeters (5 cm 2 ), which includes the complete penicylinder, inside and out.
- 5 cm 2 the surface of the penicylinder
- the surface of the penicylinder is fully or at least substantially homogenously covered by pathogen contained in the suspension.
- pathogen contained in the suspension.
- the entire surface of the penicylinder is substantially completely inoculated with pathogen.
- at least some test article embodiments described herein are formed to dimensions of about 2 cm x 6 cm. In these cases, a reference area about 6 cm 2 to 8 cm 2 of the subject test article is inoculated.
- the inoculated area (i.e. , about 6 cm 2 to 8 cm 2 of the subject test article) is an area of the test article that will later be exposed to a disinfection modality such as ultraviolet light (e.g. , UVC).
- a disinfection modality such as ultraviolet light (e.g. , UVC).
- the inoculated reference area is less than all of the surface area of the test article, and in at least some of these cases, an upper portion of the test article where there is a hole from which the test article hangs is not inoculated.
- a perimeter margin (e.g. , about 2 mm) of the test article is not inoculated, so the inoculated reference area region is inboard.
- Bleeding may be considered to be the intentional or unintentional act where one or more liquid fronts advances, wicks, or otherwise travels along a surface away from its intended boundary. In some cases, bleeding includes one liquid traveling and merging into another liquid, which may or may not be traveling.
- Significant testing has been performed that includes dispensing a test-mixture onto certain carrier surfaces, hydrophobic surfaces in particular.
- particular spacing between individual test pathogen deposits may be selectively greater to ensure no "bleed over" to an adjacent deposition site, and a selected drying time may be utilized between adjacent deposits, so that a droplet deposited previously is allowed to dry before another is placed adjacent.
- suspended test pathogens will distribute throughout the suspending liquid phase with substantial homogeneity and not settle or cream as their density is very close to that of the liquid phase.
- the pathogen will not floe together, assemble, or adhere in any great amount to inner surfaces of a dispensing mechanism such that the suspension concentration changes meaningfully during dispensing.
- no stirring or agitation is performed once the test pathogen is prepared for deposition over a "reasonable" amount of time, which in some cases is less than or equal to about 60 minutes.
- a test pathogen reservoir may be agitated or mixed periodically during one or more methods of deposition.
- test pathogen commonly tends to move toward the air-liquid interface of the drying micro-droplet. This effect may be caused by the test pathogen being "caught” by the shrinking/contracting wall of the droplet as the liquid therein evaporates during drying.
- ACD i.e. , the number of pathogens per unit area
- the concentration may be affected or even strongly affected by the actual shape of the drying "puddle" of test-pathogen mixture, and so it is desirable to deposit micro-droplets, or other test-pathogen mixture shapes, having consistent size and shape to reduce possible migration of test pathogen within the micro-droplet.
- Such migration may be caused by convection and other concentration gradient and diffusion related forces that can result as the suspension agent (e.g. , water) evaporates.
- the suspension agent e.g. , water
- the local ACD of an outer ring of test-pathogen residue post-drying may be higher or lower than that in the center of the test-pathogen residue.
- a set of test data is presented in Table 1 .
- a first column represents a particular volume droplet of a test-pathogen sample.
- a second column approximates a droplet, or "dot," diameter.
- a third column sets forth a test orifice tip gauge of a test-pathogen dispenser embodiment, and a fourth column approximates a number of droplets that are dispensed to achieve a 10 ⁇ dose of the test-pathogen mixture.
- microliters deposit a 10 ⁇ in mm (approx.) (hypodermic)
- Table 1 Test Data to Deliver a 10 ⁇ Test-Pathogen Dose
- a desired number of droplets per test article having a reference area of two centimeters by four centimeters, which is about eight total square centimeters (8 cm 2 ), is between 200 and 1000.
- the droplet deposition density is at least 50 droplets per square centimeter.
- an interference agent may be added to the test- pathogen mixture to simulate the presence of human proteins in situ, which may make disinfection more difficult. Frequently in such cases, the interference agent mass is less than or about equal to five percent (5%) by mass of the test- pathogen mixture's mass.
- HSA Human Serum Albumin
- SSF Simulated Vaginal Fluid
- Other interference agents are also contemplated.
- the interference agent may be arranged in an actual or mock suspension in water. No simulated pathogen is necessary in some cases, as the interference agent is present in a very small amount that does not affect the mixture's physical properties in a meaningful way.
- the viscosity of the test-pathogen mixture will be close to the viscosity of distilled water or slightly greater; for example up to 10% greater.
- test-pathogen mixture will generally present no additional mechanical wear risk to any valve or other moving part in the fluid path of the test-pathogen deposition system embodiments disclosed herein.
- Particular cleaning procedures may be employed to remove any pathogen, interference agent, surfactant, detergent, or other material that adheres to a non-disposable part or portion (e.g. , valve, tube wall, reservoir, or the like) of the fluid path.
- the particular cleaning procedures may include heat, chemical, electromagnetic, or other sterilization means.
- the particular cleaning procedures may be changed or enhanced when test-pathogen mixtures containing different pathogens are applied in separate operating runs of the test-pathogen deposition system embodiments disclosed herein, which reduces the likelihood of cross
- cleaning and the related risk of contamination is obviated by using wetted components that may be discarded after a single use.
- a disposable reservoir, dispensing needle/cannula set, and associated fluid-path elements such as tubing or valve elements may be implemented.
- test-pathogen pattern refers to a substantially uniform distribution of the test pathogen or test-pathogen mixture on the test article.
- a test-pathogen pattern may be, but is not limited to, an array, a plurality of substantially concentric circles, a sheet, a line, a plurality of lines, a plurality of individual droplets, a plurality of layers, a matrix, a random
- a substantially uniform distribution may be understood in the context of two or more areas of a test article having a same size, same shape, same surface type, and/or some other characteristic of sameness.
- the volume, spacing, residual pathogen mass that remains post drying, and/or some other characteristic of test pathogen distribution in one of the two or more areas of the test article is within 75%, 85%, 95% or some greater percent of a different one of the two or more areas of the test article.
- FIGS. 1 A-1 D show various views of an illustrative example of an automated test-pathogen deposition system 100.
- FIG. 1A shows a perspective view of an illustrative example of an automated test-pathogen deposition system 100.
- FIGS. 1 B, 1 C, and 1 D show a top view, front view, and side view, respectively, of the illustrative example of the automated test-pathogen deposition system 100 shown in FIG. 1A.
- the system 100 includes a base 104, a gantry 102, and a test- pathogen dispenser 106.
- the test-pathogen dispenser 106 is structured and moveably connected to the gantry 102 to enable the test-pathogen dispenser 106 to move horizontally in an x-axis direction and vertically in a z-axis direction relative to a top surface 105 of the base 104.
- the gantry 102 is structured and moveably connected to the base 104 to enable the gantry 102 and the test- pathogen dispenser 106 to move horizontally in a y-axis relative to the top surface 105 of base 104.
- the base 104 is structured to include a holding mechanism 1 15, which in FIGS.
- the holding mechanism 1 15 is structured to removably secure a test article 1 12 to a portion of the system 100 such as the base 104 while maintaining a reference surface 1 13 of the test article 1 12 in a position to receive a test-pathogen mixture from the test-pathogen dispenser 106.
- FIGS. 1A-1 D illustrate the holding mechanism 1 15 as holding a single test article 1 12, embodiments are not so limited, and in other embodiments, the holding mechanism 1 15 may be structured to removably secure a plurality of joined or separate and distinct test articles.
