INSTRUMENT FOR ANALYZING BIOLOGICAL SAMPLES AND REAGENTS

专利摘要:
The present invention relates to an instrument for processing a biological sample that includes a chassis. a tape path is connected to the chassis along which a tape with a dimple matrix can be automatically advanced through the instrument, a dispensing assembly to dispense the biological sample, and a reagent in the strip dimple matrix to form a mixture of reagent and biological sample, a sealing assembly to seal the mixture of reagent and biological sample to the strip, and an amplification and detection assembly to detect a signal from the mixture of reagent and biological sample in the matrix of concavities in the strip.
公开号:BR112017001873B1
申请号:R112017001873-0
申请日:2015-07-28
公开日:2021-06-22
发明作者:Darren Lynn Cook；Eric Guy Johnson；Nathan Luther Westad；Andrew Richard Haug；James Henry Konynenbelt；Grant Edward Maasjo；Jared Whittier Patterson；Brent Conrad Urke；Ryan John Zitzmann；Chad Steven Smith
申请人:Douglas Scientific, LLC；
IPC主号:

专利说明:

BACKGROUND
[0001] The present invention relates to an instrument to analyze biological samples, and a particular, to a multifunctional instrument that has the ability to dispense, amplify and analyze biological samples.
[0002] A biological sample and reagent mixture can be subjected to amplification and analysis to detect the presence of an analyte in the mixture. Historically, biological sample and reagent mixtures have been amplified for research applications, which include DNA sequencing, genetic mapping and DNA cloning, among others. Amplification and analysis of biological sample and reagent mix is becoming increasingly popular and innovative uses are constantly being unveiled, which include medical applications, infectious disease applications and forensic applications. With the increasing popularity of amplification and analysis of biological sample and reagent mixing comes a need for more advanced equipment.
[0003] Equipment that is currently available to prepare, amplify and analyze a biological sample and reagent mixture includes laboratory equipment, handheld devices and laboratory devices on a chip. Handheld devices and laboratory devices on a chip are not capable of testing a large number of biological sample and reagent mixtures at the same time, making them unsuitable for many applications. To amplify and analyze large numbers of biological sample and reagent mixtures, laboratory equipment needs to be used. Laboratory equipment typically involves many separate pieces of equipment, where each piece of equipment is used for a different purpose. For example, a first piece of equipment can be used to prepare the biological sample and reagent mixture, a second piece of equipment can be used to amplify the biological sample and reagent mixture, and a third piece of equipment can be used to analyze the biological sample and reagent mixture. The different pieces of equipment take up a lot of space in laboratories and it can be costly to purchase all the necessary equipment to prepare, amplify and analyze the biological sample and reagent mix. Additionally, the amount of biological sample and the amount of reagent required to analyze the biological sample and reagent mixture using existing laboratory equipment can be costly due to the cost of purchasing the biological sample and reagent. SUMMARY
[0004] An instrument for processing a biological sample includes a chassis. Connected to the chassis is a strip path along which an array of wells can be automatically advanced through the instrument, a dispensing assembly to dispense the biological sample, and a reagent in the strip well array to form a biological sample and mixture of reagent, a sealing assembly to seal the biological sample and reagent mixture on the strip, and an amplification and detection assembly to detect a signal from the biological sample and reagent mixture in the array of wells on the strip.
[0005] An instrument for amplifying and analyzing a biological sample and a reagent includes a path extending through the device to advance a strip containing a plurality of wells through the instrument. Positioned along the path and downstream of an entrance to the path is a dispensing and sealing station with a dispensing assembly positioned adjacent to the dispensing and sealing station to dispense a biological sample and a reagent into the plurality of wells in the tape to form a biological sample and reagent mixture, and a sealing tape assembly positioned adjacent to the dispensing and sealing station to seal the biological sample and reagent mixture in the plurality of wells in the tape. Positioned along the path and downstream of the dispensing and sealing station is a holding station with a thermal unit positioned below the holding station to heat or cool the biological sample and reagent mixture in the plurality of wells on the strip. Positioned along the path and downstream of the holding station is an amplification and detection station with a thermal unit to amplify the biological sample and reagent mixture, and a detection unit to detect a signal from the biological sample and the mixture of reagent.
[0006] An instrument for amplifying and detecting a biological sample includes a plate rack that is capable of holding one or more plates; a plate stacker for lifting a plate from the plate shelf; a plate shuttle with a platform on which the plate stacker can place the plate from the plate shelf, where the plate shuttle can position the platform for vacuuming or dispensing; a plate holder on which a plate can be placed; a dispensing assembly with a first plurality of tips and a second plurality of tips, wherein the dispensing assembly can dispense a biological sample and a reagent into the plurality of wells over the tape to form a biological sample and a reagent mixture; a path extending through the instrument along which the tape is advanced through the instrument; a tape sealant that seals the plurality of wells in the tape; a thermal unit that heats the biological sample and reagent mixture in the plurality of wells on the tape; a heated pressure chamber that pressurizes an area over the tape; and a detection device that detects a signal from the biological sample and the reagent mixture in the plurality of wells in the strip.
[0007] An instrument for processing a biological sample includes a strip with a plurality of wells, wherein the strip has a first array of wells and a second array of wells offset from and intertwined with the first array of wells. The instrument also includes a tape path that extends through the instrument along which the tape with the plurality of wells can be automatically advanced. The instrument further includes a dispensing assembly for dispensing the biological sample and a reagent in the plurality of wells on the strip, wherein the dispensing assembly can dispense the biological sample or reagent in the first array of wells and reposition to dispense the biological sample or the reagent in the second array of wells.
[0008] A method of analyzing a biological sample and reagent mixture in an instrument includes automatically advancing a strip with an array of wells to a first position over a strip path in the instrument with the use of a strip feed and a taper mechanism. drive positioned along the tape path; automatically advance the tape to a second position on the tape path in the instrument using the drive mechanism positioned along the tape path; dispensing a biological sample into the array of wells on the tape with a dispensing assembly when the tape is positioned in the second position of the tape path; dispensing a reagent into the array of wells on the strip with the dispensing assembly when the strip is positioned in the second position of the strip path, where a biological sample and a mixture of reagent are formed; sealing a seal over the array of wells in the tape with a tape sealant when the tape is positioned in the second position; automatically advance the tape to a third position on the tape path in the instrument using the drive mechanism positioned along the tape path; automatically advance a tape to a fourth position on the tape path in the instrument using the drive mechanism positioned along the tape path; amplifying the biological sample and reagent mix in the fourth position of the tape path; and detecting a signal from the biological sample and the reagent mixture using a camera positioned above the fourth position of the tape path.
[0009] A tape path assembly for an instrument to process a biological sample includes a tape path having a front end, a rear end, a first position downstream of the front end, a second position downstream of the first position, a third position downstream of the second position, and a fourth position between the third position and the rear end. The tape path assembly also includes a tape feed attached to the front end that automatically advances a tape with a well array to the first position of the tape path, and a drive mechanism that advances the tape along the tape path. .
[0010] An instrument for processing a biological sample includes a tape path along which the tape with the well array can be automatically advanced through the instrument; a dispensing system for dispensing the biological sample and a reagent into the array of strip wells to form a biological sample and a reagent mixture; a sealing system to seal the biological sample and reagent mixture to the tape; and an amplification and detection system for detecting a signal from the biological sample in the array of wells on the tape, wherein the amplification and detection system includes a thermal unit positioned over the tape path that is capable of controlling the temperature of the biological sample and reagent mixture in the strip well array.
[0011] An apparatus for heating a plurality of tape wells includes a first layer with cavities capable of receiving tape wells, a second layer affixed to a bottom side of the first layer, and a heat pump positioned at a bottom side of the second layer, where the heat pump is positioned so that heat can be exchanged between the heat pump and a biological sample and reagent mixture in the wells on the tape through the second layer and the first layer .
[0012] An apparatus includes a strip with an array of wells, a thermal unit positioned below the strip with an array of wells, and a chamber positioned on top of the strip with an array of wells. The chamber includes a housing and a glass cover plate, wherein the housing and glass cover plate form an enclosed space above the array of tape wells.
[0013] An instrument for processing a biological sample includes a tape path along which a tape with an array of wells can be automatically advanced through the instrument. The instrument additionally includes a plate stacker with an arm that can rotate around and move vertically about a geometric z axis. The arm is configured to select a plate from a plate shelf and place the plate onto a plate shuttle. The instrument additionally includes a dispensing system for dispensing the biological sample and a reagent into the strip well array to form a biological sample and a reagent mixture, a sealing system to seal the biological sample and the reagent mixture on the strip, and an amplification and detection system for detecting a signal from the biological sample and reagent mixture in the array of wells on the strip.
[0014] A plate stacker assembly includes a plate shelf that includes a plurality of nests affixed to a frame, each of the plurality of nests having a plurality of corner supports that are capable of supporting a plate. The plate stacker assembly also includes a plate shuttle that includes a nest affixed to a support structure, the nest having a plurality of corner supports that are capable of supporting a plate. The plate stacker assembly further includes a spatula that is capable of selecting a plate from one of the plurality of nests on the plate stacker and placing it over the nest on the plate shuttle, wherein the spatula has a support member that it is capable of supporting a plate and notches are in each corner of the support member that correspond to the location of the corner supports over the nests on the plate stacker and plate shuttle.
[0015] A method for moving a board on an instrument includes selecting a board from a nesting of a board shelf using a spatula affixed to an arm of a board stacker; rotating the plate stacker arm around a geometric axis z; moving the plate stacker arm in a vertical direction along the z axis; and place the plate over a nesting of a plate shuttle.
[0016] A tape seal assembly includes a spool retainer for retaining a sealing mat, a peel plate located downstream of the spool retainer, and a support penetration mechanism downstream of the peel plate to advance the mat sealing through the take-off plate. The tape seal assembly also includes an applicator positioned above the peel plate to peel a seal from a seal mat support and apply the seal to a surface.
[0017] A dispensing assembly includes a mooring easel with an x axis track and a y axis track. The jib track y-axis track is configured to move along the jib track x-axis track. The dispensing assembly additionally includes a dispensing head affixed to a bollard y axis track below the bollard y axis track. The dispensing head includes a contact dispensing unit and a non-contact dispensing unit with a jet tip for dispensing a liquid. The dispensing assembly further includes a dispensing box affixed to a bollard y axis track on top of the bollard y axis track. The dispensing box includes a pressure reservoir. A tube connects the non-contact dispensing unit jet tip to the pressure reservoir in the dispensing box. The contact dispensing unit is affixed to a y axis track of the lashing stand with a first and z axis track, and the non-contact dispensing unit is affixed to the contact dispensing unit with a second axis track geometric z.
[0018] A method of operating a dispensing assembly includes moving a dispensing head along an x axis track and a y axis track of a mooring stand in a first suction position, aspirating a first liquid with a pipette tip of a dispensing head contact dispensing unit, moving the dispensing head along the x-axis track and the y-axis track of the bollard in a second suction position, aspirating a second liquid with a jet tip of a non-contact dispensing unit of the dispensing head, move the dispensing head along the x-axis track and the y-axis track y-axis in a first dispensing position, dispense the first liquid in a concavity of a tape with an array of wells with the pipette tip of the contact dispensing unit, move the dispensing head along the x-axis and y-axis track of the tie bar in a second dispensing position, and dispensing the second liquid into a tape concavity with an array of wells with the jet tip of the non-contact dispensing unit. The dispensing head contact dispensing unit extends and retracts along a first z-axis track connected to a y-axis track of the lashing stand, and the dispensing head non-contact dispensing unit extends and retracts along a second axis z track connected to the contact dispensing unit. BRIEF DESCRIPTION OF THE GENERAL INSTRUMENT DRAWINGS
[0019] Figure 1A is an isometric view of a cart-top instrument for amplifying and analyzing a biological sample and a reagent mixture.
[0020] Figure 1B is a side view of the instrument seen in Figure 1A.
[0021] Figure 1C is a top plan view of the instrument seen in Figure 1A.
[0022] Figure 1D is an exploded view of the instrument seen in Figure 1A.
[0023] Figure 1E is a front isometric view of a tape path assembly that runs through the instrument seen in Figure 1A.
[0024] Figure 1F is a rear perspective view of the tape path assembly as seen in Figure 1E.
[0025] Figure 2A is an isometric view of the instrument.
[0026] Figures 2B to 2D are perspective views of the instrument. Figures 2E through 2F are rear perspective views of the tape path assembly that runs through the instrument.
[0027] Figure 3A is a top plan view of a thermal management system in the instrument.
[0028] Figure 3B is a perspective view of the thermal management system seen in Figure 3A.
[0029] Figure 3C is a schematic view of the thermal management system seen in Figures 3A and 3B.
[0030] Figure 4A is a top plan view of a tape with a plurality of wells.
[0031] Figure 4B is a schematic view of the tape seen in Figure 4A with a first plurality of wells and a second plurality of wells. ASSEMBLY OF PLATE FORKLIFT
[0032] Figure 5A is an isometric view of a plate stacker assembly on the instrument.
[0033] Figure 5B is a cut-away top view of the plate stacker assembly on the instrument.
[0034] Figure 5C is an isometric view of the plate stacker assembly. Figure 6A is an isometric view of a plate shelf.
[0035] Figure 6B is a top plan view of a nesting plate shelf.
[0036] Figure 7A is a perspective view of a plate stacker.
[0037] Figure 7B is a perspective view of a portion of the plate stacker and a portion of the plate shelf.
[0038]7C is an isometric view of a portion of the plate stacker seen in Figure 7A.
[0039] Figure 8A is an isometric view of a plate shuttle.
[0040] Figure 8B is an isometric view of a plate shuttle on the instrument.
[0041] Figure 9A is an isometric view of the plate shelf and plate stacker when a spatula is in an initial position.
[0042] Figure 9B is an isometric view of the plate shelf and plate stacker when the spatula has been removed from the home position.
[0043] Figure 9C is an isometric view of the plate shelf and plate stacker when the spatula is positioned to select a plate.
[0044] Figure 9D is a perspective view of the plate stacker and plate shuttle when the spatula was placed on the plate in a plate shuttle nest. SUPPORT PLATE ASSEMBLY
[0045] Figure 10 is an isometric view of a support plate assembly on the instrument.
[0046] Figure 11A is a partially transparent isometric view of a support plate station of the support plate assembly.
[0047] Figures 11B to 11D are perspective views of the support plate station seen in Figure 11A. Figures 12A and 12B are partially transparent perspective views of the support plate station.
[0048] Figure 13 is a partially transparent perspective view from below of the support plate station.
[0049] Figure 14 is a bottom view of the support plate station.
[0050] Figure 15 is a partially transparent side view of the support plate station.
[0051] Figure 16 is a side view of the support plate station inside the instrument. TAPE PATH ASSEMBLY
[0052] Figure 17A is an isometric view of a tape path assembly on the instrument.
[0053] Figure 17B is an isometric front view of the tape path assembly.
[0054] Figure 18A is an isometric front view of the tape path assembly with a tape feed in a retracted position. Figure 18B is an isometric front view of the tape path assembly seen in Figure 19A with the tape feed in an extended position.
[0055] Figure 19A is a rear perspective view of the tape path assembly with a drive mechanism.
[0056] Figure 19B is an isometric view from behind the drive mechanism.
[0057] Figure 19C is a perspective view of a roll on tape path assembly.
[0058] Figure 20A is a front plan view of a tape feed over tape path assembly.
[0059] Figure 20B is an isometric front view of the tape feed on the tape path assembly.
[0060] Figure 21A is a rear perspective view of a tape cutter on the tape path assembly.
[0061] Figure 21B is a plan view of a front side of the tape cutter that has the blade in a retracted position.
[0062] Figure 21C is a plan view of a front side of the tape cutter that has the blade in an extended position.
[0063] Figure 21D is a plan view on an ingress of the tape path assembly with the tape cutter having the blade in a retracted position.
[0064] Figure 21E is a partially transparent plan view on an ingress of the tape path assembly with the tape cutter having the blade in an extended position.
[0065] Figure 22A is a partially transparent front perspective view of a lifting mechanism.
[0066] Figure 22B is a plan view of the lifting mechanism.
[0067] Figure 23A is a front plan view of the lift mechanism on the tape path assembly in a retracted position.
[0068] Figure 23B is a front plan view of the lift mechanism on the tape path assembly in an extended position.
[0069] Figure 24 is a front perspective view of thermal units on the tape path assembly.
[0070] Figure 25 is a bottom view of fluid paths on the tape path assembly.
[0071] Figure 26A is a partially transparent side view of a retractable retainer.
[0072] Figure 26B is a rear perspective view of the retractable detent on the tape path assembly with the retractable detent in a retracted position.
[0073] Figure 26C is a rear perspective view of the retractable detent on the tape path assembly with the retractable detent in an extended position.
[0074] Figure 27 is a perspective view of a rewind assembly that can accumulate processed tape exiting the tape path assembly. DISPENSING ASSEMBLY
[0075] Figure 28 is an isometric view of a dispensing assembly on the instrument.
[0076] Figure 29 is a schematic diagram of the dispensing assembly seen in Figure 28.
[0077] Figure 30 is a perspective view of the y axis mooring easel of the dispensing assembly seen in Figure 28.
[0078] Figures 31A to 31B are isometric views of the dispensing head of the dispensing assembly seen in Figure 28.
[0079] Figure 31C is a partially transparent perspective view of the two geometric z axes of the dispensing head seen in Figures 31A to 31B.
[0080] Figure 32A is a transparent isometric view of the dispensing box of the dispensing assembly seen in Figure 28.
[0081] Figure 32B is a transparent perspective view of the dispensing box of the dispensing assembly seen in Figure 28.
[0082] Figure 33 is a schematic diagram of non-contact dispensing components of the dispensing box and dispensing head seen in Figures 31A to 31C and 32A to 32B. TAPE SEALING ASSEMBLY
[0083] Figure 34A is an isometric view of a tape seal assembly on the instrument.