- the test-pathogen dispenser 106 is structured to deposit a test pathogen in a test-pathogen pattern on the reference surface 1 13 of the test article 1 12, which provides a uniform and repeatable distribution of a test- pathogen mixture across the reference surface 1 13.
- the system 100 deposits a known or otherwise defined amount of test-pathogen mixture of a known concentration or volume population of a test-pathogen species.
- the test pathogen may be suspended or otherwise combined in a liquid buffer solution, mixture or some other concoction (e.g., an aqueous-based liquid).
- the test pathogen comprises 5% or less of the test-pathogen mixture, wherein traceable amounts of the test pathogen are greater than 0%.
- the test-pathogen mixture may be specified according to at least one official Association of Official Analytical Chemists (AOAC) International method.
- the test-pathogen mixture may also include other buffers, minerals such as metallic salts, and biological material such as albumin (e.g., human albumin or bovine albumin), mucus, blood serum, fetal calf serum, and other biological substances (e.g., proteins, peptides, or enzymes) that may act as to simulate in vivo conditions, to enhance or interfere with the condition of the pathogen or its susceptibility to electromagnetic radiation (EMR), or by simply blocking some of the EMR.
- EMR electromagnetic radiation
- the test-pathogen dispenser 106 includes a suspension reservoir 108 and a dispenser tip 1 10.
- the suspension reservoir 108 is structured to store or control the flow of the test-pathogen mixture from the test-pathogen dispenser 106 to the dispenser tip 1 10 and onto the reference surface 1 13 of the test article 1 12.
- Typical suspension reservoir 108 volumes may be three cubic centimeters (3 cc), five cubic centimeters (5 cc), 10 cc, 30 cc, or some other volume. In cases where a nominal 10 ⁇ total volume of test-pathogen mixture is deposited per test article 1 12, a total of one milliliter (1 ml), which is one cubic centimeter (1 cc), is consumed in the treatment of 100 test articles 1 12.
- a larger volume reservoir may be selected and loaded with significantly more test-pathogen mixture than will be consumed.
- the dispenser tip 1 10 is structured to deliver the test-pathogen mixture (e.g., the inoculating fluid suspension of test pathogens) to the reference surface 1 13.
- the dispenser tip 1 10 may be a liquid-fed roller (e.g., a roller having a cavity to store a determined volume of the test-pathogen mixture and at least one orifice from which to deposit the test-pathogen mixture), liquid-fed or loaded brush (e.g., a capillary-fed delivery system), pressure-fed slot or orifice, liquid loaded screen- print, cannula, needle, or some other fluid transport and deposition mechanism.
- the dispenser tip 1 10 may have a conical shape, substantially cylindrical shape, substantially cannular shape, or some other shape that has an exit orifice for the test-pathogen mixture to be deposited onto the reference surface 1 13 with an inside diameter of approximately 0.05-1 .0 millimeters.
- the dispenser is arranged as a "print pad," which is a flexibly compliant surface (e.g., silicone) etched with a selected image pattern.
- the print pad is first treated with an a test- pathogen mixture, and then the print pad is brought into communication with (e.g. , pressed against) the test article 1 12 such that the test-pathogen mixture is deposited on the reference surface 1 13.
- the compliance of the flexible print pad while administering its test-pathogen suspension payload increases the likelihood of good contact and test-pathogen delivery with even irregular or warped reference surfaces 1 13.
- the dispenser tip 1 10 may include a mechanically, digitally, manually, and/or automatically controlled atomizing head such that the test-pathogen dispenser 106 "sprays" the test-pathogen mixture on the reference surface 1 13 of the test article 1 12.
- This type of test- pathogen dispenser 106 may include one or multiple nozzles or other openings that emit liquid (e.g. , atomized) pathogen suspension as airborne droplets that traverse some distance from the dispenser tip 1 10 to the reference surface 1 13.
- Such devices may include one or more piezo-electric driven sprayers with single emitters or multi-head arrays or other liquid atomizing mechanisms, such as electro-spray, thermal ink-jet, vibrating mesh atomizers, or pressure wave (e.g. , ultrasound) driven elements.
- the test-pathogen dispenser 106 may include a pressure source arranged to pressurize the test-pathogen dispenser 106 in a range of between approximately 0.1 -10 PS I (e.g. , about 2 PS I in at least one embodiment), which may include pressurizing the suspension reservoir 108 to grow test-pathogen mixture droplets of a given volume at the exit orifice of the dispenser tip 1 10, as described herein.
- the pressurization mechanism may be operated in response to a timer, a pressure sensor, or some other pressure control mechanism. Locally, the pressurization system may be arranged to apply high pressures (e.g. , up to about 10,000 PSI) in a piezo crystal pump.
- the pressurization may be carried out using compressed air, nitrogen, or another medium.
- the test- pathogen dispenser 106 may include a fluid pump (e.g. , a mechanical displacement pump such as a piston/syringe, peristaltic device, or another such apparatus) interposed between the suspension reservoir 108 and the dispenser tip 1 10.
- a load cell may be utilized to continuously weigh the test-pathogen dispenser 106 to track the loss of fluid mass as the test-pathogen mixture droplets are deposited onto the reference surface 1 13.
- Other techniques such as electro-fluidic techniques or capacitance
- measurement systems may also be used to assess the mass, volume, or other measurable characteristics of the deposited droplets.
- test-pathogen dispenser 106 and suspension reservoir 108 are presented in a non-limiting orientation above the test article 1 12.
- a suspension reservoir is positioned below a test article.
- a dispenser tip may be arranged as a liquid-fed roller positioned between the reference area of the test article and the suspension reservoir. In this case, the roller will pass the test- pathogen suspension reservoir, pick up fluid on one side, rotate to another side, and roll into contact with the test article.
- the dispenser tip 1 10 may be arranged to cooperate with a valve (not shown).
- the valve may be structured to cycle at up to 600 Hz and run at low air pressures, from one to six pounds per square inch (1 -6 PSI) for example. In other embodiments, the valve may be structured to operate at higher air pressures, for example up to 100 PSI (e.g., 6.9 bar).
- the test-pathogen dispenser 106 is structured to deposit a controlled amount of the test-pathogen mixture on the reference surface 1 13 of the test article 1 12.
- the test-pathogen dispenser 106 may include a micro-droplet dispenser that is configured to introduce a substantially accurate volume of the test-pathogen mixture about the reference surface 1 13. The deposition of the test-pathogen mixture is performed in a desired pattern.
- the test-pathogen dispenser 106 deposits a test-pathogen pattern of one or more continuous lines or beads of the test-pathogen mixture.
- the test-pathogen dispenser 106 deposits a plurality of discrete droplets or "dots" 120 of the test-pathogen mixture, where each droplet is deposited separate from an adjacent droplet.
- the test-pathogen dispenser 106 deposits a known (e.g., fixed) or otherwise selected volume or pathogen density (i.e., population counts per unit area, or Colony Forming Units/unit area, referred to here, for example, as CFU/mm 2 ) of the test-pathogen mixture along each line or at each droplet location.
- a known (e.g., fixed) or otherwise selected volume or pathogen density i.e., population counts per unit area, or Colony Forming Units/unit area, referred to here, for example, as CFU/mm 2
- each droplet may be between approximately 0.001 ⁇ and 0.1 ml, although smaller or larger amounts may also be utilized.
- the number of CFU contained in a drop can be determined by the
- FIGS. 1A-1 D illustrate only a single dispenser tip 1 10, other embodiments may include a plurality of dispenser tips that concurrently deposit multiple droplets or lines of the test-pathogen mixture onto the test article 1 12.
- test-pathogen pattern of the droplets may include a plurality of rows or columns.
- the rows and columns of droplets may be aligned with one another, as illustrated in FIG. 2A.
- each row or column may be at least partially offset relative to its respective adjacent row(s) or column(s), such as illustrated in FIG. 2B.
- test-pathogen patterns may also be employed.
- the droplets can be deposited onto the reference surface 1 13 in a different order depending on the distance between the droplets, the size of each droplet, or other testing parameters.
- FIGS. 3A-3B and 4A-4B illustrate two non-limiting test-pathogen patterns and the sequence in which each test-pathogen mixture droplet in the pattern is deposited.
- test-pathogen dispenser 106 suspension reservoir 108, or dispenser tip 1 10 may be reusable or single use components, depending on the type of test pathogen being tested and acceptable levels or probabilities of cross contamination from the testing of one type of test pathogen to another.
- all or portions of the reservoir 108, pumping system, and/or dispenser tip 1 10 may be
- the reservoir 108 and/or dispenser tip 1 10 may be arranged for removal and sterilization or other cleaning.
- the reservoir 108 and/or dispenser tip 1 10 may include a disposable pumping system and/or a disposable liner, bladder, container, receptacle, or some other repository (not shown), which is disposable.
- the system 100 may also include a sensor 1 14 (e.g. , a range sensor, proximity sensor, force sensor, or another type of distance sensor) to determine the distance between the end of the dispenser tip 1 10 nearest to the test article 1 12 and the reference surface 1 13 of the test article 1 12.
- the sensor 1 14 may utilize reflected sound or light, or capacitance, or other magneto- or electro-optical devices to determine this distance.
- the sensor 1 14 may also be utilized to confirm that the test-pathogen mixture has been properly deposited onto the reference surface 1 13. This confirmation may be performed by determining the same distance at the position where the test-pathogen mixture was deposited. If the test-pathogen mixture was properly deposited, then the distance would be less than without the test-pathogen mixture but within a threshold range that is predetermined for an acceptably accurate deposition of the test-pathogen mixture.
- test-pathogen dispenser 106 or the test article 1 12 translate with respect to each other.
- the test article 1 12 may be removably affixed to the base 104, and the gantry 102 and test-pathogen dispenser 106 may move relative to the base 104 and the stationary test article 1 12.
- the test-pathogen dispenser 106 or the gantry 102, or both may be stationary relative to the base 104, and the base 104 may include a mechanism (not illustrated) that moves the test article 1 12 relative to the stationary test-pathogen dispenser 106.
- the system 100 may be structured such that both the test- pathogen dispenser 106 and the test article 1 12 can move relative to one another.
- test-pathogen dispenser 106 may be structured to move in a vertical direction (z-axis) relative to the top surface 105 of the base 104. In this way, the test-pathogen dispenser 106 can move towards and closer to the test article 1 12 to deposit the test-pathogen mixture on the reference surface 1 13 of the test article 1 12, and then move away and further from the test article 1 12 so that the test-pathogen dispenser 106 is
- FIGS. 1A-1 D illustrate the reference surface 1 13 as being substantially planar or flat, embodiments are not so limited. Rather, the reference surface 1 13 may be a convex surface, concave surface, planar surface, otherwise shaped surface, irregular surface, or some combination thereof. With these types of curved, multi-structured, or varying contoured reference surfaces, the system 100 may include one, two, or three additional rotational axes so that the test-pathogen dispenser 106 can be properly oriented and aligned with the test article 1 12 to deposit the test pathogen on the reference surface 1 13 of the test article 1 12. The test article may also be translated, rotated, and otherwise manipulated alone or in concert with movements of the pathogen dispenser 106, to accomplish inoculation. In some embodiments, the reference surface may be substantially devoid of fissures, cracks, and occlusions.
- the reference surface 1 13 of the test article 1 12 may have an area of suitable size to receive an adequate amount of the test-pathogen mixture to test the efficacy of an electromagnetic radiation process that is performed to disinfect or sterilize the test article 1 12.
- the reference area of the reference surface 1 13 may be approximately 10-25 centimeters long and between two (2) and 10 centimeters wide. In other embodiments, the reference area may be between four (4) and 250 square centimeters. In yet other embodiments, the reference area may be between 10 square millimeters and 20 square centimeters.
- other sizes or shapes e.g. , a disc or a square, the surface of a Petri dish, or a compliant material or membrane
- other sizes or shapes e.g. , a disc or a square, the surface of a Petri dish, or a compliant material or membrane
- FIGS. 2A-2B show illustrative examples of two different test-pathogen patterns.
- test pattern 200A includes a plurality of test-pathogen mixture droplets 130 in a uniform grid pattern of rows 131 and columns 132 on the reference surface 1 13 of the test article 1 12.
- the number of droplets 130 in each column 132 is equal to the total number of rows such that each row 131 and each column 132 are at right angles to one another.
- An enlarged portion 133 of FIG. 2A shows one non-limiting embodiment of droplets in a "wet” state and corresponding droplets in a “dry” state.
- the reference surface 1 13 is divided into a grid of equally sized "squares," though any other shape may also be selected, and only four squares are illustrated in the enlarged portion 133 for simplicity.
- each differential element of the entire reference surface 1 13 i.e. , each square
- a droplet of a specified volume e.g. , a volume in the range of 0.01 to 1 .0 ⁇ ).
- Each droplet is formed to contain a population of CFUs of a pathogen or pathogen-mixture, including any other elements such as an interfering substance.
- the liquid (i.e. , "wet") phase in the droplet which in many cases is substantially water, evaporates off, and the resulting approximately circular “dot” (i.e. , "dry") remains.
- the droplet diameter in the "wet" state may be larger than the side length of a target square. Subsequently, as the circular droplet shrinks in size due to
- the pathogen-laced residue gets smaller and is then contained within the boundaries of the differential square element.
- recognition may in some cases lead to a pattern of droplet deposition that is coordinated with a drying rate or time of a given droplet.
- the target range of CFU/dot is between about 1 .0e02 CFU/dot to 100e03 CFU/dot.
- the automated test-pathogen deposition system 100 is arranged to produce droplets in the target range of 5.0 to 20 CFU/dot.
- One approach for example, arranges system 100 to form 7,500 CFU per dot, and to deposit 840 dots across a reference surface of 8 cm 2 .
- the differential square area includes sides of 1.0 mm down to 0.1 mm, or 10-100 per cm, non-interlaced.
- 1 mm square, or 100 x 1 mm 2 landing spots per cm 2 (non-interlaced) would be arranged as 800 squares over an 8 cm 2 area.
- depositing droplets in an interlacing pattern can increase the dot density.
- Other patterns may also be chosen to change dot density in other ways.
- the number of CFU in a given deposited volume can vary.
- system 100 as contemplated herein is flexibly arranged to permit a wide range of local ACD that is reproducible with acceptable accuracy. The flexibility permits any number of test articles to be created for specific testing use cases, such as how sensitive a particular pathogen is to a particular disinfection procedure. Bacteria may be 100 times larger than viruses, but viruses may be more sensitive to a particular disinfection procedure.