[0084] Figure 34B is a perspective view of a sealing blanket.
[0085] Figure 35 is a perspective view of the tape seal assembly positioned adjacent to a tape path assembly.
[0086] Figure 36A is a top view of the tape seal assembly inside the instrument.
[0087] Figures 36B and 36C are perspective views of the tape seal assembly.
[0088] Figure 37A is an isometric view of a portion of the tape seal assembly.
[0089] Figure 37B is a side view of the sealing tape assembly with a threaded path of sealing blanket.
[0090] Figure 38A is a perspective view of a support penetration mechanism of the tape seal assembly.
[0091] Figure 38B is a side view of the support penetration mechanism in Figure 38A with friction roller in a closed position
[0092] Figure 38C is a side view of the support penetration mechanism in Figure 38A with friction roller in an open position
[0093] Figure 39A is a cross-sectional view of a locking mechanism of the tape seal assembly in an unlocked position.
[0094] Figure 39B is a cross-sectional view of a locking mechanism of the tape seal assembly in a locked position.
[0095] Figure 40 is a partially transparent perspective view of an applicator of the tape seal assembly.
[0096] Figure 41 is a bottom view of an applicator block.
[0097] Figures 42A and 42B are partially transparent perspective views of a portion of the tape seal assembly that removes a seal from a sealing blanket support.
[0098] Figures 43A and 43B are side views of the tape seal assembly that applies a seal to a tape over the tape path assembly. THERMAL UNIT AND HEATED PRESSURE CHAMBER
[0099] Figure 44 is an isometric view of a tape path assembly that travels through an instrument.
[0100] Figure 45A is a perspective view of a thermal unit and a heated pressure chamber, with the heated pressure chamber in a closed position.
[0101] Figure 45B is a perspective view of a thermal unit and a heated pressure chamber, with the heated pressure chamber in a closed position.
[0102] Figure 45C is an exploded view of the thermal unit and the heated pressure chamber.
[0103] Figure 45D is an exploded view of the thermal unit.
[0104] Figure 45E is an exploded view of the heated pressure chamber.
[0105] Figure 46A is a perspective view of the thermal unit.
[0106] Figure 46B is a perspective view of the bottom of the thermal unit.
[0107] Figure 46C is a top view of the thermal unit.
[0108] Figure 46D is an isometric view of a ribbon arrangement in the thermal unit.
[0109] Figure 47A is a cross-sectional side view of the thermal unit.
[0110] Figure 47B is a cross-sectional cutaway side view of the thermal unit.
[0111] Figure 47C is a schematic view of a cross-section of the thermal unit.
[0112] Figure 48 is a clear top view of a top side of the thermal unit.
[0113] Figure 49 is a transparent bottom view of the thermal unit.
[0114] Figure 50 is a cross-sectional view of the heated pressure chamber and the thermal unit.
[0115] Figure 51 is an isometric view of the heated pressure chamber.
[0116] Figure 52 is a top view of the heated pressure chamber. ALTERNATIVE MODALITIES OF THE GENERAL INSTRUMENT
[0117] Figure 53A is a schematic view of an alternative embodiment of the instrument seen in Figures 1A to 52. Figure 53B is a schematic view of an alternative embodiment of the instrument seen in Figures 1A to 52. DETAILED DESCRIPTION
[0118] In general, the present disclosure refers to an instrument for analyzing biological sample and reagent mixtures. The instrument is a multifunctional instrument that is capable of dispensing, amplifying and analyzing biological samples and reagents in a compact design. A tape containing a plurality of wells is automatically advanced through the instrument along a tape path assembly. The tape path assembly includes a first position, a second position, a third position and a fourth position. In the first position, the tape can be cut so that a segment of tape with a single array of wells proceeds through the instrument. Alternatively, the tape can advance through the first position to the second position without being cut. Additionally, the tape can advance without being cut until any number of arrays of wells have passed through the first position and the tape can then be cut. In the second position, a biological sample and a reagent are dispensed into the plurality of wells on the tape with a dispensing assembly to form a biological sample and a reagent mixture. After the biological sample and reagent are dispensed onto the tape, a tape seal assembly seals the tape with a seal, such as an optically clear cover seal. Then the tape advances to the third position. In the third position, the tape containing the biological sample and reagent mixture can either be cooled to prevent the biological sample and reagent mixture from being subjected to a chemical reaction or heated to incubate the biological sample and reagent mixture. Then the tape will advance to the fourth position. In the fourth position, the biological sample and reagent mixture in the plurality of wells on the strip can be amplified and analyzed with a detection assembly. The multifunctional instrument is capable of amplifying nucleic acids in the biological sample and reagent mixture by thermally cycling the biological sample and the reagent mixture (polymerase chain reaction) or heating the biological sample and the mixture of reagent at a constant temperature (isothermal amplification). As the strip progresses through the system, the second position, third position, and fourth position can function at the same time to allow the instrument to continuously dispense, amplify and analyze the biological sample and reagent mixture on the strip.
[0119] The multifunctional instrument is advantageous, as it performs all the necessary functions to dispense, amplify and analyze a biological sample and a reagent mixture without the need for human intervention. A user can simply select parameters for the instrument and place a biological sample and a reagent on the instrument. Then, the instrument can aspirate the biological sample and reagent, automatically advance the strip through the instrument, dispense the biological sample and reagent onto the strip, and amplify and analyze the biological sample and reagent mixture on the strip. The instrument is additionally advantageous as it has a compact design that holds all the components needed to carry out the instrument's functions in a single chassis. Additionally, the functions provided in the instrument allow the instrument to be used for large scale test with high throughput or small scale test with low throughput. The instrument's compact design, efficiency and versatility allow the instrument to be used in a wide variety of configurations and for a large number of different applications. GENERAL INSTRUMENT Figure 1A is an isometric view of instrument 100 mounted on cart assembly 101. Figure 1B is a side view of instrument 100 on cart assembly 101 seen in Figure 1A. Figure 1C is a top plan view of instrument 100. Figure 1D is an exploded view of instrument 100. Figure 1E is a front isometric view of the tape path assembly 118 that runs through instrument 100. Figure 1F is a rear perspective view of tape path assembly 118 as seen in Figure 1D. Instrument 100 is mounted on cart assembly 101 and includes chassis 102, box 103 (removed for clarity in subsequent figures), tape 104 (as shown in Figures 1E and 1F), seal 106 (as shown in Figures 1E and 1F) , plate stacker assembly 110, support plate assembly 112, dispensing assembly 114, wash assembly 116, tape path assembly 118, tape seal assembly 120, detection assembly 122 (as shown in Figures 1C and 1D) and electronic assembly 124. Box 103 provides a controlled environment for a reaction to occur in instrument 100. Box 103 includes absorption filters, an exhaust filter and an exhaust blower in order to control air quality within instrument 100 .
[0120] Also mounted to the cart assembly 101 is the rewind assembly 108. The rewind assembly 108 is aligned with the tape path assembly 118. The cart assembly 101 includes a bleach reservoir, a waste tank with a exhaust filter and an activated carbon filter for the wash assembly 116. The trolley assembly 101 also includes two water tanks to supply system fluid to the dispensing assembly 114 and the wash assembly 116. As shown in Figures 1E and 1F, the tape path assembly 118 includes first position 130, second position 132, third position 134, and fourth position 136.
[0121] Instrument 100 can be used to dispense, amplify and analyze a biological sample and reagent mixture. Instrument 100 includes a plurality of mounts that are all positioned on chassis 102. Ribbon 104 is advanced through instrument 100. Ribbon 104 has a plurality of wells that can receive a biological sample and a reagent for amplification and analysis. The plurality of wells in tape 104 are arranged in arrays so that each array is separate from adjacent arrays. In the embodiment shown, tape 104 is an opaque white tape. In alternative embodiments, tape 104 can be black, white or gray and transparent, semi-transparent or opaque. Tape 104 can be produced from a plastic material such as polypropylene or another suitable material such as metallic foil.
[0122] As tape 104 advances through instrument 100, the plurality of mounts on instrument 100 will interact with tape 104. The mounts that are included on instrument 100 are the plate stacker assembly 110, the plate assembly bracket 112, dispensing assembly 114, wash assembly 116, tape path assembly 118, tape seal assembly 120, detection assembly 122, and electronic assembly 124. The plurality of assemblies are positioned on chassis 102 of instrument 100 to minimize the size of chassis 102 and instrument 100. Minimizing the size of chassis 102 and therefore instrument 100 allows instrument 100 to have a compact design.
[0123] Each assembly in instrument 100 performs a function related to dispensing, amplifying and/or analyzing a biological sample and a reagent mixture so that instrument 100 can operate as a multifunctional assembly. The plate stacker assembly 110 is capable of receiving and moving plates that contain a biological sample and/or a reagent in instrument 100. The support plate assembly 112 is capable of receiving plates that contain a biological sample and/or a reagent. . Dispensing assembly 114 can aspirate biological sample and/or reagent from a plate in plate stacker assembly 110 and dispense biological sample and/or reagent onto strip 104 in instrument 100. Dispensing assembly 114 can also aspirate a biological sample and/or a reagent from a plate on the support plate assembly 112 and dispense the biological sample and/or the reagent on the strip 104 on the instrument 100. Additionally, the dispensing assembly 114 can aspirate a biological sample and/or reagent from any one of a plate in the plate stacker assembly 110, a plate in the support plate assembly 112, or tape 104, and may dispense the biological sample and/or the reagent on a plate in the plate stacker assembly 110 , a plate on the backing plate assembly 112 or tape 104. The wash assembly 116 is used to clean the dispensing assembly 114 before and/or after the dispensing assembly 114 is used to dispense the biological sample a and the reagent on tape 104.
[0124] Tape 104 advances along tape path assembly 118 through instrument 100. Tape path assembly 118 extends through instrument 100 and provides a path along which tape 104 can advance. Tape path assembly 118 includes first position 130, second position 132, third position 134, and fourth position 136. Different functions are completed at each position along tape path assembly 118. At first position 130, tape 104 it can be cut to single tape 104 into a tape segment with a single array of wells. Alternatively, tape 104 may advance as a mat through first position 130 without being cut, or tape 104 may be cut after any number of wells have passed first position 130. At second position 132, dispensing assembly 114 dispenses the biological sample and the reagent on tape 104 to form a biological sample and a reagent mixture. Additionally, tape seal assembly 120 is positioned adjacent to second position 132 of tape path assembly 118 and seals an array on tape 104 with seal 106 after biological sample and reagent are dispensed on tape 104. Thermal management of tape 104 may occur at second position 132. For example, tape 104 may be cooled at second position 132 to prevent the biological sample and reagent mixture from being subjected to a chemical reaction, or tape 104 may be heated at second position 132 to incubate the biological sample and reagent mixture. Thermal management of ribbon 104 can occur in third position 134 as concavity. At third position 134, tape 104 can again be cooled to prevent the biological sample and reagent mixture from being subjected to a chemical reaction or heated to incubate the biological sample and reagent mixture. Tape 104 waits at third position 134 until instrument 100 is prepared to amplify and analyze the biological sample and reagent mixture on tape 104. At fourth position 136, tape 104 can be amplified and analyzed using the assembly of detection assembly 122 which is positioned adjacent to the fourth position 136 of the tape path assembly 118. The detection assembly 122 can heat the biological sample and reagent mixture on the tape 104 and further includes a camera that can be used to analyze the biological sample and the reagent mixture on tape 104. Electronic assembly 124 is included in instrument 100 to power instrument 100 and control the other assemblies in instrument 100.
[0125] Instrument 100 is advantageous for a number of reasons. First, each of the plurality of mounts is positioned on a single chassis 102. This allows instrument 100 to have a compact design, which makes instrument 100 suitable for use in a variety of different configurations. Second, instrument 100 is a multifunctional system that has the capability to perform every step necessary to dispense, amplify and analyze a biological sample and a reagent mixture that must be tested on instrument 100. This allows instrument 100 to be used without the need for additional equipment to perform different functions for dispensing, amplifying and analyzing biological sample and reagent mix. Third, instrument 100 can be used for large-scale or small-scale testing. Instrument 100 includes all the components needed to test a large number of biological samples or a small number of biological samples. This versatility allows the instrument 100 to be used in a wide variety of configurations and for a large number of different applications. Figure 2A is an isometric view of instrument 100. Figures 2B through 2D are perspective views of instrument 100. Figures 2E and 2F are rear perspective views of tape path assembly 118 on instrument 100. Instrument 100 includes chassis 102, tape 104, seal 106, plate stacker assembly 110, support plate assembly 112, dispensing assembly 114, wash assembly 116, tape path assembly 118, tape seal assembly 120, detection assembly 122 and electronic assembly 124. Tape path assembly 118 includes first position 130, second position 132, third position 134, and fourth position 136.
[0126] The plate stacker assembly 110 includes plate shelf 140, plate stacker 142 and plate shuttle 144. In the embodiment shown in Figures 2A to 2D, the plate stacker assembly 110 is used to receive, retain and move plates that contain a biological sample. In alternative embodiments, plate stacker assembly 110 could also be used to receive, hold and move plates containing a reagent. A plate shelf 140 is a chute or hotel that can receive and retain a plurality of plates. Plate shelf 140 is affixed to chassis 102 of instrument 100 and can be moved in and out of instrument 100 using any suitable mechanism, which includes having a plate shelf for user to pull 140 out of instrument 100 The plate stacker 142 includes an arm with a spatula that can move up and down and pivot on a support structure. The plate stacker spatula 142 can lift plates off the plate shelf 140 and move them in instrument 100. Plate shuttle 144 includes a nesting portion that can move horizontally along a support structure. The plates from the plate shelf 140 can be moved by the plate stacker 142 to the nesting portion of the plate shuttle 144. When a plate is positioned over the nesting portion of the plate shuttle 144, the nesting portion can move across. of instrument 100 to be positioned for aspiration or dispensing.
[0127] Plates containing a biological sample and/or a reagent can be placed in the plate stacker assembly 110 in two ways. Firstly, the plate shelf 140 can be pulled out of the instrument 100 and plates can be positioned on the plate shelf 140. Second, the nesting portion of the plate shuttle 144 can extend outside the instrument 100, as seen in Figures 2B and 2D. A plate may then be positioned over the nesting portion of the plate shuttle 144 and the nesting portion may then move back to the instrument 100. In alternative embodiments, the plate stacker assembly 110 may additionally receive a tip tray retainer that holds tips for the dispensing assembly 114, a matrix shelf that holds a plurality of matrix tubes, a concavity curve, or any other container that is capable of holding a biological sample and/or a reagent. .
[0128] The support plate assembly 112 includes the support plate station 150, the support plate station 152 and the support plate station 154. In the embodiment shown in Figures 2A to 2F, the support plate assembly 112 is used to receive and hold plates that contain a reagent. In alternative embodiments, the support plate assembly 112 can be used to receive and retain plates that contain a biological sample. The support plate station 150, the support plate station 152 and the support plate station 154 each can receive and retain a plate. Support plate station 150, support plate station 152 and support plate station 154 each include a retainer to hold the plate in place. The plates are positioned in support plate station 150, support plate station 152 and support plate station 154 by lifting the retainer, positioning the plate and then lowering the retainer to secure the plate to the place. In alternative embodiments, support plate station 150, support plate station 152 and support plate station 154 may additionally receive a die shelf which holds a plurality of die tubes, a concavity curve, or any other. container that is capable of holding a biological sample and/or a reagent.
[0129] Dispensing assembly 114 includes sample dispenser 160 and reagent dispenser 162. Sample dispenser 160 and reagent dispenser 162 both include one or more tips that can be used to aspirate and dispense biological samples and reagents. In alternative embodiments, the tips could be pin tools that can be used to transfer the biological sample and/or the reagent. The reagent dispenser 162 is positioned on one side of the sample dispenser 160. The sample dispenser 160 and the reagent dispenser 162 move together in an x and a y direction on a lashing stand at a top end of the instrument 100 In the embodiment shown, when sample dispenser 160 moves in a z direction, reagent dispenser 162 will move with sample dispenser 160. Reagent dispenser 162 may further move in a z direction relative to the sample dispenser. sample 160. In the embodiment shown in Figures 2A through 2F, sample dispenser 160 is used to aspirate a biological sample from a plate onto plate shuttle 144 and then dispense the biological sample onto strip 104. Reagent dispenser 162 is used to aspirating a reagent from a plate in the support plate assembly 112 and then dispensing the reagent onto the strip 104. In alternative embodiments, the sample dispenser 160 can aspirate and disperse the reagent and reagent dispenser 162 can aspirate and disperse the biological sample.
[0130] The wash assembly 116 includes the sample dispenser wash 170 and the reagent dispenser wash 172. The sample dispenser wash 170 can be used to wash the tips in the sample dispenser 160. The sample dispenser wash 170 is a vacuum based system that can use a cleaning solution and/or water with air flow to evacuate any residual biological sample or reagent from the tips to decontaminate them so they can be reused. An example sample dispenser wash 170 is disclosed in published PCT application No. WO 2014/179584, which is incorporated herein by reference in its entirety. The 172 Reagent Dispenser Wash is used to wash the tips in the 162 Reagent Dispenser. The 172 Reagent Dispenser Wash uses water and airflow to clean the tips.
[0131] As shown in Figures 2E and 2F, the tape path assembly 118 includes first position 130, second position 132, third position 134 and fourth position 136. The tape path assembly 118 also includes the tape feed 180, tape cutter 182, retractable retainer 184, actuation mechanism 186, thermal unit 188, and thermal unit 190. Tape feed 180 is positioned near a first end of tape path assembly 118 upstream of the first position 130. Tape feed 180 includes a retractable spool that can hold a tape cartridge 104. Tape feed 180 is positioned near the first end of tape path assembly 118 so that tape 104 can be fed into the assembly. tape path assembly 118. The tape 104 that is fed into the tape path assembly 118 can then advance to the first position 130. Positioned adjacent to the first position 130 is the tape cutter 182. tape 182 includes a blade that can be actuated upward to cut the desired tape 104 1F. Tape 104 can also advance along tape path assembly 118 without being cut by tape cutter 182.