- the test pattern 200B in FIG. 2B includes a plurality of test- pathogen mixture droplets 140 that are in an offset, interlaced pattern of rows 141 and columns 142 on the reference surface 1 13 of the test article 1 12.
- each row 141 is offset from its adjacent rows 141 such that the droplets 140 in a given row 141 are not in the same column 142 of the droplets 140 in an adjacent row 141.
- droplets 140 are offset from one another, which can enable the droplets 140 to be closer to one another than in the grid pattern illustrated in FIG. 2A.
- FIGS. 3A-3B show an illustrative example of the sequence 300 of depositing test-pathogen mixture droplets into the test-pathogen pattern.
- the test-pathogen mixture droplets can be deposited onto the reference surface 1 13 of the test article 1 12.
- the sequence 300 starts by depositing test-pathogen mixture droplet 151 onto the reference surface 1 13.
- the sequence 300 then proceeds to deposit test-pathogen mixture droplet 152 adjacent to test- pathogen mixture droplet 151 and then deposit test-pathogen mixture droplet 153 adjacent to test-pathogen mixture droplet 152, and so on.
- a row of discrete sequential droplets is formed on the reference surface 1 13 of the test article 1 12.
- droplets can be continuously deposited onto the reference surface 1 13 at an acceptable rate.
- test-pathogen mixture droplets deposited onto the reference surface 1 13 may be on the order of 0.5 ⁇ or smaller (although other amounts may be utilized).
- the droplets may be a suspension of liquid (e.g., water) and the test-pathogen species itself. Due to their size, droplets may be affected by rapid evaporation of the fluid contained therein. After the fluid evaporates, what remains is a film comprising the payload test pathogen and other non-volatile components of the suspension if any. This "residue" is contained within the region of the reference surface that the droplet was originally in contact with.
- test-pathogen mixture droplet In order to promote a more homogenous distribution of test- pathogen over the entire reference surface, it may be desirable to prevent one test-pathogen mixture droplet from touching and "bleeding into” another adjacent droplet on the reference surface 1 13 (FIG. 2A). In some
- this may be achieved by simply increasing the distance between adjacent droplets as they are deposited.
- an array of spaced-apart droplets may be deposited first, and then after sufficient time has elapsed (e.g., at least 10 milliseconds, at least 100 milliseconds, at least 500 milliseconds), for example to allow drying and therefore shrinkage or some other desirable evolution of the droplet, the test-pathogen dispenser 106 may return and deposit additional droplets interstitially to the initial array, such as further illustrated in FIGS. 4A-4B. In this way, the homogenous distribution of test pathogen may be formed by a plurality of non-touching arrays of test- pathogen mixture droplets.
- FIGS. 4A-4B show another illustrative example of a sequence 400 of depositing test-pathogen mixture droplets into the test-pathogen pattern.
- the sequence 400 starts by depositing test-pathogen mixture droplets 161 and 162 in a row 167 onto the reference surface 1 13 of the test article 1 12.
- the sequence 400 proceeds to deposit additional test- pathogen mixture droplets into row 167 and then into row 168 along the lines of what is described above in conjunction with sequence 300 of FIGS. 3A-3B.
- sequence 400 spaces the test-pathogen mixture droplets (e.g., test-pathogen mixture droplets 161 and 162) and rows (e.g., rows 167 and 168) further apart during a first series of droplet deposits.
- sequence 400 can deposit a second series of test-pathogen mixture droplets in between the previously deposited test-pathogen mixture droplets.
- test- pathogen mixture droplet 163 is deposited between test-pathogen mixture droplets 161 and 162.
- sequence 400 proceeds to deposit the intermediate droplets along the lines of what is described above.
- test-pathogen mixture droplet 164 is in row 169 and offset from test-pathogen mixture droplets 161 and 163 in row 167.
- sequence 400 can skip and not deposit the intermediate test-pathogen mixture droplets during this third series. This is illustrated by there being an absence of a test-pathogen mixture droplet in row 169 between test-pathogen mixture droplets 164 and 165.
- the sequence 400 can then proceed with a fourth series of droplet deposits to deposit the intermediate droplets that were not deposited in the previously deposited third series of droplet deposits.
- test-pathogen mixture droplet 166 is deposited between test-pathogen mixture droplets 164 and 165 in row 169 while being offset between test-pathogen mixture droplets 163 and 162 in row 167, which results in a test-pathogen pattern similar to what is illustrated in FIG. 2B.
- 3A-3B and 4A-4B may increase the local area density of test pathogens while reducing bleed over, as the early droplets will have evaporated away from the boundary area and thus be much less likely to combine with the droplets deposited on subsequent passes. Accordingly, one or multiple passes, along with one or multiple dispenser tips, may be utilized to provide an acceptably dense and consistent test-pathogen deposition without bleed over into neighboring sites and while reducing transit time of the test-pathogen dispenser 106 articulating over the reference surface 1 13 of the test article 1 12.
- differently sized or differently constituted droplets may be deposited.
- discernible space is recognized between individually dispensed droplets.
- Such spacing is non-limiting, and is illustrated to convey certain features of the systems and methods discussed herein.
- additional droplets may be applied to spaces on the reference surface that have not been wetted. These interstitial spaces could be filled with smaller droplets, larger droplets, or the same size droplets to increase packing and overall coverage of the underlying reference surface 1 13.
- the different droplets may also have a different concentration, density, or be different in some other way.
- one droplet may even be permitted that one droplet bleeds over into another adjacent droplet.
- four "corner" droplets are deposited in a particular area and permitted to dry. After the four corner droplets have dried, a fifth droplet, which may be larger, smaller, or the same size, is deposited in the space between the four corner droplets. In some cases, bleed over is reduced if the center droplets are deposited after the corner droplets have dried off.
- the system 100 deposits separate, discrete droplets of the test-pathogen mixture onto the test article 1 12, as described herein.
- the size of any one or more of these droplets may be controllably varied due to a number of different factors.
- one controllable factor may be the distance between the dispenser tip 1 10 of the test-pathogen dispenser 106 and the reference surface 1 13 of the test article 1 12. This gap between the dispenser tip 1 10 and the reference surface 1 13 is accurately established and maintained during the generation of the test- pathogen pattern, increasing assurance that a controlled or otherwise acceptably known volume of the test-pathogen mixture (e.g., the inoculating liquid suspension that includes the test pathogen) is deposited at each droplet location.
- Height sensors and position (e.g., servo) controllers may be used to further enhance gap control, and thus further improve accuracy and precision.
- FIGS. 3A-3B and 4A-4B illustrate two sequences of depositing test-pathogen mixture droplets for a given test-pathogen pattern in accordance with embodiments described herein, other embodiments are not so limited, and other sequences and patterns may be utilized.
- the system may continuously deposit one or more lines of test-pathogen mixture in a snake-like or raster pattern on the reference surface of the test article. Such patterns may be determined to permit the desired amount of drying time to elapse such that a residue forms before the dispenser returns to apply another portion of the liquid inoculating mixture.
- FIGS. 3A-3B and 4A-4B illustrate examples of two sequences that deposit discrete test-pathogen mixture droplets that are independent of one another and not touching or intersecting.
- test-pathogen mixture droplets or lines may be deposited onto the reference surface 1 13 such that the droplets or lines touch, intersect, overlap, or otherwise create one or more layers of test pathogens.
- FIG. 5A illustrates a test-pathogen pattern 500 of droplets or "dots" 170 on a test article 1 12 with distance measurement positions 172 therein.
- the illustrated example includes a plurality of distance measurement positions 172 on the reference surface 1 13 of the test article 1 12.
- a location of each distance measurement position 172 on the reference surface 1 13 is predetermined.
- the distance measurement positions 172 may be equidistant apart from one another or they may be positioned based on other conditions such as changes in the contours of the reference surface 1 13.
- the system 100 may utilize one or a plurality of distance measurement positions 172 across the reference surface 1 13. In other embodiments, more or fewer distance measurement positions 172, or different arrangements of distance measurement positions 172, on the reference surface 1 13, other than what is illustrated in FIG. 5A, may be utilized.
- the distance measurement positions 172 may be vacuum reservoirs, protuberances, or some other structural formation to reduce the likelihood that any test-pathogen mixture or droplet enters the distance measurement positions 172.
- the distance measurement positions 172 may be locations where there is a greater distance between test-pathogen mixture droplets, to reduce the possibility of the adjacent test-pathogen mixture droplets from bleeding into one another.
- the reference surface 1 13 maintains one or more pathogen-free areas that can be used as a benchmark location to determine the distance between the reference surface 1 13 and the dispenser tip 1 10 of the test-article dispenser 106 at that location. By knowing the distance between the reference surface 1 13 and the dispenser tip 1 10, the system 100 can more accurately deposit uniform test-pathogen mixture droplets or lines on the reference surface 1 13.
- the system 100 may include a force- feedback sensor that detects when the dispenser tip of the test-pathogen dispenser 106 or a droplet formed thereon contacts (e.g., touches) the reference surface 1 13. Prior to actually depositing any test-pathogen mixture onto the reference surface, the system 100 may first touch or "palpate" various local points (i.e., distance measurement positions 172) around a target area of the reference surface and create a mathematical model of where the surface is, prior to then depositing test-pathogen mixture droplets in that target area. This allows the system 100 to maintain acceptably close control over the gap between the dispenser tip 1 10 and the reference surface 1 13 in the target area, which permits an accommodation of surfaces that are locally tilted or non- planar(e.g., curved).
- the target area may be the entire reference surface 1 13 or just a portion of the reference surface 1 13 that is less than the entire reference surface 1 13. Accordingly, the system 100 may determine one or more different target areas of the reference surface 1 13 prior to, or during, the deposition of the test-pathogen mixture onto the reference surface 1 13.
- the dispenser tip may be brought into contact with the reference surface during a test-pathogen mixture droplet deposition.
- the force-feedback sensor detects that the dispenser tip or a droplet formed thereon is touching the reference surface 1 13, which may be used to terminate the descent of the test-pathogen dispenser 106.
- the system 100 may then "grow" the test-pathogen mixture droplet on the reference surface 1 13 as the test-pathogen dispenser 106 is withdrawn and the dispenser tip 1 10 pulls away from the reference surface 1 13, which may help to reduce buildup of the test-pathogen mixture on the dispenser tip 1 10.
- non-contact methods of determining the dispenser tip 1 10 height above the reference surface may be employed.
- electromagnetic, acoustic, capacitive, light-based, or other telemetry systems or sensors may be utilized to calculate the distance from the respective sensor to the reference surface 1 13. By predetermining the distance between the sensor and the dispenser tip 1 10, the distance between the dispenser tip 1 10 and the reference surface 1 13 may be determined.
- FIG. 5B illustrates a mounting fixture 500A embodiment arranged to removably receive a plurality of test articles 1 12A-1 12H.
- the holding mechanism 1 15 of the automated test-pathogen deposition system 100 of FIGS. 1 A-1 D is arranged to removably secure the mounting fixture 500A.
- same or different test-pathogen patterns having same or different test-pathogen mixtures may be deposited on the reference surfaces 1 13A-1 13H of any one or more of the plurality of test articles 1 12A-1 12H.
- the mounting fixture 500A has an approximate size of 1 1 cm by 13 cm.
- the mounting fixture 500A may further be mounted on a platen (not shown) of the automated test- pathogen deposition system 100, In some cases, such a platen has an approximate size of 20 cm by 20 cm.
- a platen has an approximate size of 20 cm by 20 cm.
- Other sizes of mounting fixtures and platens are contemplated.
- Other configurations are also configured including, but not limited to, continuously fed belts, horizontally rotating dials, a cylinder along which one or more carriers may be affixed, and other systems that appropriately arrange a test-pathogen dispensing means with one or more test article means.
- test articles 1 12A-1 12H of FIG. 5B are illustrated as all having a same or nearly same size, shape, and orientation for ease in understanding.
- One or more of test articles 1 12A-1 12H in other embodiments may have different sizes, shapes, thicknesses, material compositions, orientations, or other characteristics.
- each test article 1 12A-1 12H is rectangular and sized to approximately two centimeters (2 cm) by four centimeters (4 cm) for an approximate area of eight square centimeters (8 cm 2 ).
- each test article 1 12A-1 12H has a thickness of two millimeters to three millimeters (2-3 mm), and each test article 1 12A-1 12H has a similar "flatness,” which may vary up to about one half millimeter (0.5 mm) across the surface of a respective test article 1 12A-1 12H.
- the variance in flatness between test articles 1 12A-1 12H may be caused by cleaning, sterilization, or other processes, which may cause some amount of distortion or warp.
- each test article 1 12A-1 12H has a respective reference area 1 13A-1 13H that begins at about one millimeter (1 mm) inside each edge of the test article 1 12A-1 12H.
- the deposition target region (i.e. , reference area 1 13A-1 13H) of each test article 1 12A-1 12H has test-pathogen mixture deposited in an area one millimeter (1 mm) inside each edge of the test article 1 12A-1 12H, for an actual treated area of 1 .8 cm x 3.8 cm, which is a total area of about 6.84 cm 2 .
- This arrangement provides a pathogen-free boundary area around the test articles 1 12A-1 12H to allow gripping the respective test article on its sides with a reduced risk of cross contamination.
- test articles 1 12A-1 12H may be formed of porcelain ceramic, silicon rubber, Schott-type laboratory glass, stainless steel (e.g. , grade 304 commonly), acrylonitrile butadiene styrene (ABS), polybutylene terephthalate (PBT), polycarbonate, nylons, other plastics in use in the medical device industry, or some other material or combination of materials.
- ABS acrylonitrile butadiene styrene
- PBT polybutylene terephthalate
- nylons polycarbonate
- other plastics in use in the medical device industry, or some other material or combination of materials.
- top surfaces i.e. , reference areas 1 13A-1 13H
- other surfaces of the test articles 1 12A-1 12H are not treated.
- the reference areas 1 13A-1 13H are air dried, post deposition.
- each test article 1 12A-1 12H may include one or more locating features (not shown). Locating features may include markings or other like indicia, protuberances, holes, or other features arranged to register a particular location.
- a locating feature includes or provides a reference surface such as a tapered "pin" that mates with an angled surface or surfaces.
- cooperating locating features bias together a pair of mating surfaces to establish a well-controlled relative position.
- Other locating features are contemplated.
- the locating features may be arranged on any one or more of the mounting fixture 500A and test articles 1 12A-1 12H.
- a vacuum structure (not shown) is employed to retain and hold one or more of the mounting fixture 500A and test articles 1 12A- 1 12H.
- the vacuum structure may include a HEPA filter.
- a different type of structure is arranged to removably affix the one or more of the mounting fixture 500A and test articles 1 12A-1 12H to the automated test- pathogen deposition system 100.