[0132] Tape 104 advances from first position 130 to second position 132 along tape path assembly 118. At second position 132, biological sample and reagent are dispensed onto tape 104 with dispensing assembly 114 to form a biological sample and a reagent mixture. To retain flat tape 104 during dispensing, retractable retainer 184 is positioned adjacent to second position 132 (and on top of third position 134). The retractable retainer 184 includes a retractable bar that can be automatically actuated to retain the tape 104 flat. Positioned below second position 132 is thermal unit 188. Thermal unit 188 includes one or more thermoelectric modules (TEMs) that can be used to both cool and heat the biological sample and reagent mixture on strip 104. Positioned adjacent to the second position 132 is the tape seal assembly 120. An arrangement on the tape 104 may be sealed with a seal 106 using the tape seal assembly 120 when that arrangement is positioned at the second position 132.
[0133] After dispensing and sealing, tape 104 advances to third position 134. Positioned above third position 134 is retractable retainer 184 to hold tape 104 flat when tape 104 is in second position 132. 134 is thermal unit 190. Thermal unit 190 includes one or more thermoelectric modules that can be used to both cool and heat the biological sample and reagent mixture in strip 104. Strip 104 can wait in third position 134 until instrument 100 is prepared to amplify and analyze the biological sample and reagent mixture on sliver 104.
[0134] When instrument 100 is prepared to amplify and analyze the biological sample and reagent mixture, the strip 104 can advance to the fourth position 136. Positioned below the fourth position 136 is the thermal unit 210 for heating the biological sample and mixing of reagent on strip 104. Positioned in fourth position 136 is heated pressure chamber 212 to pressurize an area above strip 104 to push down and maintain seal 106 on strip 104. Biological sample and reagent mixture on strip 104 is amplified using the thermal unit 210 at the fourth position 136. Both after and during amplification, the biological sample and reagent mixture can be analyzed using the chamber 214. The heated pressure chamber 212 additionally heats the biological sample and mixing reagent e prevents condensation at seal 106 on tape 104 to ensure accurate analysis with camera 214.
[0135] The tape 104 advances along the tape path assembly 118 through the instrument 100 with the actuation mechanism 186. The actuation mechanism 186 is a belt that drives the tape 104 with frictional engagement in the modality shown in Figures 2A to 2F. In alternative embodiments, actuation mechanism 186 may actuate tape 104 with any suitable mechanism. Tape 104 advances through instrument 100 along tape path assembly 118 until tape 104 exits instrument 100 at a second end of tape path assembly 118.
[0136] As shown in Figures 2A, 2C and 2D, the tape seal assembly 120 includes spool 200 and applicator 202. The tape seal assembly 120 is capable of moving in both x and y directions with respect to instrument 100. The spool 200 can hold a sealing blanket 106 that can be used to seal the tape 104 to the instrument 100. The seals 106 are cover seals that can be applied to the tape 104 to contain the biological sample and reagent mixture in the tape 104. and prevent evaporation and contamination of the biological sample and reagent mixture on tape 104. The seals 106 that are held on the spool 200 are routed through the tape seal assembly 120 so that the applicator 202 can capture the seal 106 on demand. that the seal 106 is removed from the back seal 106 which is retained. The applicator 202 can then apply seal 106 to a tape array 104. The tape seal assembly 120 is positioned adjacent the second position 132 of the tape path assembly 118 so that the tape 104 can be sealed with the seal. 106 in the second position 132.
[0137] The detection assembly 122 includes the thermal unit 210, the heated pressure chamber 212 and the camera 214. The detection assembly 122 is positioned in the fourth position 136 to amplify and analyze the biological sample and the reagent mixture on the strip 104. Thermal unit 210 is positioned below fourth position 136 and includes one or more TEMs that can be used to hold the biological sample and reagent mixture at a constant temperature or cycle of the biological sample and the reagent mixture through multiple temperatures. Heated pressure chamber 212 is positioned above and around fourth position 136. Heated pressure chamber 212 seals, pressurizes, and heats the area above fourth position 136 so that the biological sample and the reagent mixture in the strip 104 can be analyzed. The heated pressure chamber 212 also prevents condensation on the seal 106 so that the chamber 214 can properly detect a signal from the biological sample and reagent mixture on the strip 104.
[0138] The detection assembly 122 includes excitation light-emitting diodes to illuminate the biological sample and the reagent mixture on strip 104 to excite a dye or probe in the biological sample and the reagent mixture. The dye or probe emits a signal, such as fluorescence, and an emission filter concavity filters the signal entering camera 214 to a desired wavelength. Camera 214 is positioned above fourth position 136 and heated pressure chamber 212 and can detect the signal emitted from the biological sample and reagent mixture on tape 104. Camera 214 is a CCD camera in the embodiment shown, but can be any suitable camera or other detection device in alternative modalities.
[0139] As shown in Figures 2A through 2D, electronic assembly 124 includes lighting strips 216, power supply 220, printed circuit boards 222, industrial PC 224 and display 226. provide additional illumination during operation of instrument 100. In the embodiment shown, illumination strips 216 are light-emitting diodes. In an alternative embodiment, the illumination strips 216 may include an ultraviolet light source to assist in decontaminating instrument 100. Power source 220 powers instrument 100 and each of the plurality of mounts positioned on instrument 100. printed circuit boards 222 include electronic components that are used to control the operation of instrument 100. Printed circuit boards 222 are positioned at a rear portion of instrument 100 and are located further along instrument 100 to control each of the plurality of mounts on instrument 100. Industrial PC 224 is also positioned on a rear portion of instrument 100 and additionally controls the operation of instrument 100. Industrial PC 224 can communicate with 222 printer circuit boards throughout instrument 100 to perform the functions of instrument 100. Display 226 is positioned on a first side of instrument 100 and to a touch-sensitive display that a user can use to control tests on instrument 100. Display 226 can also display data that is collected on instrument 100 during operation. Display 226 can be affixed to a multi-directional arm so that a user can move display 226 to a suitable position for it. Instrument 100 additionally includes an analytical system to gather data that is collected during the analysis of the biological sample and the reagent mixture.
[0140] Instrument 100 is advantageous over prior art devices in that instrument 100 can test a large sample set or a small sample set. This versatility allows the instrument 100 to be used in a variety of configurations. The multifunctional operation and compact design additionally allow the 100 to be used in a variety of different configurations and for a wide variety of different applications. Instrument 100 can amplify and analyze a biological sample and a reagent mixture according to polymerase chain reaction (PCR) steps. This includes real-time PCR, endpoint PCR and other suitable PCR variations. Real-time PCR (or quantitative PCR) includes thermal cycling and amplifies the biological sample and the reagent mixture and detects a signal from the biological sample and the reagent mixture at the same time. Endpoint PCR includes detecting a signal from the biological sample and the reagent mixture after they have been amplified. Biological sample and reagent mixture can be amplified according to any suitable procedure with suitable endpoint PCR. Additionally, the biological sample and reagent mixture can be dispensed and sealed onto tape 104 on instrument 100, removed from instrument 100 to undergo amplification using an external device, and then inserted back into instrument 100 for detection of endpoint with instrument 100. Instrument 100 can also amplify and analyze a biological sample and a reagent mixture using isothermal amplification. Isothermal amplification includes amplifying the biological sample and reagent mixture at a constant temperature. Instrument 100 can also be used for other PCR processes or for any process that detects a signal from a biological sample and reagent mixture with the use of a camera.
[0141] Figure 3A is a top plan view of thermal management system 240 on instrument 100. Figure 3B is a perspective view of thermal management system 240. Figure 3C is a schematic view of thermal management system 240. Instrument 100 includes support plate assembly 112 (which includes support plate station 150, support plate station 152 and support plate station 154) and tape path assembly 118 (which includes second position 132 , third position 134 and fourth position 136). Thermal management system 240 includes reservoir 242, fluid pump 243, radiator 244, cooling fan 245, fluid path 246, fluid path 248, fluid path 250, fluid path 252, fluid path 254, fluid path fluid 256 and fluid path 258.
[0142] Thermal management system 240 cycles through instrument 100 to provide a heat exchange fluid for thermal units that are positioned on instrument 100. Thermal management system 240 is a closed loop fluidic thermal management system. Fluid not being used for heat exchanger can be stored in reservoir 242. Fluid not being used for heat exchanger can flow through radiator 244 so that the fluid temperature can be controlled. Cooling fan 245 assists in controlling the fluid temperature by blowing cooling air through radiator 244 to remove heat from the fluid flowing through radiate 244. Fluid from radiator 244 can then flow through a plurality of fluid paths in the instrument 100.
[0143] Fluid path 246 and fluid path 248 are both positioned below fourth position 136 of tape path assembly 118. Fluid path 246 travels along a first side of fourth position 136 and fluid path 248 travels. a second side of fourth position 136. Fluid path 250 is positioned below third position 134 of tape path assembly 118. Fluid path 252 is positioned below second position 132 of tape path assembly 118. fluid path 254 is positioned below support plate station 154 of support plate assembly 112. Fluid path 256 is positioned below support plate station 152 of support plate assembly 112. Fluid path 258 is positioned below the support plate station 150 of the support plate assembly 112. Fluid paths 246 through 258 all include a cavity that curves back and forth through a block so that fluid can flow the cavity and exchange heat with the components that are positioned above the cavity.
[0144] When heat exchange is required, fluid pump 243 pumps fluid from reservoir 242 to radiator 244. Radiator 244 and cooling fan 245 can adjust the fluid temperature for use in instrument 100. fluid temperature is regulated, fluid flows through instrument 100 along two separate paths. The first path is through fluid path 246 and 248, fluid path 250, fluid path 252 and back to reservoir 242. The second path is through fluid path 254, fluid path 256, path of fluid 258 and back to reservoir 242. Fluid flowing from radiator 244 to fluid paths 246, 248 and 254 is routed through a base portion of instrument 100. Additionally, fluid flowing from fluid paths 252 and 258 to reservoir 242 is routed through a base portion of instrument 100. Fluid routing through a base portion of instrument 100 allows the space on the main surface of instrument 100 to retain other components. This allows for flexibility in the design of instrument 100 and allows instrument 100 to be compact in design.
[0145] Thermal management system 240 is advantageous as it is a closed loop system. This means that instrument 100 does not have to be connected to a fluid source to regulate the temperature of components in instrument 100, as the fluid is stored in thermal management system 240 and cycled through thermal management system 240 as needed. This allows instrument 100 to be used in configurations where there is no access to a temperature-controlled fluid source. Thermal management system 240 is additionally advantageous in that it can effectively and efficiently regulate the temperature of components that are positioned along thermal management system 240 using convective heat transfer.
[0146] Figure 4A is a top plan view of strip 104 with wells 270. Figure 4B is a schematic view of strip 104 with first plurality of wells 272 and second plurality of wells 274. Strip 104 includes wells 270, which includes first plurality of wells 272 (which includes recess 276), second plurality of wells 274 (which includes recess 278), and array identifier 280.
[0147] Strip 104 includes wells 270. Wells 270 are formed in strip 104 to receive and retain a biological sample and a reagent for amplification and analysis. Strip 104 can include any number of wells 270, which includes a concavity 270 or a plurality of wells 270. For example, strip 104 can include wells 270 arranged in a 96-well configuration, a 192-well configuration, a configuration a 384-well configuration, a 768-well configuration, or a 1536-well configuration. Arrangement identifier 280 is an identifier, such as a bar code, that identifies the contents in wells 270. Tape 104 is produced from a polymer material and wells 270 are created by embedding in the embodiment shown, although the they are created using other suitable methods in alternative modalities. In the embodiment shown, tape 104 is an opaque white tape. In alternative embodiments, tape 104 can be black, white or gray and transparent, semi-transparent or opaque.
[0148] In the embodiment shown in Figures 4A and 4B, the wells 270 include the first plurality of wells 272 and the second plurality of wells 274 that are offset from and intertwined with the first plurality of wells 272. As seen in Figure 4B, the first plurality of wells 272 are represented with white circles and the second plurality of wells 274 are represented with black circles. Strip 104 includes 768 wells, with 384 wells constituting the first plurality of wells 272 and 384 wells constituting the second plurality of wells 274. In alternative embodiments, strip 104 may include any number and size of wells 270 with a first plurality of wells is interwoven with a second plurality of wells.
[0149] The first plurality of wells 272 and the second plurality of wells 274 are positioned on tape 104 so that the wells in the first plurality of wells 272 and the wells in the second plurality of wells 274 are offset from each other at an angle of 45°. degrees. For example, the concavity 276 of the first plurality of wells 272 is offset from the concavity 278 of the second plurality of wells 274 at an angle of 45 degrees. Each concavity in the first plurality of wells 272 is offset from each adjacent concavity in the second plurality of wells 274 at an angle of 45 degrees. This allows the first plurality of wells 272 and the second plurality of wells 274 to be interwoven with each other in an offset pattern.
[0150] Interlacing the first plurality of wells 272 and the second plurality of wells 274 together in tape 104 is advantageous. If the first plurality of wells 272 or the second plurality of wells 274 were removed, a 384-well format would be left on tape 104. Interlacing is advantageous for a number of reasons. First, tape 104 allows a standard 384-well format to be duplicated in essentially the same amount of space as previously required for the 384-well format. This doubles the number of results that can be collected when a single array of tape 104 is tested, which increases the efficiency and throughput of the test device. Second, tape 104 can easily interface with standard equipment, such as pipette tips, which is currently available in either the 384-well or 96-well format. Third, interweaving the first plurality of wells 272 and the second plurality of wells 274 with each other allows for maximum spacing between the wells 270, which allows for larger wells than would otherwise be possible. Fourth, the surface area between the wells 270 is maximized in the tape 104, which is advantageous when the tape 104 is sealed. A larger surface area allows for a better seal as there is more contact between tape 104 and seal 106. ASSEMBLY OF PLATE FORKLIFT
[0151] Figure 5A is an isometric view of the plate stacker 110 assembly on instrument 100. Figure 5B is a top cutaway view of the plate stacker 110 assembly on instrument 100. Figure 5C is an isometric view of the plate stacker assembly 110. Plate stacker assembly 110 is positioned in a first corner of instrument 100. Plate stacker assembly 110 is capable of receiving, retaining, and moving plates in instrument 100. In the embodiment shown in Figures 5A at 5C, plate stacker assembly 110 receives plates that contain a biological sample. In alternative embodiments, plate stacker assembly 110 can receive plates that contain other samples or reagents.
[0152] The plate stacker assembly 110 includes the plate rack 302, the plate stacker 304, and the plate shuttle 306. The plate shelf 302 is a conduit or shelter that can receive and retain a plurality of plates. Plate shelf 302 is attached to instrument 100 and can be moved in and out of instrument 100 using any suitable mechanism. The plate stacker 304 includes an arm that can move up and down on and rotate on a support structure with a spatula attached to the arm. The spatula and arm of plate stacker 304 can pick plates from plate shelf 302 and move them on instrument 100 with rotary and vertical movement. Plate shuttle 306 includes a nesting portion that can move horizontally along a support structure. Plate shelf plates 302 can be moved by plate stacker 304 and placed in the nesting portion of plate shuttle 306. When a plate is positioned in the nesting portion of plate shuttle 306, the nesting portion can move through of instrument 100 to be positioned by aspiration and dispensing.
[0153] Plates containing a biological sample can be placed in the plate stacker assembly 110 in two ways. First, the plate shelf 302 can be pulled from the instrument 100 and the plates containing the biological sample can be positioned on the plate shelf 302. Second, the nesting portion of the plate shuttle 306 can extend outside the instrument 100 ( as seen in Figure 8B). This allows instrument 100 to interface with plate storage units or plate cover removal equipment outside instrument 100. The plate can then be positioned in the nesting portion of the plate shuttle 306 and the nesting portion can move back to instrument 100.
[0154] The plate stacker assembly 110 can receive, retain and move the plates or other components compatible with the instrument 100, such as tip trays for the dispense assembly 114. Additionally, the plate stacker assembly 110 can complete these functions in a small area. This makes the plate stacker assembly 110 advantageous for use in instrument 100, which is a compact instrument with limited space.
[0155] Figure 6A is an isometric view of the plate shelf 302. Figure 6B is a top plan view of the nesting 312 of the plate shelf 302. The plate shelf 302 includes the frame 310, the nests 312, the rails 314, rails 315, knobs 316, and contact 318, as shown in Figure 6A. Each nest 312 includes frame 320, corner brackets 322, aperture 324, and slot 326 as shown in Figure 6B.
[0156] Plate shelf 302 includes frame 310 that forms a body portion of plate shelf 302. As shown in the embodiment shown in Figures 6A to 6B, attached to frame 310 are a plurality of nests 312. In alternative embodiments, a nest 312 or any number of nests 312 can be secured to frame 310. Nests 312 are positioned in a vertical row on frame 310. Each nest 312 can receive and retain a plate. When a plate is required for aspiration or dispensing, the plate can be selected from nesting 312 in which the plate is positioned and moved through instrument 100 to be positioned for aspiration or dispensing.
[0157] Rails 314 are attached to frame 310 on an outer side surface of frame 310. Rails 314 are slide rails in the embodiment shown in Figure 6A that slide over corresponding rails 315 that can be attached to instrument 100. Rails 314 and rails 315 allow plate shelf 302 to slide in and out of instrument 100. In alternative embodiments, rails 314 and rails 315 can be any mechanism that retains plate shelf 302 on instrument 100 and allows the shelf to of plate shelf 302 slides in and out of instrument 100. In some embodiments, when plate shelf 302 is slid out of instrument 100, plate shelf 302 may be completely removed. This allows a user to remove plate shelf 302, load plate shelf 302 with plates at a location away from instrument 100, and then reinsert plate shelf 302 into instrument 100 once plates have been placed in the plate shelf 302. Handles 316 are secured to an outer front surface of frame 310. Handles 316 can be attached by a user to slide plate shelf 302 out of instrument 100 along rails 314 and rails 315. Handles 316 can also be used to move plate shelf 302 when plate shelf 302 is removed from instrument 100.