- the mounting fixture 500A is arranged for easy and quick connection and disconnection of a mounting fixture 500A from the automated test-pathogen deposition system 100. Such connection or disconnection may be performed by one person or automatically. In some cases, two or more mounting fixtures 500A may be connected or disconnected in just a few seconds or even less.
- the mounting fixture 500A, a platen, or one or more other structures are arranged for covering by a laminar flow hood, another open or closed containment system, or a disposable or sterilizable shroud (not shown).
- a shroud may be formed of TYVEK, polyethylene sheet, or some other suitable shroud material.
- the shroud may be used in pathogen-mixture deposition procedures to reduce the likelihood of undesirable contamination of particular areas and structures while also permitting concurrent inoculation of one or more test articles 1 12A-1 12H.
- hood, shroud, or other containment system operates to reduce or prevent contamination of test articles, once inoculated, by externally originating pathogens.
- FIG. 6 is a system diagram of a computing system 600 that controls the system 100 to deposit test-pathogen mixture onto a reference surface 1 13 of a test article 1 12.
- the system 600 which may be a part of the test-pathogen deposition system 100, includes a test-pathogen computing system 602, a plurality of controllers 610-615, and one or more optional distance sensors 616.
- the test-pathogen computing system 602 includes a processor 604, a memory 606, and an input/output interface 608.
- the processor 604 includes one or more processing units (e.g. , central processing units) that execute instructions to perform actions, including actions to perform
- test pathogens onto a test article 1 12.
- the system 602 is arranged to generate and distribute one or more control signals that move one or more portions of the test-pathogen dispenser 106, the test article 1 12, or some combination thereof.
- one or more control signals may also be generated to form, release (e.g., spray, deposit, or the like), or form and release a substantially accurate volume (e.g., quantity, mass, or the like) of the test-pathogen mixture.
- the control signals may be generated and applied based on mechanical input, electronic input, one or more computer programs, or a combination thereof.
- the memory 606 includes one or more types of non-volatile and/or volatile storage technologies. Examples of memory 606 include, but are not limited to, flash memory, hard disk drives, optical drives, solid-state drives, various types of random access memory (RAM), various types of read-only memory (ROM), other transitory and/or non-transitory computer-readable storage media, which may also be referred to as processor-readable storage media, or other memory technologies, or any combination thereof.
- the memory 606 may be utilized to store information, such as the computer- readable instructions that are executed by the processor 604 and other information, such as, for example, test-pathogen patterns, reference surface contours or one or more data structures to store such information, or other information that is utilized to deposit test pathogens onto a test article 1 12.
- At least one sensor e.g., a force- feedback sensor
- the test- pathogen computing system 602 can generate at least one data structure representing a location of the reference area of the exposed test article 1 12, at least one data structure representing a shape of the reference area of the exposed test article 1 12, at least one data structure representing a model of the reference area of the exposed test article 1 12, or some other representation of the reference area of interest.
- the test-pathogen computing system 602 can be operated as a learning mechanism that travels about the reference area, interrogates the reference area, and records data points, which become points of the model.
- test-pathogen computing system 602 uses data of the model to generate at least one data structure representing a dispensation pattern for the test pathogen based on the recorded data points associated with the reference area, and repeatably position at least one orifice of the test-pathogen dispenser 106.
- the input/output interface 608 provides a communication interface between the test-pathogen computing system 602 and a plurality of other components.
- the test-pathogen computing system 602 provides information to the controllers 610-615 via the input/output interface 608 and receives information from the optional distance sensor(s) 616.
- the test-pathogen dispenser controller 610 is utilized to control the formation or release of test-pathogen mixture droplets or lines onto the reference surface 1 13 of the test article 1 12.
- the x-axis controller 61 1 controls one or more motors, actuators, or other mechanical devices that move the test- pathogen dispenser 106 in an x-axis direction (FIGS. 1A, 1 B, 1 C) relative to the test article 1 12.
- the y-axis controller 612 controls one or more motors, actuators, or other mechanical devices that move the test-pathogen dispenser 106 in a y-axis direction (FIGS. 1A, 1 B, 1 D) relative to the test article 1 12.
- the z-axis controller 613 controls one or more motors, actuators, or other mechanical devices that move the test-pathogen dispenser 106 in a z-axis direction (FIGS. 1A, 1 C, 1 D) relative to the test article 1 12.
- the optional other-axis controller(s) 614 control one or more motors, actuators, or other mechanical devices that move the test-pathogen dispenser 106 in additional axes relative to the test article 1 12 to add additional degrees-of-freedom to the rotation and positioning of the test-pathogen dispenser 106.
- these other-axis controller(s) 614 may be optional and may not be utilized.
- one or more of the x-axis, y-axis, z-axis controllers, and optional other-axis controllers 61 1 -614 may be combined in a single controller architecture.
- test-pathogen dispenser 106 or the test article 1 12, or a combination thereof may be moved relative to one another. Accordingly, the controllers 61 1 -614 may control movement of the test- pathogen dispenser 106, movement of the test article 1 12, or a combination thereof.
- An optional vibration controller 615 controls one or more motors, actuators, or other mechanical or acoustic devices that force or induce the dispenser tip 1 10 of the test-pathogen dispenser 106 to vibrate or otherwise perturbate.
- the vibration or perturbation is arranged to facilitate detachment of a test-pathogen mixture droplet from the dispenser tip 1 10.
- the vibration controller 615 may be optional and may not be utilized.
- Other types of systems may also be utilized to help detach the test- pathogen mixture droplet from the dispenser tip 1 10, such as, for example, an electrostatic charge generation device (e.g., to induce an electrostatic charge on the droplet at the opening of the dispenser tip 1 10), a pump, a heater, an aerator, or some other device.
- One or more optional distance sensors 616 may be arranged to detect a distance between the dispenser tip 1 10 and the reference surface 1 13 of the test article 1 12.
- these sensors may be non- contact sensors, such as light- or sound-based telemetry sensors and systems.
- the sensors may be based on LIDAR, RADAR, electric or magnetic fields, sensing capacitance, inductance, or some other sensors
- Light-based sensors may include at least one light-emitting source (e.g., a light emitting diode (LED) or a laser emitting visible or non-visible electromagnetic (EM) radiation, etc.) and at least one photo detector to detect reflected light from the light-emitting source.
- Sound-based or acoustic-based sensors may include at least one audio source and at least one audio detector. In other embodiments, these sensors may include one or more touch-sensitive or force-feedback sensors that react to compression forces when the dispenser tip 1 10 contacts the reference surface 1 13.
- the test-pathogen computing system 602 utilizes the measurements from the optional distance sensor(s) 616 to determine the distance between the dispenser tip 1 10 and the reference surface 1 13, which is then utilized to adjust the deposition of the test-pathogen mixture onto the reference surface 1 13 via the test-pathogen dispenser controller 610 or to adjust the position of the test-pathogen dispenser 106 via one or more of the axis controllers 61 1 -614.
- the distance sensor(s) 616 may also be utilized to determine a size, shape, contours, or three-dimensional (3-D) model of an area the reference surface 1 13 of the test article 1 12 in which the test-pathogen mixture is to be deposited.
- the sensors may be utilized as a learning mechanism to traverse the reference area and record data points that become points of the model.
- at least one force-feedback sensor is arranged to provide data points associated with a 3-D location of a contacted point of the reference area. These data points can then be used or otherwise applied by the test-pathogen computing system 602 to repeatedly position the dispenser tip 1 10 of the test-pathogen dispenser 106, as described herein.