[0158] Contact 318 is also secured to an outer side surface of frame 310. Contact 318 will be contiguous with a contact that is secured to instrument 100 when plate shelf 302 is positioned on instrument 100. Contact 318 is contact attached to instrument 100 act as a sensor to indicate to instrument 100 that plate shelf 302 is positioned on instrument 100. Additionally, contact 318 can communicate with contact wired to instrument 100 to indicate which configuration or size of plate shelf 302 has been placed on instrument 100. In alternative embodiments, any identification mechanism may be positioned on plate shelf 302 and any identification reader may be placed on instrument 100. As a first example, a barcode affixed to frame 310 of the plate shelf plate 302 can be scanned by a camera on instrument 100 and used to indicate which configuration or size of plate shelf 30 2 has been placed on instrument 100. As a second example, an RFID tag affixed to frame 310 of plate shelf 302 can be scanned by an RFID reader on instrument 100 and used to indicate which configuration or size of plate shelf 302 has been placed on instrument 100. This information can then be used by instrument 100 to indicate to components that interact with plate shelf 302 which configuration and size of plate shelf 302 is on instrument 100.
[0159] As shown in Figure 6B, each nest 312 includes frame 320 that forms an outer nesting body portion 312. Frame 320 has a beveled inner edge to guide a plate that is placed in nest 312 in the proper position. The beveled inner edge on the frame 320 eliminates the need for a board to be perfectly aligned with the nest 312 before being placed. Attached to each inner corner of frame 320 is a corner support 322. Corner supports 322 are flat support structures that each have the ability to support a corner of a plate when a plate is positioned in nesting 312. into frame 320 and corner brackets 322 is opening 324. Positioned to one side of frame 320 is slit 326. Opening 324 and slit 326 are provided in each nest 312 so that an arm can traverse the nest. 312 to place the plates in the nest 312 and pick up the plates from the nest 312. The slot 326 is positioned on the side of the frame 320 through which the arm will pass. Allowing an arm to go through the opening 324 and the slot 326 allows the plate shelf 302 to be of a compact design.
[0160] Figure 7A is an isometric view of the plate stacker 304. Figure 7B is a perspective view of a portion of the plate stacker 304 and a plate shelf portion 302. Figure 7C is a perspective view of a portion of plate stacker 304. Plate stacker 304 includes column 330, screw track 332, arm 334, spatula 336, actuator 338, actuator 340, camera 342, mount 343, cable carrier 344, sensor 346, mirror 348, and mirror 349. Spatula 336 includes support member 350 and notches 352. Also shown in Figure 7B is plate 390A positioned on plate shelf 302. Also shown in Figures 7B and 7C are camera path C.
[0161] Plate stacker 304 includes column 330 which forms a support structure for plate stacker 304. Positioned within column 330 is screw track 332. Arm 334 is attached to screw track 332. 334 includes spatula 336 which can be used to pick up and place plates on instrument 100. Arm 334 can move up and down in a vertical direction on screw track 332. Arm 334 can also rotate with column 330 on a vertical geometric axis. Actuator 338 is positioned on a base portion of plate stacker 304 and controls the rotary movement of column 330 and arm 334. Actuator 340 is positioned on a top end of column 330 and controls the vertical movement of arm 334 at the screw track 332. In the embodiment shown, actuator 340 includes a servo motor that tracks the vertical position of arm 334 on screw track 332.
[0162] Camera 342 is attached to plate stacker 304 with support 343. Camera 342 is used to scan barcodes or other plate identifiers on plates that are positioned on instrument 100. In the embodiment shown in Figure 7B, the camera 342 is used to scan barcodes on plates positioned on plate shelf 302. Camera 342 is attached to mount 343 so that camera 342 moves up and down with arm 334 on screw track 332. camera path C shows the path from a barcode on board 390A to camera 342. Camera 342 is positioned so that camera 342 captures the barcode image reflected in mirrors 348 and 349. with cameras 342 allows instrument 100 to determine which plate should be moved with spatula 336. Cable carrier 344 is positioned on adjacent column 330 and contains cables that connect camera 342 to a power supply and other electronics which are required to communicate with instrument 100. Also attached to plate stacker 304 is sensor 346. Sensor 346 detects the presence of a plate on spatula 336.
[0163] Spatula 336 of arm 334 is used to pick up and place plates on instrument 100. Spatula 336 includes support member 350 and notches 352. Support member 350 is a base portion with a signal shape of "more". Notches 352 are open areas at each corner of spatula 336. Support member 350 and notches 352 are shaped so that spatula 336 can traverse the nests in instrument 100. Support member 350 is used to engage a bottom of a plate on instrument 100. This hook holds a plate and allows spatula 336 to move the plate on instrument 100. Support member 350 has a bevelled inner edge to guide a plate that is gripped with spatula 336 in proper position. The bevelled inner edge on support member 350 eliminates the need for a plate to be perfectly aligned with the spatula 336 prior to gripping. Using spatula 336 to move plates in instrument 100 is advantageous as support member 350 of spatula 336 fully supports a plate and eliminates concerns that the plate will drop as it moves in instrument 100.
[0164] Figure 8A is an isometric view of the plate shuttle 306. Figure 8B is an isometric view of the plate shuttle 306 on instrument 100. The plate shuttle 306 includes a support 360, a rail 362, a nesting 364, a cradle 366, a drive mechanism 368 (including the drive belt 369 and the actuator 370), a clamp 372, a home position sensor 374, and a plate sensor 378. The nest 364 includes the frame 380, the mounting brackets. corner 382, opening 384 and slot 386.
[0165] The plate hook 306 includes the 360 bracket which forms a support structure for the plate hook 306. The 360 bracket extends in a horizontal direction through the instrument 100. Attached to the 360 bracket is the rail 362. The rail 362 also extends in the horizontal direction through instrument 100 along support 360. Nest 364 can be secured to rail 362 with support 366. Nest 364 moves along rail 362 in a horizontal direction across instrument 100 Bracket 366 secures nest 364 to rail 362. Bracket 366 secures nest 364 to drive mechanism 368 with clamp 372. Drive mechanism 368 is a belt driven system in the embodiment shown in Figures 8A through 8B, but it can be any suitable triggering mechanism in alternative modalities. Actuator 370 is secured to support 360 and controls the movement of drive mechanism 368. Support 366 attaches to drive belt 369 of drive mechanism 368 with clamp 372. Conform to drive belt 369 of drive mechanism 368 se moves, clamp 372 will move with drive belt 369 and thus move holder 366. As holder 366 moves with drive mechanism 368, holder 366 will slide over rail 362 and move nest 364 in the instrument 100.
[0166] Also attached to mount 360 are home position sensor 374 and plate sensor 378. Home position sensor 374 is positioned at a first end of mount 360. Home position sensor 374 detects when nesting 364 is positioned near the first end of support 360. This is the starting position for nest 364. As shown in Figure 8B, nest 364 can extend outside instrument 100 through an opening in instrument 100. Plate sensor 378 is positioned between the middle portion and the first end of support 360. Plate sensor 378 detects when a plate is positioned in nest 364. When a plate is positioned in nest 364, plate sensor 378 will indicate to instrument 100 that a plate exists positioned in nest 364 to prevent instrument 100 from trying to place another plate in nest 364. When a plate is positioned in nest tion 364, plate sensor 378 will also indicate to instrument 100 that a plate is available for dispensing operations.
[0167] As shown in Figure 8A, nesting 364 includes frame 380 which forms an outer body portion of nesting 364. Frame 380 has a bevelled inner edge to guide a plate that is placed in nesting 364 in the proper position. The bevelled inner edge on frame 380 eliminates the need for a board to be perfectly aligned with nesting 364 before the board is placed. Attached to each inner corner of frame 380 is a corner support 382. Corner supports 382 are flat support structures that each have the ability to support a corner of a plate when a plate is positioned in nesting 364. into frame 380 and corner brackets 382 is opening 384. Positioned on one side of frame 380 is slit 386. Opening 384 and slit 386 are provided in nest 364 so that an arm 334 of the plate stacker 304 can pass through the nest 364 to place the plates in the nest 364 and pick up the plates from the nest 364. The slot 326 is positioned on the side of the frame 320 through which the arm 334 will pass. Allowing arm 334 to pass through opening 384 and slot 386 of nest 364 allows the board to be easily picked up or placed in nest 364.
[0168] Figure 9A is an isometric view of the plate rack 302 and plate stacker 304 when the spatula 336 is in an initial position. Figure 9B is an isometric view of the plate rack 302 and plate stacker 304 when the spatula 336 has been moved from the home position. Figure 9C is an isometric view of plate rack 302 and plate stacker 304 when spatula 336 is positioned to pick up plate 390A. Figure 9D is a perspective view of plate stacker 304 and plate shuttle 306 when spatula 336 has placed plate 390A in nest 364 of plate shuttle 306. Plate shelf 302 includes frame 310, the plurality of nests 312 (including nest 312A) and rails 314. Each nest 312 includes frame 320, corner brackets 322, aperture 324, and slot 326 (as shown in Figure 6B). Plate stacker 304 includes column 330, screw track 332, arm 334, spatula 336, actuator 338, actuator 340, camera 342, cable carrier 344, and sensor 346. support member 350 and notches 352. Plate shuttle 306 includes support 360, rail 362, nesting 364, support 366, drive mechanism 368, home position sensor 374, and plate sensor 378 Nesting 364 includes frame 380. Plates 390 (including plate 390A) are also shown.
[0169] As shown in Figure 9A, plate stacker 304 is in a home position when arm 334 with spatula 336 is positioned over a top end of plate rack 302. To move arm 334 from home position , actuator 338 will rotate arm 334 and column 330 so that arm 334 is no longer positioned on plate shelf 302. Actuator 340 can then move arm 334 up and down along the platen track. screw 332.
[0170] As shown in Figure 9B, arm 334 has been rotated and moved vertically from the home position. This prepares the plate stacker 304 to pick up a plate from the plate shelf 302. To take a plate from the plate shelf 302, the actuator 340 moves the arm 334 vertically so that the arm 334 is positioned just below a bottom surface. of nesting 312 that contains the plate that is to be picked up. Actuator 338 then rotates arm 334 until spatula 336 is positioned under the plate that is to be gripped. Spaces are left between each nest 312 in plate shelf 302 to allow spatula 336 to move between nests 312.
[0171] As shown in Figure 9C, spatula 336 is positioned under plate 390A in nesting 312A at the bottom end of plate shelf 302. After spatula 336 is rotated to that position, actuator 340 can move arm 334 to top so that the spatula 336 engages and catches the plate 390A positioned in the nesting 312A. Actuator 340 drives screw track 332 to move arm 334 and spatula 336 up to grip plate 390A so that plate 390A no longer touches nesting 312A and so plate 390A and spatula 336 are positioned just above a top surface of the 312A nest. This allows actuator 338 to rotate arm 334 away from plate shelf 302, which thereby moves plate 390A off plate shelf 302. When spatula 336 engages plate 390A in plate shelf nesting 312A 302, spatula 336 and arm 334 traverse opening 324 and slot 326 of nest 312A. Support member 350 engages a bottom side of plate 390A and catches plate 390A from corner brackets 322 of nesting 312A. The notches 352 of the spatula 336 are sized and shaped so that they pass close to the corner supports 322. This allows the spatula 336 to move through the opening 324.
[0172] After the plate 390A has been taken from the plate shelf 302, the arm 334 and the spatula 336 are rotated away from the plate shelf 302 and positioned above the plate shuttle 306. The plate shuttle 306 then moves nesting 364 into a position to receive plate 390A of plate stacker 304. Arm 334 and spatula 336 are then lowered. As arm 334 and spatula 336 are lowered, spatula 336 goes through opening 384 and slot 386 of nest 364. Notches 352 of spatula 336 pass around corner supports 382 of nest 364. nesting 364, each corner of plate 390A on spatula 336 will contact a corner support 382. This will pull plate 390A off spatula 336 as spatula 336 traverses nesting 364 as seen in Figure 9D. Plate shuttle 306 can then move nest 364 into position for aspiration or dispense and instrument 100 can aspirate or dispense a fluid from plate 390A into nest 364.
[0173] After aspiration, plate 390A can be picked up from nesting 364 with arm 334 of plate stacker 304. To pick plate 390A from nesting 364, spatula 336 and arm 334 of plate stacker 304, first, they need to be positioned below the position at which the 390A board will be picked up. Plate shuttle 306 can then move nest 364 so that nest 364 is positioned over spatula 336 and arm 334. Spatula 336 and arm 334 can then be driven up by actuator 340. spatula 336 and arm 334 will pass through nest 364 will engage and catch plate 390A that has been positioned in nest 364. When spatula 336 engages plate 390A in nest 364 of plate shuttle 306, spatula 336 and arm 334 traverse through slot 384 and slot 386 of nest 364 (shown in Figure 8A). Support member 350 engages a bottom side of plate 390A and grips plate 390A from corner supports 382 of nest 364. Notches 352 of spatula 336 are sized and shaped so that they pass close to corner supports 382. This allows the spatula 336 to move through the opening 384.
[0174] After plate 390A has been taken from nesting 364 of plate shuttle 306, arm 334 and spatula 336 can be moved vertically until they are aligned just above a top surface in a nesting 312 on the shelf of 302 board on which the 390A board is to be placed. If the nest 312 in which the plate 390A is to be placed is lower than the nest 364 of the plate hook 306, the plate hook 306 will need to move the nest 364 out of the way before the arm 334 and spatula 336 can be moved vertically to a position just above a top surface of a nest 312 in plate shelf 302. Once arm 334 and spatula 336 are aligned just above a nest 312 in plate shelf 302, actuator 338 can rotate the arm 334 and spatula 336. This will position arm 334 and spatula 336 just above a top surface of nesting 312 where plate 390A is to be placed. Actuator 340 can then lower arm 334 and spatula 336. This will cause arm 334 and spatula 336 to go through opening 324 and slot 326 of nest 312. As spatula 336 traverses nest 312, each The corner of plate 390A on spatula 336 will contact a corner support 322. This will pull plate 390A off spatula 336 as spatula 336 traverses nesting 312. Spatula 336 will then be positioned just below a bottom surface of the nesting 312 and actuator 338 can rotate spatula 336 and arm 334 off plate shelf 302.
[0175] Plate shelf 302 can hold any number of plates 390. When a plate 390 is needed, plate stacker 304 can use camera 342 to determine which plate 390 the arm 334 should engage with. This allows a user to place boards 390 into nests 312 of board shelf 302 in any order. This is advantageous as it allows for great flexibility with the use of instrument 100. A user does not need to determine the test order before configuring instrument 100, as instrument 100 will be able to select and move plates 390 in any order.
[0176] The plate stacker assembly 110 is additionally advantageous, as the arm 334 and spatula 336 provide contact and firm engagement with the plates on instrument 100. Prior art systems grip plates with a robotic arm to move them on instrument 100. Picking up plates 390 with spatula 336 provides better contact with plates 390, which ensures that plates 390 will move through instrument 100 without being dropped. This makes the 110 plate stacker assembly more reliable than prior art systems.
[0177] The plate stacker assembly 110 is also advantageous in that it allows rotary movement and vertical movement about a common z-axis. This movement around a common geometric z axis allows the plate stacker assembly 110 to have a compact design. This saves space on instrument 100 while still allowing a large range of motion to move plates on instrument 100. SUPPORT PLATE ASSEMBLY
[0178] Figure 10 is an isometric view of the support plate assembly 112 within the instrument 100. The support plate assembly 112 includes the support plate station 402, the support plate station 404 and the plate station Plate Holder Station 406. Plate Holder Station 402, Plate Holder Station 404, and Plate Holder Station 406 hold plates or shelves that contain reagents (reagent plates). Dispense assembly 114 of instrument 100 dispenses reagents on tape 104 which proceeds through instrument 100. In alternative embodiments, support plate station 402, support plate station 404 and support plate station 406 can be used to receive and retain plates or shelves that contain biological samples. In alternative embodiments, support plate assembly 112 may include a single support plate station, two support plate stations, or four or more support plate stations.
[0179] Figure 11A is a partially transparent isometric view of the support plate station 406. Figures 11B to 11D are perspective views of the support plate station 406. As shown in Figures 11A to 11D, the support plate station bracket 406 includes housing 408, bracket cover 410 (shown transparent in Figure 11A) with Al position 412, thermoelectric modules (TEMs) 414, temperature sensor 416, spring-loaded clamp 418, retainer 420 with trefoil leaf pattern 422, the pivot 424, the locking boss 426, the drain port 428, the fluid inlet port 430, the fluid outlet port 432, the retaining height adjustment screw 434, the mirror 474 and camera 476. In the embodiment shown in Figures 11B and 11D, plate 442 with wells 444 rests on support cover 410. In an alternative embodiment shown in Figure 11C, shelf 446 with the plurality of matrix tubes 448 rests on the support coverage 410. The plurality of 448 die tubes includes releasable caps. In alternative embodiments, any suitable plate or shelf can rest on support cover 410. Camera 476 captures an image of a barcode on plate 442 or shelf 446 using mirror 474 (see Figure 16 for more details).
[0180] Housing 408 surrounds support cover 410. TEMs 414 and temperature sensor 416 are located under support cover 410. TEMs 414 provide thermal management of support cover 410. For example, when board 442 is placed on the support cover 410, the support cover 410 can cool the plate 442 to a desired temperature. Plate 442 can be a plate that contains reagents in wells 444, and support cover 410 can cool plate 442 to prevent reagents in wells 444 from denaturing, degrading, or otherwise reacting. Temperature sensor 416 provides feedback to maintain support cover 410 at a desired temperature. Fluid inlet port 430 and fluid outlet port 432 are connected to thermal management system 240 of instrument 100 to provide a heat sink for TEMs 414 (see Figures 13 through 14 for more details).
[0181] Plate 442 is secured and aligned at position Al 412 on support cover 410 with spring loaded clip 418. Spring loaded clip 418 is secured to support cover 410 and can be retracted in order to place the plate 442 on the support cover 410. The spring-loaded clip 418 includes a spring that allows the spring-loaded clip 418 to secure the plate 442 on the support cover 410. When the plate 442 is placed on the support cover 410, the clip is loaded spring 418 holds plate 442 so that a first concavity of wells 444 is aligned at position A1 412. Aligning plate 442 at position A1 412 aligns wells 444 of plate 442 so that the trefoil leaf pattern holes 422 line up with wells 444 of plate 442 so that the dispense assembly 114 of instrument 100 can accurately locate wells 444 and aspirate the contents of wells 444 of plate 442. Drain 428 is located in housing 408. plate 442 for cooled in support cover 410, condensation can accumulate on plate 442 and support cover 410. Housing 408 is shaped with an angled through hole so that condensation is directed away from plate 442 and support cover 410 and exits support plate station 406 through drain 428.
[0182] Retention 420 is in the open position in Figures 11B and 11C and in the closed position in Figure 11D. When retainer 420 is in the open position, plate 442 or shelf 446 can be placed in support plate station 406. When retainer 420 is in the closed position, plate 442 or shelf 446 is secured to support cover 410 and the contents of wells 444 or the plurality of matrix tubes 448 can be drawn from plate 442. Plate 442 can include a seal over each recess 444. Dispense assembly 114 of instrument 100 uses spikes to break the seal over each recess 444 and aspirating a reagent from each well 444. Retainer 420 secures plate 442 to support cover 410 so that plate 442 is not lifted from support plate station 406 when the tips are retracted after they have punched through the copper seal. each concavity 444.
[0183] Pivot 424 is connected to detent 420 and allows a user to manually rotate detent 420 between the open position and the closed position. Latch boss 426 attaches to pivot 424 and allows a user to manually secure detent 420 in the open or closed position. In the embodiment shown, locking boss 426 is a spring-loaded retractable plunger. In order to lock or unlock the detent 420 and move the detent 420 to the open or closed position, the user pulls the locking boss 426 away from the pivot 424, turns the locking boss 426 in half rotation, rotates the detent 420 to up or down to open or closed position, flips locking boss 426 into half detent and releases locking boss 426.
[0184] Retainer 420 includes trefoil leaf pattern 422 to accommodate variations in wells 444 of plate 442 and the plurality of matrix tubes 448 of shelf 446. Trefoil leaf pattern 422 includes 96 patterned holes four-leaf clover. In the embodiment shown in Figure 11D, plate 442 includes 96 wells. When retainer 420 is in the closed position, as shown in Figure 11D, the center of each four-leaf trefoil-shaped hole of trefoil-leaf pattern 422 is aligned with one of the wells 444 so that each recess 444 is accessible for the dispensation. In an alternative embodiment, plate 442 can include 384 wells. In this alternative embodiment, when the retainer 420 is in the closed position, each leaf of each four-leaf trefoil-shaped hole of the trefoil leaf pattern 422 is aligned with one of the wells 444 so that each recess 444 is accessible for dispensing .
[0185] Figures 12A and 12B are partially transparent perspective views of support plate station 406. Support plate station 406 includes housing 408, support cover 410, spring loaded clamp 418, retainer 420 with trefoil leaf pattern 422, pivot 424, locking boss 426, fluid outlet port 432, retaining height adjustment screw 434, rail clamp nut 436, guides 460, and rail 464 (shown partially transparent in Figures 12A and 12B).
[0186] Detent height adjustment screw 434 is attached to rail clamp nut 436. Rail clamp nut 436 is installed in a groove of rail 464 so that the rail clamp nut can slide freely. Rail clamp nut 436 and detent height adjustment screw 434 cooperate with track clip 464 against one of guides 460 to maintain detent 420 at a desired height. Retainer Height Adjustment Screw 434 allows the user to manually adjust the height of the retainer 420 up and down to accommodate different heights of the plate 442 or shelf 446 and to vary how tightly the retainer 420 is attached to the plate 442 or shelf 446.
[0187] When a user loosens the detent height adjustment screw 434 (using, for example, a hex wrench), the rail clamp nut 436 releases the rail 464 so that the user can manually adjust the height of the hold 420 up or down. The rail 464 slides up and down within the guides 460. Once the desired height is selected based on the height of the plate 442 or shelf 446, the user tightens the detent adjustment screw 434 to secure the detent position. 420. As the detent adjustment screw 434 is tightened, the rail clamp nut 436 pulls the rail 464 into one of the guides 460 to secure the detent 420 at the desired height. Retainer 420 is held in place on plate 442 or shelf 446 with friction and gravity.
[0188] Figure 13 is a partially transparent isometric view from below of support plate station 406. Support plate station 406 includes housing 408, support cover 410, retainer 420 with sheet pattern of trefoil 422, locking boss 426, fluid inlet port 430, fluid outlet port 432, guides 460, and jacket 466 with fluid path 468.
[0189] Sleeve 466 with fluid path 468 is located under support cover 410 (shown in Figures 11A through 11D). TEMs 414 are located between jacket 466 and support cover 410. Housing 408 surrounds jacket 466. Fluid path 468 is connected to thermal management system 240 of instrument 100 through fluid inlet port 430 and the fluid outlet port 432.
[0190] Figure 14 is a bottom view of the support plate station 406. The support plate station includes the housing 408, the TEMs 414 (shown in dashed line), the fluid inlet port 430, the port outlet 432 and jacket 466 with fluid path 468. As shown in Figures 13 and 14, fluid flows through fluid path 468 to provide thermal management such as cooling and can create a heat sink for the heat generated by the TEMs 414.
[0191] Fluid path 468 is a cavity that snakes back and forth within jacket 466. Fluid, as cooling water, enters fluid path 468 through fluid inlet port 430, goes through fluid path 468. fluid 468 and exits fluid path 468 through fluid outlet port 432. Jacket 466 with fluid path 468 provides a heat sink that removes heat generated by TEMs 414 when TEMs 414 operate to cool the cover of support 410. Housing 408 is made of a phenolic material to provide insulation so that heat from TEMs 414 does not reach support cover 410. In alternative embodiments, housing 408 can be made of any other insulating material.
[0192] Figure 15 is a partially transparent side view of support plate station 406. Support plate station 406 includes housing 408, drain port 428, retainer 420, pivot 424 and limit switch 470. Limit switch 470 detects the position of detent 420, including whether detent 420 is in the open position or in the closed position (Figures 11B and 11D). Limit switch 470 provides a signal for instrument 100 to prevent other assemblies such as dispense assembly 114 from extending onto support plate station 406.
[0193] Figure 16 is a side view of the support plate station 406 of the support plate assembly 112 within the instrument 100. The support plate station 406 represents the support plate station 402 and the support plate station bracket 404. Bracket plate station 406 includes housing 408, retainer 420, plate 442 with barcode 472, mirror 474, and camera 476. Also shown in Figure 16 is camera path P.
[0194] Barcode 472 is located on plate 442. Barcode 472 identifies the contents of plate 442. Plate 442 is positioned on support plate assembly 406 so that barcode 472 is reflected in the mirror 474. Camera path P shows the path from barcode 472 to camera 476. Camera 476 is positioned so that camera 476 captures the image of barcode 472 reflected in mirror 474. Camera 476 captures the barcode image 472, which allows instrument 100 to identify the contents of plate 442. TAPE PATH ASSEMBLY
[0195] Figure 17A is an isometric view of the tape path assembly 118 on instrument 100. Figure 17B is a front isometric view of the tape path assembly 118. The tape path assembly 118 includes the first position 130, second position 132, third position 134, fourth position 136, tape feed 510, tape spool 512, drive mechanism 514, tape cutter 516, lift mechanism 518, a retractable retainer 520, and the covers 522. The covers 522 include the tape take-up ends 524. The tape path assembly 118 also includes the ENT inlet on a first end and the EXT outlet on a second end. Also shown in Figure 17B is tape 104.
[0196] The tape path assembly 118 extends through the instrument 100 and provides a path along which the tape 104, which has a plurality of wells, can advance. Tape 104 moves through instrument 100 from the ENT input to the EXT output of the tape path assembly 118 through the different positions in the tape path assembly 118. The first position 130 is positioned between the ENT input and the second position 132 ; second position 132 is positioned between first position 130 and third position 134; third position 134 is positioned between second position 132 and fourth position 136; and the fourth position 136 is positioned between the third position 134 and the EXT output. The different functions are completed at each position along the tape path assembly 118.
[0197] Tape feed 510 is positioned adjacent to the ENT input and can be extended to a loading position (not shown in Figures 17A to 17B) to load tape spool 512. Tape feed 510 can be retracted then , to the retracted position R, where the tape feed 510 and tape spool 512 can be closed within the instrument 100. In the retracted position R, the tape 104 can be driven towards the ENT input and advanced along the path of tape 118 toward the EXT output. Thus, tape feed 510 enables manual loading of tape reel 512, while tape 104 can be automatically advanced into instrument 100, which reduces the likelihood of well contamination. Tape feed 510 also enables continuous feeding of a desired length of tape 104 for processing and analysis. Specifically, tape 104 is guided between the ENT input and the EXT output, tape 104 can be cut to a desired length, processed and analyzed along a single compact path.
[0198] After tape 104 has been fed into tape path assembly 118 with tape feed 510, tape 104 can advance to first position 130. Tape 104 automatically advances along tape path assembly 118 with the use of drive mechanism 514. Drive mechanism 514 is positioned under a top surface of tape path assembly 118 and includes a belt that can be used to drive tape 104 along tape path assembly 118. At first position 130, tape 104 can be cut with tape cutter 516 so that any number of arrays of wells can advance through instrument 100, including a segment of tape with a single array of wells. Alternatively, tape 104 may advance as a web through first position 130 without being cut. At second position 132, the dispensing assembly 114 (not shown in Figures 17A through 17B) can dispense a biological sample and a reagent on tape 104 to form a biological sample and a mixture of reagents. Additionally, tape seal assembly 120 (not shown in Figures 17A to 17B) can be positioned adjacent to second position 132 to seal the biological sample and reagent mixture on tape 104. Positioned below second position 132 and fourth position 136 is the lifting mechanism 518. The lifting mechanism 518 raises the second position 132 and the fourth position 136 when the tape 104 is held in a stationary position in the tape path assembly 118, but can lower the second position 132 and the fourth position 136 when tape 104 is advanced along the tape path assembly 118. Positioned adjacent to second position 132 and over third position 134 is retractable detent 520. Retractable detent 520 may extend toward second position 132 to retain tape 104 flat while in second position 132 during dispensing. Tape 104 can also be cooled at second position 132 to prevent the biological sample and reagent mixture from undergoing a chemical reaction, or tape 104 can be heated at second position 132 to incubate the biological sample and reagent mixture. . At third position 134, tape 104 can again be cooled to prevent the biological sample and reagent mixture from being subjected to a chemical reaction or heated to incubate the biological sample and reagent mixture. At third position 134, tape 104 can be held in place while tape 104 downstream of third position 134 is processed at fourth position 136. At fourth position 136, the biological sample and reagent mixture in tape 104 can be amplified and analyzed using the detection assembly 122 (not shown in Figures 17A to 17B) which is positioned adjacent to the fourth position 136. The biological sample and reagent mixture can be subjected to thermal oscillation or heated to a constant temperature in the fourth position 136 with the detection assembly 122. The detection assembly 122 additionally includes a camera (not shown in Figures 17A to 17B) that can be used to analyze the biological sample and reagent mixture in tape 104. Thus, the assembly Tape path length 118 has a compact design, which makes the instrument suitable for use in a variety of different configurations.
[0199] Covers 522 are located above first position 130, above third position 134 and between fourth position 136 and the EXT output. Covers 522 may extend the width of ribbon 104 and include ribbon receiving ends 524 at a first end of each covering 522. Covers 522 may be V-shaped at ribbon receiving ends 524. In the embodiment shown in Figures 17A to 17B, covers 522 are made of stainless steel. In alternative embodiments, covers 522 can be made of any suitable material. Covers 522 can prevent tape 104 from bending up out of the tape path assembly 118.
[0200] Figure 18A is an isometric front view of the tape path assembly 118 with the tape feed 510 in a retracted position R. Figure 18B is an isometric front view of the tape path assembly 118 seen in Figure 18A with tape feed 510 at an extended position E. Tape path assembly 118 includes first position 130, second position 132, third position 134, fourth position 136, tape feed 510, and tape spool 512 The tape path assembly 118 also includes ENT input on a first end and EXT output on a second end. Also shown in Figures 18A through 18B is tape 104.
[0201] The 510 tape feed is adjacent to the ENT input. When tape feed 510 is in the retracted position R (as shown in Figure 18A), tape 104 is advanced from tape spool 512 through tape feed 510 towards first position 130 by a plurality of rollers (not shown in detail in Figures 18A to 18B). When the tape feed 510 is in the extended position E (as shown in Figure 18B), the tape spool 512 that holds the tape 104 can be loaded into the tape feed 510. In this way, the tape 104 can be manually loaded into the instrument 100, but automatically advanced along the tape path assembly 118 by tape feed 510.
[0202] Figure 19A is a rear perspective view of the tape path assembly 118 with drive mechanism 514. Figure 19B is an isometric rear view of drive mechanism 514. Figure 19C is a perspective view of one of the rollers 550 of the tape path assembly 118. The tape path assembly 118 includes first position 130, second position 132, third position 134, fourth position 136, drive mechanism 514, and covers 522 Drive mechanism 514 includes axle 532, guide wheel pulleys 536, drive belts 538, actuator 540, actuator drive pulleys 542, guide wheel guide pulleys 544, rollers 550 and springs 552. The tape path assembly 118 also includes the ENT inlet on a first end and the EXT outlet on a second end. Also shown in Figure 19A is tape 104.
[0203] Tape 104 advances along tape path assembly 118 through instrument 100 via drive mechanism 514. Drive mechanism 514 includes guide wheel pulleys 536 positioned near the ENT inlet of the path assembly of tape 118. Guide wheel pulleys 536 are mounted on each side of the tape path assembly 118. Drive mechanism 514 also includes actuator drive pulleys 542 and guide wheel guide pulleys 544 positioned close together. to the EXT output of tape path assembly 118. Actuator drive pulleys 542 and idler guide pulleys 544 are mounted on each side of tape path assembly 118. Actuator drive pulleys 542 are connected one another with axle 532. Drive belts 538 extend between and wrap around actuator drive pulleys 542 and guide wheel pulleys 536. action 538 aligned with actuator drive pulleys 542 and guide wheel pulleys 536. In the embodiment shown, there are two guide wheel pulleys 536, two actuator drive pulleys 542, four guide wheel guide pulleys 544 and two drive belts 538. A guide wheel pulley 536, an actuator drive pulley 542, two guide wheel guide pulleys 544, and a drive belt 538 are each positioned between a front side and one side. rear of the tape path assembly 118 and are positioned parallel to approximately a width of the tape 104. On each side, the actuator drive pulley 542 is aligned with the guide wheel pulley 536 so that the drive belt 538 can wrap around each of the actuator drive pulley 542 and the idler pulley 536.
[0204] Drive belts 538 are driven by actuator 540. Actuator 540 is attached to shaft 532. Shaft 532 extends between actuator drive pulleys 542. In the embodiment shown in Figures 19A through 19C, actuator 540 is a motor. In alternative embodiments, actuator 540 may actuate drive belts 538 with any suitable mechanism such as an electric motor, pneumatic motor, or hydraulic motor. Actuator 540 rotates shaft 532 and actuator drive pulleys 542, which transfer motion to drive belts 538. Drive belts 538 move around idler pulleys 536, drive pulleys 542, and of the guide wheel guide pulleys 544. The guide wheel guide pulleys 544 keep the drive belts 538 in line with the actuator drive pulleys 542 and the guide wheel pulleys 536.
[0205] Rollers 550 are located along both sides of the tape path assembly 118 between the ENT inlet and the EXT outlet. Rollers 550 are located directly above drive belts 538. As shown in Figure 19C, rollers 550 are spring loaded with springs 552. Springs 552 hold rollers 550 in compression against drive belts 538. Tape 104 is positioned between the rollers 550 and the drive belts 538. The drive belts 538 are driven, the tape 104 will move with the drive belts 538 along the tape path assembly 118 due to friction between the tape 104 and the drive belts 538. The rollers 550 hold the tape 104 securely against the drive belts 538 as the tape 104 is advanced along the tape path assembly 118. Additionally, the covers 522 keep the tape 104 flat along the tape path assembly 118 and maintain contact with drive belts 538. Tape 104 is thus driven through instrument 100 along tape path assembly 118 by friction.
[0206] Figure 20A is a front plan view of the tape feed 510 on the tape path assembly 118. Figure 20B is an isometric front view of the tape feed 510 on the tape path assembly 118. The tape feed 510 includes driven rollers 560, first tension rollers 562, actuator 564, pulley 566, drive belt 568, transfer rollers 570, extender portion 572, extender portion rollers 574, and second tension rollers 576. The 118 tape path assembly also includes the ENT input. Also shown in Figure 20B is tape 104.