- process 700 described in conjunction with FIG. 7 may be implemented by or executed on one or more computing devices, such as test-pathogen computing system 602.
- FIG. 7 is a logical flow diagram generally showing one embodiment of a process 700 for depositing test pathogens onto a test article
- Process 700 begins after a start block.
- a test-pathogen pattern is determined.
- a user inputs the desired test-pathogen pattern.
- a test- pathogen pattern may be determined or otherwise selected, such as a previously used test-pathogen pattern.
- the test- pathogen pattern may differ, and thus be determined, based on the type of test article 1 12, the contours of the reference surface 1 13 of the test article 1 12, the material of the reference surface 1 13, the type test pathogen being utilized, or other testing parameters.
- Process 700 proceeds to block 704, where the test-pathogen dispenser 106 is positioned in accordance with the test-pathogen pattern. As described herein, the test-pathogen dispenser 106 may systematically deposit one or more test-pathogen lines or droplets at a time in the test-pathogen pattern. Initially, the test-pathogen dispenser 106 is positioned at a first location of the test-pathogen pattern in which to deposit the test-pathogen mixture onto the reference surface 1 13 of the test article 1 12.
- Process 700 continues at block 706, where a distance from the dispenser tip 1 10 of the test-pathogen dispenser 106 to the reference surface
- the contours or a three-dimensional (3-D) model of the reference surface 1 13, or a test area of the reference surface 1 13, may be initially determined prior to the positioning of the test-pathogen dispenser 106 at block 704.
- the distance from the dispenser tip 1 10 to the reference surface may be determined at the current position of the test-pathogen dispenser 106 based on the predetermined contours of the reference surface 1 13.
- the use of a vertical z-axis may be employed.
- the distance between the dispenser tip 1 10 and the reference surface 1 13 may be determined for each location or for a plurality of locations where the test-pathogen mixture is deposited onto the reference surface 1 13.
- Process 700 proceeds to block 708, where the test-pathogen mixture is deposited onto the reference surface 1 13 of the test article 1 12.
- the test-pathogen mixture may be applied to the reference surface 1 13 as one or more lines or one or more droplets.
- one or more test-pathogen lines or droplets may be deposited simultaneously before depositing another set of test-pathogen lines or droplets.
- a first local region of the test article 1 12 may be treated, and then a second local region may be treated after the dispenser tip 1 10 transits to the second local region.
- application of the test-pathogen mixture may include many cycles of partial treatment of a plurality of sub-regions, and these multiple cycles may include repeated returns for second, third, and more "coats" (i.e. , applications of test-pathogen mixture) to a same region.
- test-pathogen mixture droplets are deposited onto the reference surface 1 13
- a fixed, substantially accurate volume of the test-pathogen mixture is issued from and "grown" on the tip of the dispenser tip 1 10 (e.g. , where the dispenser tip 1 10 is a cannula or needle).
- this process of growing the test-pathogen mixture droplet is performed when the test-pathogen dispenser 106 is stationary at the just- deposited site, at the position of the to-be-deposited test-pathogen mixture droplet site, or at some other location. In other embodiments, this process of growing the test-pathogen mixture droplet may begin before or while the test- pathogen dispenser 106 is in motion from its initial position or from the position of one droplet to the next.
- droplet formation may start while the dispenser tip 1 10 is still laterally stationary in a prior spot but while the apparatus is retracting along one or more of its axes. Then, the droplet may keep growing as the dispenser tip 1 10 transits to new location. Droplet formation may finish before the dispenser tip 1 10 is lowered to touch the reference surface 1 13. Alternatively, droplet formation may complete its growth while the dispenser tip 1 10 is in its desired z-axis position such that the droplet is "grown" into the reference surface 1 13.
- a device may be utilized to supply positive pressure to grow and form a test-pathogen mixture droplet at an orifice of the dispenser tip 1 10 and to supply negative pressure to hold the test- pathogen mixture droplet at the orifice of the dispenser tip 1 10.
- test-pathogen mixture droplet may remain in contact with (or "hang from") the tip/orifice of the dispenser tip 1 10 where it was generated.
- the test-pathogen dispenser 106 or the dispenser tip 1 10 may move so that test-pathogen mixture droplet is brought into contact with the reference surface 1 13. This contact initiates "wetting" forces to act and pull on the droplet, which results in the test-pathogen mixture droplet being separated or otherwise disconnected from the dispenser tip 1 10 and "touched-off" onto the reference surface 1 13.
- the test-pathogen dispenser 106 or the dispenser tip 1 10 may be moved away from the reference surface 1 13 to quickly stretch and "snap-off" the test-pathogen mixture droplet so the droplet becomes free of the dispenser tip 1 10.
- test-pathogen mixture droplet may be employed to induce the test-pathogen mixture droplet to detach from the dispenser tip 1 10 and to attach to the reference surface 1 13.
- Such techniques may also be configured or otherwise selected to reduce the amount of pathogen-mixture residue that remains on the dispenser tip 1 10.
- mechanical vibrational energy may be applied to the dispenser tip 1 10.
- the dispenser tip 1 10 may be treated with polymers or other chemicals having low surface energy with respect to the inoculating fluid of the test-pathogen mixture droplet.
- the dispenser tip 1 10 may be designed to reduce its surface area contact with the suspended test-pathogen mixture droplet.
- a companion device may be arranged proximate to the dispenser tip 1 10 and configured to treat certain target locations in advance of depositing the test-pathogen mixture droplet.
- the companion device may apply a corona discharge or liquid wetting agent, for example, to a particular target surface to temporarily increase hydrophilicity.
- a corona discharge or liquid wetting agent for example, to a particular target surface to temporarily increase hydrophilicity.
- the reference surface 1 13 may be treated with a chemical (e.g. , a surfactant, a detergent, or the like) to increase its wetting or adhesion properties and to increase the tension forces between the test-pathogen mixture droplet and the reference surface 1 13, which also can increase the ability of the test-pathogen mixture droplet to attach to the reference surface 1 13.
- a chemical e.g. , a surfactant, a detergent, or the like
- non-chemical wetting agents e.g., corona discharge
- At least one drying structure is integrated with or otherwise associated with the automated test-pathogen deposition system 100.
- the drying structure may be integrated with the base 104 of the system 100, the gantry 102, or some other portion.
- the drying structure may be used to accelerate evaporation of droplets, and thereby increase throughput or achieve other desirable results.
- the drying structure may include heated or un-heated air that is directed onto, over, past, or in other proximity to the reference surface 1 13.
- the drying structure may use ambient, filtered air, or another drying gas.
- the drying gas may contain another substance, such as a percentage of water, a dissolved vapor of an organic solvent (e.g., ethanol, acetone), or another substance that acts as a drying agent.
- the air that passes the reference surface 1 13 may be dehumidified.
- the drying structure may provide heat to a reference surface 1 13 from below, from above, from any side, or some combination thereof.
- the heat may be transferred to the reference surface 1 13 by conduction, convection, or another method.
- the heat source may be of any desirable technology (e.g., resistive, infrared, and the like).
- the heat source may direct or otherwise focus heat toward one or more specific regions of the reference surface 1 13 and not toward other areas. It has been recognized that long wavelength electromagnetic radiation may not be effective to sterilize certain pathogens.