[0207] Tape feed 510 is fixed to tape path assembly 118 adjacent to ENT input. The driven rollers 560, the first tension rollers 562, the transfer rollers 570, the stretch-portion rollers 574 and the second tension rollers 576 all comprise a pair of rollers that are parallel to each other approximately in the width of the tape. 104. The driven rollers 560 comprise sticky rollers connected to the tape path assembly 118 upstream of the first position 130. The first tension rollers 562 are positioned on top of the driven rollers 560 and can be weighed, tensioned with springs or otherwise compacted. mode against driven rollers 560. Driven rollers 560 are driven by actuator 564. In this mode, actuator 564 is a motor. In alternative embodiments, actuator 564 can drive driven rollers 560 with any suitable mechanism such as an electric motor, pneumatic motor, or hydraulic motor.
[0208] The actuator 564 is connected to the driven rollers 560 via the pulley 566 and the drive belt 568. The transfer rollers 570 are positioned upstream of the driven rollers 560 so as to be in contact with the driven rollers 560. In this embodiment, the transfer rollers 570 are held in tension against the spring-actuated rollers 560. In alternative embodiments, transfer rollers 570 may be held in tension against driven rollers 560 with any suitable mechanism. The extensible portion 572 is positioned upstream of the transfer rollers 570. The extensible portion 572 comprises the extensible portion rolls 574 and the second tension rolls 576. The rolls of the second tension rolls 576 are positioned on top of rolls of the extensible portion 574 and can be weighed, tensioned with springs, or otherwise compacted against the rolls of the extensible portion 574. The rolls of the extensible portion 574 are positioned so that when the extensible portion 572 is in a retracted position (as shown in Figure 20A ), the stretch portion rollers 574 contact the transfer rollers 570. When the stretch portion 572 is in an extended position, the stretch portion rollers 574 do not contact the transfer rollers 570.
[0209] When the stretch portion 572 is in an extended position, the tape spool 512 holding the tape 104 can be manually loaded into the stretch portion 572. The tape 104 can then be manually advanced and fed between the portion rolls extender 574 and second tension rollers 576, which are configured to capture and hold the leading edge of tape 104. When extender portion 572 is in a retracted position, actuator 564 can rotate driven rollers 560 via pulley 566 and of the drive belt 568. The motion of the driven rollers 560 is transferred to the stretch-portion rollers 574 via the transfer rollers 570. The motion of the driven rollers 560 transferred to the stretch-portion rollers 574 advances the ribbon 104 until the tape 104 is captured between the driven rollers 560 and the first tension rollers 562, which further advances the tape 104 along the tape path assembly 118. the 512 holding the tape 104 can be manually loaded outside the instrument, while the tape 104 can be automatically advanced into the instrument, which simplifies loading the tape reel 512 with the tape 104.
[0210] Figure 21 A is a rear perspective view of the tape cutter 516 in the tape path assembly 118. Figure 21 B is a front side plan view of the tape cutter 516 having the movable blade 580 in a retracted position. Figure 21C is a front side plan view of the tape cutter 516 having the movable blade 580 in an extended position. Figure 21D is a plan view of the ENT inlet of the tape path assembly 118 with the tape cutter 516 having the movable blade 580 in a retracted position. Figure 21E is a partially transparent plan view at the ENT inlet of the tape path assembly 118, with the tape cutter 516 having the movable blade 580 in an extended position. Tape path assembly 118 includes first position 130, driven rollers 560, first tension rollers 562, and tape cutter 516. A tape cutter 516 includes sensor 578, movable paddle 580, actuator 582, the tape clip 584 with the sticky end 586, the fixed paddle 588, the guard 590, the fixed paddle assembly 592, the movable paddle assembly 594, and the ball spring detents 596. The tape path assembly 118 also includes the ENT input. Also shown in Figures 21A through 21E is tape 104.
[0211] Tape cutter 516 is located just before the first position 130 and adjacent to the ENT input. Tape 104 can be cut with tape cutter 516 or tape 104 can pass through tape cutter 516 without being cut. Tape 104 is advanced along the tape path assembly 118, between first tension rollers 562 and driven rollers 560. Sensor 578 senses when tape spool 512 (shown in Figures 18A through 18B) is out of tape 104. As tape 104 passes between movable paddle 580 and fixed paddle 588, a sensor (not shown) located downstream of tape cutter 516 can monitor the position of tape 104 to indicate to actuator 582 when a desired tape length 104 has passed between movable paddle 580 and fixed paddle 588. Actuator 582 can then drive movable paddle 580 upward to cut tape 104. In the embodiment shown in Figures 21A through 21E, actuator 582 is a linear actuator. In alternative embodiments, actuator 582 can drive movable paddle 580 with any suitable mechanism. The 594 movable shovel mount can rotate slightly against a single point. Ball spring detents 596 are positioned against a bottom end of movable paddle 580 and give movable paddle 580 a slight angle relative to fixed paddle 588. This slight angle of movable paddle 580 improves cutting with movable paddle 580.
[0212] Tape clip 584 is spring loaded and moves up with movable paddle 580. Tape clip 584 is configured to contact tape 104 before movable paddle 580. The sticky end 586 of the tape clip 584 positively holds tape 104 against a bottom surface of fixed paddle assembly 592 while tape 104 is being cut between movable paddle 580 and fixed paddle 588. As movable paddle 580 is driven upward, the protective device is loaded by spring 590 is retracted to allow the movable paddle 580 to cross the fixed paddle 588 and cut the tape 104. After the tape 104 has been cut, the movable paddle 580 retracts with the tape clip 584 and the protective device 590 sec. extends to contact a side surface of the fixed blade assembly 592. In this way, the tape cutter 516 can easily cut the tape 104 to a desired length.
[0213] Figure 22A is a partially transparent front perspective view of the lift mechanism 518. Figure 22B is a plan view of the lift mechanism 518. The lift mechanism 518 includes the platform 600, the axle 604, the first link 606, second link 608, actuator 610, drive pulley 612, timing pulley 614, and drive belt 616. Lifting mechanism 518 is positioned under a top surface of tape path assembly 118. Platform 600 is raised and lowered with axle 604. axle 604 connects platform 600 with first link 606 and second link 608.
[0214] Lifting mechanism 518 is actuated with actuator 610. Actuator 610 can be a motor, such as an electric motor, a pneumatic motor, or a hydraulic motor. Actuator 610 is connected to and can rotate a drive pulley 612. Timing pulley 614 is positioned on shaft 604. Drive belt 616 extends between and wraps around drive pulley 612 and timing pulley 614. As actuator 610 rotates drive pulley 612, drive belt 616 will move with drive pulley 612 and will rotate timing pulley 614. As timing pulley 614 is rotated, timing pulley 614 rotates shaft 604 , which moves the first link 606 and the second link 608 which then move the platform 600. In this way, the actuator 610 can move the platform 600 up and down. Platform 600 can be actuated up and down to move portions of the tape path assembly 118 up and down.
[0215] Figure 23A is a front plan view of the lift mechanism 518 on the tape path assembly 118 in a retracted position. Figure 23B is a front plan view of the lift mechanism 518 on the tape path assembly 118 in an extended position. Tape path assembly 118 includes second position 132, third position 134, fourth position 136, and lift mechanism 518. Lift mechanism 518 includes platform 600, shaft 604, first link 606 (shown in Figures 22A through 22B), second link 608 (shown in Figures 22A through 22B), actuator 610, drive pulley 612, timing pulley 614, and drive belt 616. Also shown in Figures 23A through 23B is the tape level T.
[0216] Lifting mechanism 518 is located under the tape level T of the tape path assembly 118. Platform 600 is positioned under second position 132, third position 134 and fourth position 136. Platform 600 is spun. to the third position 134. When the tape 104 (not shown in Figures 23A to 23B) is advanced to the second position 132 or the fourth position 136, the lifting mechanism 518 can be actuated upward to raise the second position 132 and the fourth position 136 for tape level T. Platform 600 is raised and lowered with axle 604 extending between first link 606 and second link 608. In alternative embodiments, platform 600 may be split to allow portions under the second link position 132 and fourth position 136 are raised and lowered separately.
[0217] Lifting mechanism 518 is driven by actuator 610. Actuator 610 rotates drive pulley 612, which in turn rotates timing pulley 614 on shaft 604 with belt 616. Thus, platform 600 can be driven up (as seen in Figure 23B) so that second position 132 and fourth position 136 are at tape level T. This holds tape 104 as tape 104 is processed at second position 132 and fourth position 136.
[0218] Figure 24 is a front perspective view of thermal units 620 and 622 in the tape path assembly 118. The tape path assembly 118 includes the second position 132, the third position 134, the thermal unit 620, and the thermal unit 622. Thermal unit 620 includes 624 thermoelectric modules (TEMs). Thermal unit 622 includes 626 TEMs.
[0219] Thermal units 620 and 622 are positioned in the tape path assembly 118. Thermal unit 620 is positioned in second position 132 and thermal unit 622 is positioned in third position 134. In the embodiment shown in Figure 24, the unit thermal 620 includes two TEMs 624 and thermal unit 622 includes two TEMs 626. In alternative embodiments, thermal units 620 and 622 can include any number of TEMs 624 or 626, or any other mechanism capable of heating or cooling second position 132 and the third position 134. When heating or cooling is required, electricity flows through TEMs 624 and 626 in one direction for heating and in the other direction for cooling. This allows thermal units 620 and 622 to both cool and heat the biological sample and reagent mixture on strip 104 at second position 132 and third position 134.
[0220] Figure 25 is a bottom view of fluid paths 630 and 640 in tape path assembly 118. Tape path assembly 118 includes second position 132, third position 134, fourth position 136, thermal unit 620, thermal unit 622, fluid path 630, inlet port 632, outlet port 634, fluid path 640, inlet port 642, and outlet port 644.
[0221] Fluid paths 630 and 640 are positioned in tape path assembly 118. Fluid path 630 is positioned in second position 132 and fluid path 640 is positioned in third position 134. Fluid path 630 is positioned in second position 132. connected to input port 632 on a first end and output port 634 on a second end. Fluid path 640 is connected to inlet port 642 at a first end and outlet port 644 at a second end. Fluid paths 630 and 640 are cavities that curve back and forth under second position 132 and third position 134. Fluid from a reservoir (not shown in Figure 26) can be delivered to fluid paths 630 and 640 through input ports 632 and 642, respectively. That fluid then can flow through fluid paths 630 and 640 to exchange heat with components positioned above fluid paths 630 and 640 at second position 132 and third position 134, respectively. Fluid in fluid paths 630 and 640 can then flow out through outlet ports 634 and 644, respectively. Directing the fluid under the second position 132 and the third position 134 in this way allows the space on the top surface of the second position 132 and the third position 134 to hold components that require regulated temperatures.
[0222] Figure 26A is a partially transparent side view of the retractable detent 520. Figure 26B is a rear perspective view of the retractable detent 520 in the tape path assembly 118 with the retractable detent 520 in a retracted position. Figure 26C is a rear perspective view of the retractable detent 520 in the tape path assembly 118 with the retractable detent 520 in an extended position. Tape path assembly 118 includes second position 132, third position 134, fourth position 136, and retractable detent 520. Retractable detent 520 includes roller 650, arm 652, track roller 654, track 656 , air cylinder 658, inlet port 660, inlet port 662, and bars 664.
[0223] The retractable detent 520 is positioned over the third position 134 and can be moved between an extended and retracted position. Retractable detent 520 includes roll 650 secured to a first end of arm 652. When retractable detent 520 is in an extended position, arm 652 can be extended outward and downward so that roll 650 can retain tape 104 at second position 132. A second end of arm 652 is secured to track roller 654. Track roller 654 is positioned and rolls along track 656 to move arm 652 and roller 650 between an extended and retracted position.
[0224] Retractable Detent 520 additionally includes Air Cylinder 658. Inlet Port 660 and Inlet Port 662 are secured to Air Cylinder 658. Air can flow through Inlet Port 660 and Inlet Port 662 to air cylinder 658. A first end of bars 664 is positioned on air cylinder 658. Bars 664 slide in and out of air cylinder 658, which moves air cylinder 658 between a retracted and extended position. . A second end of bars 664 is secured to arm 652.
[0225] To move the retractable detent 520 from a retracted to an extended position, air may flow through inlet port 660 to air cylinder 658. As air from inlet port 660 flows to air cylinder 658 , it causes bars 664 to extend outward from air cylinder 658. This causes track roller 654 to slide along track 656 so that arm 652 can move to an extended position. Track 656 has a first end that is positioned at an elevation that is lower than the elevation of a second end of track 656. As track roller 654 moves from the first end to the second end of track 656, the second end of arm 652 will be pulled up. This, in turn, causes the first end of arm 652 to be driven downward. This movement can force roll 650 at the first end of arm 652 down against tape 104 and/or into second position 132 of tape path assembly 118.
[0226] To move the retractable detent 520 from an extended position to a retracted position, air can flow through inlet port 662 to air cylinder 658. As air from inlet port 662 flows to air cylinder 658, it causes bars 664 to retract back to air cylinder 658. This causes track roller 654 to slide along track 656 so that arm 652 can move to a retracted position. This movement will cause roller 650 at the first end of arm 652 to move upward from tape 104 and/or to second position 132 of tape path assembly 118.
[0227] When a leading edge, positioning hole, or other marking identifying tape 104 (not shown) is detected by a sensor positioned along tape path assembly 118, the retractable retainer 520 may extend roll 650 to retain the leading edge or an intermediate portion of the tape 104. The tape 104 can be processed when the retractable retainer roller 650 520 is extended. After tape 104 is processed, retractable retainer 520 can retract and allow tape 104 to be processed or advanced further to third position 134. For example, roll 650 can be extended to retain tape 104 in second position 132 while tape 104 is being dispensed. After tape 104 has been dispensed, roll 650 can be retracted and a sealing operation can be performed. In this way, multiple operations, such as dispensing and sealing, can be performed on the same portion of tape 104 at the same location, which reduces the overall size of the instrument 100.
[0228] Figure 27 is a perspective view of the rewind assembly 108. The rewind assembly 108 can be attached to the trolley assembly 101 and aligned with the tape path assembly 118 to accumulate the processed tape exiting the carriage assembly. tape path 118 (see Figures 1B to 1C). Rewind assembly 108 includes mounting bracket 670, motor 672, shaft 674, spool 676, retainer clips 678, and spool retainer 680.
[0229] Mounting bracket 670 secures rewind mount 108 to cart mount 101 (see Figures 1B to 1C). Motor 672 is secured to shaft 674. Shaft 674 mechanically engages spool 676. Reel 676 is secured to shaft 674 with spool retainer 680. tape path 118. Once tape 104 begins to exit the tape path assembly 118, tape 104 is secured to spool 676 using tape or other securing means. Rotation of motor 672 causes spool 676 to rotate and accumulate tape 104 on spool 676. After all of the tape 104 arrangements are complete, tape 104 is secured to spool 676 with retainer clips 678. can be removed from rewind assembly 108 by removing spool cap 680 and sliding spool 676 off shaft 674. DISPENSING ASSEMBLY
[0230] Figure 28 is an isometric view of the instrument 100 with the dispensing assembly 114. The dispensing assembly 114 includes the lashing bridge x axis track 702, the lashing bridge y axis track 704, the dispensing housing 706; and the dispensing head 708. The jib 702 axis track x includes actuator 710, drive belt 712, and cable carrier 714. 704 includes actuator 716, drive belt 718, and cable carrier 720. Actuator 710 is attached to drive belt 712, and actuator 716 is attached to drive belt 718.
[0231] Mooring gantry x axis track 702 and tie gantry y axis track 704 allow the dispensing box 706 and dispensing head 708 to move in the x and y directions within the instrument 100. A Mooring gantry y-axis track 704 is connected to cable carrier 714. Dispensing box 706 is situated on top of berthing gantry y-axis track 704 and is connected to dispensing head 708 and to the lashing carrier. cable 720. Cable carrier 714 and cable carrier 720 guide the wiring and tubing that go to dispensing box 706 and dispensing head 708. Dispensing head 708 is situated below the easel y axis track. lashing 704. Dispensing box 706 and dispensing head 708 can move simultaneously along lashing easel y axis track 704.
[0232] In order to move the lashing gantry y axis track 704 with the dispensing box 706 and the dispensing head 708 in the x direction along the lashing gantry x axis track 702, the actuator 710 drives drive belt 712. Drive belt 712 moves slack gantry y-axis track 704 along slack gantry x-axis track 702. Cable carrier 714 includes a stationary end that does not fall apart. moves and one end attached to the Mooring Trestle Y-axis track 704 which moves along with the Mooring Trestle Y-axis track 704. The Cable Carrier 714 retains all the cabling and tubing necessary for the dispensing assembly 114 properly aligned when the lashing gantry y axis track 704 moves along the lashing gantry x axis track 702. In the embodiment shown, the actuator 710 is servo motor, and the axis rotation position of the servo motor is controlled by instrument control systems 100, including industrial PC and associated interface cards in electronic assembly 124.
[0233] In order to move the dispensing box 706 and the dispensing head 708 in the y direction along the y-axis track of tie bar 704, the actuator 716 drives the drive belt 718. The drive belt 718 moves dispensing box 706 and dispensing head 708 along tie gantry Y axis track 704. Cable carrier 720 includes a stationary end that does not move and an end secured to dispensing box 706 that moves moves along with dispensing box 706. Cable carrier 720 keeps all cables and tubing necessary for dispensing assembly 114 properly aligned when dispensing box 706 and dispensing head 708 move in the y direction along the track y-axis yaw axis 704. In the embodiment shown, the actuator 710 is servo motor, and the axis rotation position of the servo motor is controlled by the control systems of the instrument 100, including. the industrial PC and associated interface cards in the electronic assembly 124.
[0234] The dispensing assembly 114 aspirates a sample or reagent from a sample plate or a reagent plate and dispenses the sample or reagent into the wells of tape 104 positioned in second position 132 of the tape path assembly 118 The dispensing assembly 114 moves the dispensing box 706 and the dispensing head 708 in the x direction and the y direction along the lashing gantry x axis track 702 and the lashing gantry y axis track 704 a in order to position the dispensing box 706 and the dispensing head 708 above a sample plate or reagent plate. Dispensing assembly 114 then extends dispensing head 708 in the z direction in order to aspirate a sample or reagent from the sample plate or reagent plate. The dispensing assembly 114 subsequently retracts the dispensing head 708 in the z direction and again moves the dispensing box 706 and the dispensing head 708 in the x direction and in the y direction in order to position the dispensing box 706 and the dispensing head 708 above the strip 104. The dispensing assembly 114 then extends the dispensing head 708 in the z direction in order to dispense the sample or reagent into the wells of the strip 104. While aspirating or dispensing, if necessary, the dispensing assembly 114 can move the dispensing head 708 in the x direction, y direction, and z direction to reposition the dispensing head 708. Figure 29 is a schematic view of the dispensing assembly 114 seen in Figure 28. The dispensing assembly 114 includes the x-axis track of easel 702, the y-axis track of the easel 704, the dispensing housing 706, and the dispensing head 708. The x-axis track of the easel 702 includes the actuated r 710, drive belt 712, and cable carrier 714. The y-axis track of easel 704 includes actuator 716, drive belt 718, and cable carrier 720. Dispensing box 706 includes the reservoir of dispensing pressure 722, metering pump 724, manifold 726, system fluid supply and disposal 728, and electronics 730. Dispensing head 708 includes contact dispensing unit 732 and non-contact dispensing unit 734.
[0235] Dispensing assembly 114 combines multiple dispensing technologies in a single head providing both contact and non-contact dispensing with the 708 dispensing head. Mooring easel y axis 704 provide shared x and y geometry axes for the 708 dispensing head, which reduces cost and conserves space within the instrument 100.
[0236] Figure 30 is a perspective view of the y-axis track of mooring easel 704, dispensing box 706, and dispensing head 708 of the dispensing assembly 114 seen in Figure 28. The y-axis track of Tie stand 704 includes actuator 716, drive belt 718, and cable carrier 720. Dispensing box 706 includes dispenser 726 with 736 channels. Dispensing head 708 includes 732 contact dispensing unit with 738 pipette tips and dispensing unit 734 non-contact dispensing with jet tips 740 and valves 742. Tubes 744 connect the non-contact dispensing unit 734 to dispensing box 706. Tubes 744 attach to jet tips 740 and channels 736 of manifold 726.
[0237] As shown in Figures 28 through 30, the contact dispensing unit 732 dispenses a liquid onto tape 104 (not shown). In an alternative embodiment, the contact dispensing unit 732 can dispense a liquid into a plate with a plurality of wells, such as a microtiter plate. In an alternative embodiment, the contact dispensing unit 732 can dispense onto a flat surface. The 732 contact dispensing unit can be a parallel channel pipettor. The 732 Contact Dispensing Unit aspirates and dispenses liquid with the 738 pipette tips. The liquid can be a biological sample. In an alternative embodiment, the liquid can be a reactant. The contact dispensing unit 732 can include a single pipette tip 738. In alternative embodiments, the contact dispensing unit 732 can include a number of pipette tips 738 including 96 pipette tips 738 or 384 pipette tips 738. Contact Dispensing 732 dispenses a liquid while the liquid is still in the tips 740. The tips 740 contact the wells into which the liquid is dispensed.
[0238] The non-contact dispensing unit 734 dispenses a liquid onto the tape 104. In an alternative embodiment, the non-contact dispensing unit 734 can dispense a liquid into a plate with a plurality of wells, such as a microtiter plate. In an alternative embodiment, the non-contact dispensing unit 734 can dispense onto a flat surface. The 734 non-contact dispensing unit can be a standalone channel non-contact jet dispenser. The 732 non-contact dispensing unit aspirates and dispenses liquid with jet tips 740. The liquid can be a reagent. In an alternative embodiment, the liquid can be a biological sample. The non-contact dispensing unit 732 can include a single jet tip 740. In alternative embodiments, the non-contact dispensing unit 732 can include a number of jet tips 740, including two, four, eight, or sixteen jet tips 740. When the non-contact dispensing unit 732 dispenses a liquid, the liquid separates from the jet tips 740 and only the liquid comes into contact with the wells into which the liquid is dispensed.
[0239] In order to separate a liquid from the jet tips 740, the metering pump 724 of the dispensing box 706 pressurizes the pressure reservoir 722, tubes 744 and jet tips 740 to a desired pressure based on the fluid viscosity of dispensing and a desired dispensing volume. Pressure reservoir 722 is used to store pressure created by metering pump 724. Pressure reservoir 722 provides a constant pressure for dispensing. In order to dispense liquid, electronics 730 actuate valves 742 to open valves 742, and pressure in tubes 744 allows liquid to be expelled from jet tips 740. In the embodiment shown, valves 742 are solenoid valves . Valves 742 can be opened one at a time to dispense liquid from jet tips 740 one at a time. In an alternative embodiment, valves 742 can be opened simultaneously to dispense liquid from jet tips 740 at the same time. As stated above with reference to Figure 28, dispensing box 706 and dispensing head 708 are connected and move simultaneously along tie gantry y axis track 704. This prevents flexing and stretching of tubes 744 during dispensing, thereby minimizing pressure fluctuations within the 744 tubing. Reducing pressure fluctuations in the 744 tubing improves the dispensing accuracy of the 734 non-contact dispensing unit, especially at dispensing volumes as low as 800 nanoliters.
[0240] Figure 31A is an isometric view of the dispensing head 708 with the contact dispensing unit 732 in an extended position and the non-contact dispensing unit 734 with jet tips 740 in a retracted position. Figure 31B is an isometric view of the dispensing head 708 with the contact dispensing unit 732 in a retracted position and the non-contact dispensing unit 734 in an extended position. The non-contact dispensing unit 734 includes jet tips 740 and valves 742. In addition to the contact dispensing unit 732 and the non-contact dispensing unit 734, the dispensing head 708 includes the first z-axis track 746 with rails 748 , 750 spring, and 752 actuator. The 708 dispensing head also includes the second 754 z-axis track with 756 rail, 758 spring (shown in Figure 31C), and 760 actuator. The 752 actuator moves the 732 contact dispensing unit in the z direction along rails 748. Actuator 760 moves the non-contact dispensing unit 734 in the z direction along rail 756.
[0241] Figure 31C is a partially transparent perspective view of the first z-axis track 746 and second z-axis track 754 of the dispensing head 708 seen in Figures 31A to 31B. The non-contact dispensing unit 734 with jet tips 740 is attached to the second z-axis track 754. The first z-axis track 746 includes rails 748, spring 750, actuator 752, clamping plate 762, adjusting mechanism. short pitch 764, pivot pin 766, and identification mechanism 768. Second geometry z axis track 754 includes rail 756, spring 758, and actuator 760.
[0242] As shown in Figures 30, 31A, 31B and 31C, in the embodiment shown, the first z axis track 746 is attached to the lashing easel y axis track 704. The contact dispensing unit 732 is attached ae moves along the first z-axis track 746 and the non-contact dispensing unit 734 is secured to and moves along the second z-axis track 754. In the embodiment shown, the second z-axis track 754 is fixed to the contact dispensing unit 732 so that the second z axis track 754 and the non-contact dispensing unit 734 move in the z direction when the contact dispensing unit 732 moves in the z direction along the first track of z-axis 746. In an alternative embodiment, the second z-axis track 754 can be secured to the tying gantry y-axis track 704 so that the non-contact dispensing unit 734 moves in the z direction only. and along the second z axis track 754, independent of z axis movement of the contact dispensing unit 732. In another alternative embodiment, wherein the second z axis track 754 is attached to the axis track y of mooring easel 704, the first z-axis track 746 can be fixed to the non-contact dispensing unit 734 so that the first z-axis track 746 and the contact dispensing unit 732 move in the z direction when the non-contact dispensing unit 734 moves in the z-direction along the second z-axis track 754. In an alternative embodiment, each individual valve 742 attached to a corresponding jet tip 740 can be mounted to an independent axis track. z to enable each individual valve 742 and corresponding jet tip 740 to move independently in the z direction.
[0243] The contact dispensing unit 732 attaches to the clamping plate 762 of the first geometric axis track 746. Before clamping the contact dispensing unit 732, the short pitch adjustment mechanism 764 rotates the clamping plate 762 around pivot pin 766 in order to help angle the clamp plate 762. This ensures that the contact dispensing unit 732 is secured to the clamp plate 762 so that the pipette tips 738 are aligned and level with the strip 104 well array, sample plate, or reagent plate for aspiration and dispensing.
[0244] When the contact dispensing unit 732 is in an extended position, the spring 750 is compressed. In the event of a loss of power to actuator 752, spring 750 will either retain the z direction position of contact dispensing unit 732 or retract contact dispensing unit 732 along the first z axis track 746. damages to the 738 pipette tips and serves as a safety mechanism in the event a user interacts with the 708 dispensing head within the instrument 100. In alternative embodiments, a gas damper, alternative spring type or friction limit via a gear train can be used. The second z axis track 754 includes spring 758, which functions in the same way as spring 750 to retain the z-direction position of the non-contact dispensing unit 734 or retract the non-contact dispensing unit 734 in the event of a loss of power to the 760 actuator. This prevents damage to the 740 jet tips and serves as a safety mechanism in the event an operator interacts with the 708 dispensing head within the instrument 100.
[0245] In order to aspirate and dispense, the contact dispensing unit 732 moves along the first z axis track 746 to an extended position (Figure 31A). The non-contact dispensing unit 734 remains in a retracted position along the second z-axis track 754. In order to aspirate and dispense, the non-contact dispensing unit 734 moves along the second z-axis track 754 to an extended position (Figure 31B) so that the jet tips 740 extend beyond the contact dispensing unit 732. The contact dispensing unit 732 can be in an extended position or a retracted position when the dispensing unit is non-contact 734 aspires and dispenses. During or prior to aspiration or dispensing, identification mechanism 768 can read an identifier, such as a bar code, from strip 104, a sample plate, or a reagent plate to identify the contents and configuration of strip 104, of the plate. sample or reagent plate. In one embodiment, the identification mechanism 768 may be a camera. In an alternative embodiment, the identification mechanism 768 may be a radio frequency identification reader used in combination with radio frequency identification tags on or on tape 104, a sample plate, or a reagent plate to identify the configuration and contents of the tape 104, sample plate or reagent plate.
[0246] Figure 32A is a transparent isometric view of the dispensing box 706 of the dispensing assembly 114 seen in Figures 28 to 30. Figure 32B is a perspective view of the dispensing box 706. Figures 32A to 32B are transparent to show the components enclosed in dispensing box 706. Dispensing box 706 includes pressure vessel 722, metering pump 724, distributor 726 with channels 736, system fluid supply and disposal 728, electronics 730, pressure reservoir valve 770 and pressure sensor 772. System fluid supply and disposal 728 includes supply port 774, refuse port 776, and system fluid valve 778. Supply port 774 is connected to a fluid supply and disposal port 778. system 776 is connected to a waste receptacle. Figure 33 is a schematic diagram of the non-contact dispensing components of the dispensing box 706 and the dispensing head 708 seen in Figures 31A to 31C and 32A to 32B. Dispensing box 706 includes pressure reservoir 722, metering pump 724, distributor 726 with channels 736, system fluid supply and discharge 728, pressure reservoir valve 770, pressure sensor 772, check valve 780, and filter 782 The 728 system fluid supply and discharge includes 774 supply port, 776 waste port, 778 system fluid valve, and 784 check valve. The 734 non-contact dispensing unit includes 740 jet tips and 742 valves. tubes 744 connect non-contact dispensing unit 734 to dispensing box 706. Tubes 744 are attached to jet tips 740 and channels 736 of dispenser 726.
[0247] As shown in Figures 32A to 32B and Figure 33, the dispensing box 706 is connected to jet tips 740 with tubes 744. Tubes 744 are connected to distributor 726 through channels 736, and each of tubes 744 is connected to each of the 740 jet tips. The 772 pressure sensor measures the pressure in the 726 manifold, which is the same as the pressure in the 744 tubes. The 742 valves open and close the 740 jet tips. The 730 electronics provide power and aid in the control of all components of the dispensing box 706 and dispensing head 708. In the embodiment shown, the electronics 730 consist of a printed circuit board.
[0248] The metering pump 724 provides the system fluid flow necessary to flush and pressurize the non-contact dispensing system 36 and dispensing box 706. The metering pump 724 is connected to the pressure reservoir valve 770 and the valve of system fluid 778. Supply port 774 is connected to a system fluid supply and disposal 776 is connected to a refuse receptacle. System fluid, such as water, enters dispensing box 706 through supply port 774 and system waste fluid exits through waste port 776. System fluid valve 778 controls system fluid within and refuse flow out of dispensing box 706 and through metering pump 724. Pressure reservoir 722 is connected to pressure reservoir valve 770. Pressure reservoir valve 770 controls the flow of system fluid into and outside pressure vessel 722. Pressure sensor 772 measures the pressure in pressure vessel 722 to determine if a desired pressure in pressure vessel 722 has been reached. Check valve 780 allows ambient air into pressure vessel 722 if the pressure in pressure vessel 722 drops below atmospheric pressure. The 782 filter prevents any unwanted particles from entering pressure vessel 722. The 730 electronics provide power and control all components of the 706 dispensing box and 708 dispensing head except for the actuators. In the embodiment shown, electronics 730 consist of a printed circuit board.
[0249] In order to begin operation of the dispensing box 706 together with the non-contact dispensing unit 734, the non-contact dispensing unit 734 is moved to a flush position. Pressure reservoir valve 770 is closed and valves 742 and system fluid valve 778 are opened. Metering pump 724 is then run forward to pump system fluid through supply port 774, through check valve 784, into dispenser 726, through channels 736, into tubes 744 and through jet tips 740 in order to purge any air or refuse at jet tips 740. Jet tips 740 and tubes 744 are now filled with system fluid and valves 742 are closed.
[0250] The non-contact dispensing unit 734 is then moved to an aspiration position above a reagent plate. The valves 742 are opened and closed one at a time and the metering pump 724 is run backwards in order to draw an air gap in each of the jet tips 740. In this mode, the air gap is approximately 20,000 nanoliters. Jet tips 740 are subsequently lowered into the wells of the reagent plate, valves 742 are opened and closed one at a time, and metering pump 724 is run backward to aspirate a reagent into jet tips 740. In one embodiment, the jet tips 740 aspirate between 80,000 and 700,000 nanoliters of reagent into each of the jet tips 740. In alternative embodiments, the jet tips 740 can aspirate other amounts of reagent based on the size of the tubes 744. air gap prevents system fluid and reagent from mixing. Once the reagent is drawn into one or more of the jet tips 740, the pressure reservoir valve 770 is opened, the metering pump 724 is run in advance, and the system fluid is pumped into the reservoir. of pressure 722 through the bottom of pressure vessel 722. This creates pressure by compressing the air above the system fluid in pressure vessel 722 and pressurizing the system fluid in pipes 744, the air gap between the system fluid and the reagent and reagent in tubes 744. The metering pump 724 runs until a desired pressure is reached, the pressure corresponding to the viscosity and amount of reagent required for dispensing. Pressure sensor 772 measures the pressure in pressure vessel 722 and manifold 726 components to determine when the desired pressure is reached.
[0251] The non-contact dispensing unit 734 is then moved to a dispensing position above tape 104 or above a plate. Each of the valves 742 is actuated by electronics 730 above a desired concavity. Once each of the valves 742 is actuated, the pressure in the tubes 744 and the jet tips 740 causes reagent to be fired from each of the jet tips 740 and into the wells of the strip 104. Non-contact dispensing 734 is moved in the x and y directions along the array of tape wells 104 and valves 742 are actuated repeatedly in order to dispense reagent into each of the tape wells 104. The jet tips 740 move through of tape 104 in the x and y directions during dispensing. In the embodiment shown, the jet tips 740 continuously move and dispense without having to stop above each taper concavity 104. The non-contact dispensing unit 734 can dispense between 100 and 3000 nanoliters of reagent. Valves 742 can be actuated one at a time to dispense reagent from each of the jet tips 740 one at a time. In an alternative embodiment, valves 742 can be actuated simultaneously to dispense reagent into multiple wells at once. Once the reagent is dispensed into the tape wells 104, the non-contact dispensing unit 734 can be moved back to a wash position and the process can be repeated.
[0252] As shown in Figures 28 through 33, the dispensing head 708 can move along the lashing easel x axis track 702 and the lashing gantry y axis track 704 to aspirate and dispense a reagent and/or a biological sample with the contact dispensing unit 732 and the non-contact dispensing unit 734 in a variety of sequences. In one embodiment, the dispensing head 708 moves along the beading gantry track 702 and beading gantry y track 704 to a first suction position in which the contact dispensing unit 732 aspirates a first liquid into at least one of the pipette tips 738. The dispensing head 708 subsequently moves to a second aspiration position where the non-contact dispensing unit 734 draws a second liquid into the at least one of the jet tips 740. The dispensing head 708 then moves to a first dispensing position where the contact dispensing unit 732 dispenses the first liquid with at least one of the pipette tips 738. Finally, the dispensing head dispensing 708 moves to a second dispensing position where the non-contact dispensing unit 734 dispenses the second liquid with at least one of the jet tips 740. This sequence aspiration and dispensing system minimizes evaporation of the first and second liquids during the sequence. In the alternative mode that also minimizes evaporation of the first and second liquids, the sequence can be such that the non-contact dispensing unit 734 aspirates, the contact dispensing unit 732 aspirates, the non-contact dispensing unit 734 dispenses and the unit Dispensing Contact 732 Dispensing.