- the drying source includes one or more temperature sensors and control logic to avoid
- a dispenser tip 1 10 may be a dispensing cannula or needle.
- the needle may be translated vertically downward to the reference surface 1 13 (i.e. , the dispenser tip 1 10 may be reciprocating) to deposit each test-pathogen mixture droplet.
- the dispenser tip 1 10 may be configured along its z-axis to arrange a desired gap between the dispenser tip 1 10 and the reference surface 1 13 such that a droplet may be touched off on the reference surface 1 13, but also such that the dispenser tip 1 10 does not physically contact the reference surface 1 13.
- multiple dispenser tips may be structured radially about a central axis similar to spokes on a bicycle wheel, which can rotate about the central axis.
- each dispenser tip 1 10 may not perform any reciprocation motion, which can offer improvements in speed or cycle time.
- a plurality of dispenser tips may be formed in a line, an array, or some other cluster.
- test-pathogen dispenser 106 or the test article 1 12, or both may be moved relative to one another. Accordingly, in some other embodiments, the test article 1 12 may be moved so that the reference surface 1 13 of the test article 1 12 is brought toward a fixed
- Process 700 continues at decision block 710, where a determination is made whether the test-pathogen pattern is complete. In some embodiments, this determination is based on whether the test-pathogen mixture has been deposited onto the reference surface at each location identified by the test-pathogen pattern. If the test-pathogen pattern is not complete, then process 700 returns to block 704 to adjust the position of the test-pathogen dispenser to deposit the test-pathogen mixture at another location in the test- pathogen pattern; otherwise, process 700 ends.
- test articles described in the present disclosure may be formed of selected materials and having selected dimensions. In some cases, however, the test articles may also include particular medical devices such as vaginal and rectal ultrasound probes, endo-tracheal probes, and other endocavitary (i.e., internal-cavity) ultrasound probes of similar size and construction. These devices may have uniform or non-uniform shapes, dimensions, materials of construction, and other characteristics.
- the test- pathogen mixtures described herein may be deposited as "dots,” rolled or brushed on as a "sheet,” applied with a print pad, or applied in other ways.
- the automated test-pathogen deposition system 100 may be arranged to dispense a continuous line or a line of droplets that follow a line pattern while the probe is rotating.
- the test article probe or other device will have a rotation that is synchronized with the speed of the test-pathogen dispenser 106.
- test articles described herein may have at least one dimension that is 20 to 30 cm long or longer. In these cases, some portion of the test article may extend out from the automated test-pathogen deposition system 100.
- a mounting fixture 500A (FIG. 5B) or a platen (not shown) may also be arranged to move in one, two, or three orthogonal directions.
- the test articles described herein may have at least one dimension that is even longer than 30 cm.
- the test article may be first formed as an extended length or roll to which test pathogen is applied in a continuous process. Subsequently, a later process may singulate (e.g., cut, pinch, tear) or otherwise adapt the first formed test article into a plurality of final test articles.
- a vaginal endocavitary probe is on the order of two to four centimeters (2-4 cm) across a given diameter, along the length of the probe. In at least some cases, these probes do not have a sufficiently large "flat" spot on which to deposit the test-pathogen mixture. Nevertheless, the probe may still be suitably inoculated using the automated test-pathogen deposition system 100 via the test-pathogen dispenser 106 that is controllably moved in three dimensions.
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- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Clinical Laboratory Science (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
Claims
Priority Applications (7)
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JP2020524708A JP2020532317A (en) | 2017-07-21 | 2017-07-21 | Bioassay carrier and its preparation |
AU2017424318A AU2017424318B2 (en) | 2017-07-21 | 2017-07-21 | Bioassay carrier and preparation thereof |
CN201780095079.2A CN111107885A (en) | 2017-07-21 | 2017-07-21 | Biological detection carrier and preparation thereof |
CA3070341A CA3070341A1 (en) | 2017-07-21 | 2017-07-21 | Bioassay carrier and preparation thereof |
PCT/US2017/043264 WO2019017964A1 (en) | 2017-07-21 | 2017-07-21 | Bioassay carrier and preparation thereof |
EP17745956.7A EP3655047A1 (en) | 2017-07-21 | 2017-07-21 | Bioassay carrier and preparation thereof |
US16/631,704 US11679384B2 (en) | 2017-07-21 | 2017-07-21 | Bioassay carrier and preparation thereof |
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EP (1) | EP3655047A1 (en) |
JP (1) | JP2020532317A (en) |
CN (1) | CN111107885A (en) |
AU (1) | AU2017424318B2 (en) |
CA (1) | CA3070341A1 (en) |
WO (1) | WO2019017964A1 (en) |
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CN110586220A (en) * | 2019-10-16 | 2019-12-20 | 陕西优博特生物科技有限公司 | Liquid feeding and sample feeding device for micro-fluidic chip |
EP4184176A1 (en) | 2021-11-17 | 2023-05-24 | Roche Diagnostics GmbH | Method for detection of a bottom of at least one well |
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WO2018235383A1 (en) * | 2017-06-21 | 2018-12-27 | ソニー株式会社 | Sample liquid-feeding device, flow cytometer, and sample liquid-feeding method |
CN112430528B (en) * | 2020-11-24 | 2022-05-20 | 华中科技大学 | High flux microorganism inoculation device based on spraying is supplementary |
US20220326264A1 (en) * | 2021-04-07 | 2022-10-13 | Carterra, Inc. | Interstitial printing of microarrays for biomolecular interaction analysis |
WO2024151834A1 (en) * | 2023-01-11 | 2024-07-18 | Carterra, Inc. | Microfluidic flow cell arrays |
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2017
- 2017-07-21 CA CA3070341A patent/CA3070341A1/en active Pending
- 2017-07-21 EP EP17745956.7A patent/EP3655047A1/en active Pending
- 2017-07-21 JP JP2020524708A patent/JP2020532317A/en active Pending
- 2017-07-21 WO PCT/US2017/043264 patent/WO2019017964A1/en unknown
- 2017-07-21 AU AU2017424318A patent/AU2017424318B2/en active Active
- 2017-07-21 CN CN201780095079.2A patent/CN111107885A/en active Pending
- 2017-07-21 US US16/631,704 patent/US11679384B2/en active Active
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WO1995035505A1 (en) * | 1994-06-17 | 1995-12-28 | The Board Of Trustees Of The Leland Stanford Junior University | Method and apparatus for fabricating microarrays of biological samples |
US5743960A (en) * | 1996-07-26 | 1998-04-28 | Bio-Dot, Inc. | Precision metered solenoid valve dispenser |
US20040237822A1 (en) * | 2003-05-30 | 2004-12-02 | Clemson University | Ink-jet printing of viable cells |
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CN110586220A (en) * | 2019-10-16 | 2019-12-20 | 陕西优博特生物科技有限公司 | Liquid feeding and sample feeding device for micro-fluidic chip |
EP4184176A1 (en) | 2021-11-17 | 2023-05-24 | Roche Diagnostics GmbH | Method for detection of a bottom of at least one well |
Also Published As
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JP2020532317A (en) | 2020-11-12 |
AU2017424318B2 (en) | 2023-06-08 |
CN111107885A (en) | 2020-05-05 |
EP3655047A1 (en) | 2020-05-27 |
US20200164358A1 (en) | 2020-05-28 |
CA3070341A1 (en) | 2019-01-24 |
AU2017424318A1 (en) | 2020-02-13 |
US11679384B2 (en) | 2023-06-20 |
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