[0253] In another alternative embodiment, the contactless dispensing unit 734 aspirates, the contactless dispensing unit 732 aspirates, the contactless dispensing unit 732 dispenses, and the contactless dispensing unit 734 dispenses. This sequence minimizes the time a liquid is in the 738 pipette tips of the 732 contact dispensing unit before the liquid is dispensed. In another alternative embodiment, the contact dispensing unit 732 aspirates, the contactless dispensing unit 734 aspirates, the contactless dispensing unit 734 dispenses, and the contact dispensing unit 732 dispenses. This sequence minimizes the time a liquid is in the jet tips 740 of the 734 non-contact dispensing unit before the liquid is dispensed. TAPE SEALING ASSEMBLY
[0254] Figure 34A is an isometric view of instrument 100 with tape seal assembly 120. The tape seal assembly 120 includes applicator 800 and locking mechanism 802. Sealing blanket 804 is attached to the seal assembly 120 with locking mechanism 802. Figure 34B is a perspective view of sealing blanket 804 with seals 106 on seat 806. The tape seal assembly 120 displaces seals 106 of seat 806 of sealing blanket 804. applicator 800 of tape seal assembly 120 seals tape 104 with seals 106 after a biological sample and a reagent have been dispensed onto tape104. Seals 106 contain the biological sample and reagent mixture on strip 104 and prevent spillage, evaporation and contamination of the biological sample and reagent mixture on strip 104.
[0255] Figure 35 is a perspective view of the tape seal assembly 120 positioned adjacent to the tape path assembly 118. The tape path assembly 118 includes the first position 130, the second position 132, the third position 134 and the fourth position 136. The tape seal assembly 120 includes the head 808. The tape seal assembly 120 can be moved in the y direction normal to the tape path assembly 118 and in the x direction parallel to the tape path assembly 118. Therefore, the tape seal assembly 120 can be positioned adjacent the tape path assembly 118, with the head 808 positioned in the second position 132. The tape seal assembly 120 seals the tape 104 in the second position 132 after the biological sample and reagent are dispensed.
[0256] Figure 36A is a top view of the tape seal assembly 120 within the instrument 100. Figures 36B and 36C are perspective views of the tape seal assembly 120. The tape seal assembly 120 includes the mechanism for geometry axis drive 810 with actuator 812 and drive belt 814, geometry y axis drive mechanism 816 with actuator 818 and drive belt 820, geometry axis stage x 822, geometry axis rails x 824, the y axis stage 826, and the y axis rails 828. The x axis drive mechanism 810 is connected to the axis x axis stage 822. The y axis drive mechanism 816 is connected to the y axis stage 826. The x axis stage 822 is installed on the x axis rails 824 and the y axis stage 826 is installed on the y axis rails 828. The y axis rails 828 are installed in the x822 geometry axis stage.
[0257] The 810 x shaft drive mechanism and the 816 y shaft drive mechanism move the tape seal assembly 120 in the x and y directions in order to align the tape seal assembly 120 with the tape path assembly 118 so that the seal 106 can be properly applied to the tape 104. To move the tape seal assembly 120 in the x direction, the actuator 812 drives the drive belt 814, transferring motion to the x geometry axis stage 822 and moves the x-axis stage through the x-axis rails 824. In the embodiments shown in Figures 36A through 36C, the actuator 812 is a motor. In alternative embodiments, actuator 812 can drive drive belt 814 with any suitable mechanism such as an electric motor, a pneumatic motor, or a hydraulic motor. To move the tape seal assembly 120 in the y direction, the actuator 818 drives the drive belt 820, transferring motion to the y axis stage 826 and moves the y axis stage through the y axis rails 828. In the embodiment shown in Figures 36A through 36C, the actuator 818 is a motor. In alternative embodiments, actuator 818 can drive drive belt 820 with any suitable mechanism, such as an electric motor, a pneumatic motor, or a hydraulic motor.
[0258] Figure 37A is an isometric view of a portion of the tape seal assembly 120. Figure 37B is a side view of the tape seal assembly 120 with the thread path B. The tape seal assembly 120 includes a sealing blanket 804, head 808, spool retainer 830 with locking mechanism 802, sensor 834, peel plate 836 with bottom edge 838, support penetration mechanism 840, lever 862 and slip clutch 874. The mechanism penetration plate 840 includes inner feed guide 842, top guide 844, outer feed guide 846, drive roller 848, friction roller 849, tension bar 856, tension spring 857, shaft 858, shaft actuator 860 , and fixed tension sheave 864. Sealing blanket 804 is installed on spool retainer 830 and threaded through tape seal assembly 120 along thread path B.
[0259] Before threading the sealing blanket 804 through the tape seal assembly 120, the sealing blanket 804 is placed on the spool retainer 830 and the locking mechanism 802 secures the sealing blanket 804 to the sealing tape assembly 120. In the embodiments shown in Figures 37A through 37B, the locking mechanism 802 is a lug locking mechanism (shown in greater detail in Figures 39A through 39B). In alternative embodiments, locking mechanism 802 can secure sealing blanket 804 with any suitable mechanism, such as a feedback lever. Before the sealing blanket 804 is manually threaded through the tape sealing assembly 120, several seals 106 can be removed so that only the bearing 806 is manually threaded.
[0260] Once sealing blanket 804 is secured to spool retainer 830, lever 862 is rotated clockwise approximately ninety degrees to open thread path B (see Figures 38B-38C for details), and gasket 804 can be manually threaded along thread path B through tape gasket assembly 120. gasket web 804 is first routed through peel plate 836 and around bottom edge 838 of the back plate peel-off 836. Sealing blanket 804 enters support penetration mechanism 840 through inner feed guide 842. Sealing blanket 804 is manually advanced in addition to inner feed guide 842, top guide 844, outer feed guide 846 , and through the rear of support penetration mechanism 840. Sealing blanket 804 is manually advanced beyond fixed tension sheave 864 attached to shaft 858. Thread path B is then closed by rotating the wing lever 862 counterclockwise, returning lever 862 to its original position (see Figures 38A through 38B for details). When the threading path B is closed, the friction roller 849 squeezes the bearing 806 against the drive roller 848. The tension spring 857 determines the amount of clamping force. In one embodiment, the sealing blanket 804 can be secured to a disposable receiving core (not shown) attached to the shaft 858. The use of a disposable receiving core simplifies the removal of the seat 806 from the tape seal assembly 120 after the seals 106 have been removed from the sealing blanket 804, leaving the seat 806 wrapped around the disposable receiving core (not shown).
[0261] Once the sealing blanket 804 has been manually threaded through the tape seal assembly 120, the sealing blanket 804 can be automatically advanced through the tape seal assembly 120 along the threading path B. To advance automatically the sealing blanket 804, the actuator 850 drives the drive roller 848 to advance the sealing blanket 804 between the friction roller 849 and the drive roller 848. The slip clutch 874 of the spool retainer 830 maintains a desired level of tension in sealing blanket 804 over bottom edge 838 of peel plate 836 and along thread path B between spool retainer 830, drive roller 848 and friction roller 849. After seal assembly of tape 120 has automatically advanced sealing blanket 804, shaft actuator 860 rotates shaft 858 to remove clearance created in sealing blanket 804 along thread path B between shaft 858 and the drive roller 848 and friction roller 849. Shaft 858 may wind or rewind bearing 806. As bearing 806 of sealing blanket 804 is wrapped around shaft 858, fixed tension sheave 864 may contact the sealing blanket. seal 804. As seal blanket 804 progresses through the tape seal assembly 120 and seals 106 are removed from bearing 806, bearing 806 is wrapped around shaft 858. Bearing 806 wrapped around shaft 858 can be discarded once axis 858 is full.
[0262] As the support penetration mechanism 840 automatically advances the sealing blanket 804, the sensor 834 detects the location of the seal 106 in the sealing blanket 804 through the sensor path S. The sensor 834 signals the penetration mechanism of bearing 840 to stop the advance of the seal 804 when the seal 106 is positioned over the peel plate 836. The bottom edge 838 of the peel plate 836 may have a small radius to facilitate the seal peel off when the seal assembly of tape 120 is automatically advancing sealing blanket 804. As sealing blanket 804 moves through peel plate 836 and passes around bottom edge 838, sensor 834 signals support penetration mechanism 840 to stop advancing of sealing mat 804 just before the seal 106 moves past the bottom edge 838 of the peel plate 836 and begins to separate from the bearing 806. The bottom edge 838 of the peel plate 836 is angled so that when the seal 106 moves past the bottom edge 838, a leading edge of the seal 106 is separated from the bearing 806. In alternative embodiments, a second sensor can be used to detect when a leading edge of the seal 106 has passed. by bottom edge 838, thus indicating that the leading edge of seal 106 has separated from bearing 806.
[0263] Figure 38A is a perspective view of the bearing penetration mechanism 840. Figure 38B is a side view of the bearing penetration mechanism 840 with the friction roller 849 in a closed position. Figure 38C is a side view of the bearing penetration mechanism 840 with the friction roller 849 in an open position. Bearing penetration mechanism 840 includes inner feed guide 842, top guide 844, mount 845, outer feed guide 846, drive roller 848, friction roller 849, actuator 850, pulley 852, drive belt 854, tension bar 856, tension spring 857, lever 862, and cam 863.
[0264] Although the sealing mat 804 is automatically advanced through the bearing penetration mechanism 840, the sealing mat 804 is clamped between the friction roller 849 and the drive roller 848 so that the friction roller 849 rotates with the same time as drive roller 848. To allow sealing blanket 804 to be manually threaded through threading path B (shown in Figure 37B), lever 862 can be rotated approximately ninety degrees clockwise to rotate the drive roller. friction 849 in the opposite direction to drive roller 848. This moves friction roller 849 from the closed position seen in Figure 38B to the open position seen in Figure 38C. Once friction roller 849 is in an open position, sealing blanket 804 can be manually threaded through threading path B, passing internal feed guide 842 and top guide 844, between friction roller 849 and drive roller 848 and over outer feed guide 846. Lever 862 can then be rotated counterclockwise to rotate friction roller 849 back to a closed position where sealing blanket 804 is clamped. between drive roller 848 and friction roller 849.
[0265] Friction roller 849 is opened and closed by rotation of lever 862. Lever 862 is secured to cam 863 and tension bar 856 so that when lever 862 is rotated, cam 863 also rotates. When lever 862 is rotated clockwise, cam 863 pushes assembly 845, rotating tension bar 856 clockwise to the position in Figure 38C. Clockwise rotation of tension bar 856 moves friction roller 849 in the opposite direction to drive roller 848 so that friction roller 849 no longer contacts drive roller 848. This makes it possible for the mat to seal 804 is manually fed into the bearing penetration mechanism 840. After the sealing blanket 804 has been manually fed into the bearing penetration mechanism 840, the lever 862 can be rotated counterclockwise to rotate the cam 863 in the opposite direction to return tension bar 856 to the position in Figure 38B. This allows spring 857, which pulls tension bar 856, to pull friction roller 849 to drive roller 848 until sealing blanket 804 is clamped between drive roller 848 and friction roller 849 with a determined amount of force. This makes it possible to automatically advance the sealing blanket 804.
[0266] Figures 39A to 39B are cross-sectional views of the spool holder 830, with the locking mechanism 802 in an unlocked position in Figure 39A, and the locking mechanism 802 in a locked position in Figure 39B. Spool retainer 830 includes locking mechanism 802, compression piece 866, rubber roller 868, screw 870, spool 872, and slip clutch 874.
[0267] In order to prevent the spool 872 from rotating independently of the spool retainer 830, the spool retainer 830 includes the locking mechanism 802. The locking mechanism 802 is connected to the compression part 866, which is connected to the rubber 868, so that when the locking mechanism 802 is locked, the locking mechanism 802 presses the compression part 866, which in turn compresses the rubber roller 868. The locking mechanism 802 can be locked or unlocked by manually rotating the 802 locking mechanism around the end of the screw 870. The 802 locking mechanism can be partially locked, thus providing variable pressure on the rubber roller 868 and therefore variable pressure on the spool 872. When the 802 locking mechanism is in the locked position, maximum pressure is exerted by the rubber roller 868 on the 872 spool. When the 802 locking mechanism is in the unlocked position, none A partial amount of pressure is exerted by the rubber roller 868 on the spool 872. When the locking mechanism 802 is in a partially locked position, a partial amount of pressure is exerted by the rubber roller 868 on the spool 872. In this way, the spool 872 rotates with rubber roller 868 as sealing blanket 804 is automatically advanced through tape seal assembly 120. Slip clutch 874 is adjustable to maintain a desired tension on seat 806 along thread path B (shown in Figure 37B) as the seal blanket 804 is advanced manually or automatically through the tape seal assembly 120.
[0268] Figure 40 is a partially transparent perspective view of the applicator 800 of the tape seal assembly 120. Figure 41 is a bottom view of the block 876 of the applicator 800. The applicator 800 includes head 808, block 876 that has vacuum ports 878, shaft 880, actuator 882, shaft 884, drive belt 886, pulleys 888, and vacuum chambers 890. Head 808 is attached and rotates around shaft 880. Head 808 is attached to drive belt 886 Drive belt 886 surrounds pulleys 888 and shaft 884. Shaft 884 is connected to actuator 882. Head 808 includes applicator vacuum chambers 890, which form vacuum holes 878 in applicator block 876. The convex face of head 808 is aligned with block 876, which may be produced from vulcanized rubber to facilitate compression when head 808 presses seal 106 onto tape 104. In order to move head 808, actuator 882 drives shaft 884 Shaft 884 rotates head 808 around the shaft 880 via drive belt 886 and pulleys 888. Head 808 rotates around 880 to peel seal 106 from seal blanket 804 and press seal 106 into tape 104.
[0269] Figures 42A to 42B are partially transparent perspective views of a portion of the tape seal assembly 120 that removes seal 106 from seat 806 of seal blanket 804. Seal 106 is in a peel-off position in Figure 42A . Seal 106 is completely removed from bearing 806 in Figure 42B. The tape seal assembly 120 includes applicator 800 (shown in full in Figure 40), peel plate 836 with bottom edge 838 (seen in Figure 37B), and support penetration mechanism 840 with internal feed guide 842. Applicator 800 includes head 808 with first edge 892 and second edge 894, block 876 with vacuum ports 878 (shown in Figures 40 through 41), shaft 880, and vacuum chambers 890 (shown in Figure 40). Applicator 800 moves head 808 so that block 876 faces peel plate 836 with first edge 892 of head 808 proximate a leading edge of seal 106 in a position to be peeled off. The 808 head rotates around the 880 at the same rate as the sealing blanket 804 is advanced by the 840 support penetration mechanism. The 890 vacuum chambers can be activated in stages so that the 890 vacuum chambers are gradually activated from from first edge 892 to second edge 894 of head 808 as seal 106 is peeled off bearing 806. Vacuum chambers 890 can only be activated for portion of seal 106 peeled off and in contact with block 876. When seal 106 is completely removed from the 806 support, all 890 vacuum chambers can be activated. When the seal 106 is completely removed from the seat 806 and fully captured by the head 808, the head 808 moves to a downward facing position towards the tape 104.
[0270] Support penetration mechanism 840 advances sealing blanket 804 at the same rate as applicator 800 rotates head 808 around shaft 880 to catch seal 106 of sealing blanket 804. pad 840 can automatically advance sealing mat 804 around peel plate 836 and through inner feed guide 842, and pad penetration mechanism 840 can work in combination with applicator 800 to peel seal 106 from mat. seal 804.
[0271] Figures 43A to 43B are side views of the tape seal assembly 120 applying the seal 106 to the tape 104 in the second position 132 on the tape path assembly 118. Figure 43A is a side view of the tape seal assembly. tape 120 just before seal 106 is applied. Figure 43B is a side view of the tape seal assembly 120 just after the seal 106 is applied. The tape seal assembly 120 includes head 808, geometry x 822 axis stage, x 824 axis rails, 826 y axis stage, and 828 y axis rails. Block 876 is positioned over head 808 and includes vacuum ports 878 (shown in Figures 40A through 40B), vacuum chambers 890 (shown in Figures 40A through 40B), first edge 892 and second edge 894.
[0272] To apply seal 106 to tape 104, y axis stage 826 moves along y axis rails 828 towards tape path assembly 118. At the same time, head 808 rotates downward so that second edge 894 of block 876 touches one side of tape 104, allowing seal 106 to make initial contact with tape 104 (shown in Figure 43A). Y axis stage 826 continues to advance along rails 828 in motion synchronized with the rotation of head 808. Head 808 swings from second edge 894 to first edge 892 and then from second edge 894 to first edge 892 a first time as the y-axis stage 826 advances and retracts, respectively, along the y-axis rails 828. This oscillating motion applies pressure to the seal 106 and the tape 104 to press the seal 106 onto the tape. 104. In this embodiment, if 10.34 (15) or more newtons (pounds) of pressure per square centimeter (square inch) is applied by head 808 to tape 104, the pressure sensitive adhesive on seal 106 can be activated. In an alternative embodiment, the amount of pressure required is dependent on the pressure sensitive adhesive being used. Although head 808 moves through tape 104 for the first time, vacuum chambers 890 are deactivated and seal 106 is transferred to tape 104. In an alternative embodiment, vacuum chambers 890 are not deactivated and seal 106 is still is transferred to tape 104.
[0273] After the seal 106 has been applied, the y axis stage 826 moves backward along the y axis rails 828, through the tape 104, and the actuator 812 drives the x axis stage 822 to along the x axis rails 824 slightly downstream or upstream in the x direction. This movement displaces the head 808 slightly downstream or upstream from where the seal 106 was applied, and allows the y axis stage 826 to move forward again through the tape 104 in motion synchronized with the rotation of the head 808 Head 808 swings from second edge 894 to first edge 892 and then from second edge 894 to first edge 892 a second time as y axis stage 826 advances and retracts, respectively, along the rails. 828. This second oscillating movement ensures that the pressure sensitive adhesive is active across the entire surface of seal 106, including where vacuum holes 878 have been placed relative to tape 104 and seal 106 during the first oscillating movement of head 808. THERMAL UNIT AND HEATED PRESSURE CHAMBER
[0274] Figure 44 is an isometric view of the tape path assembly 118 that travels through the instrument 100. The tape path assembly 118 includes first position 130, second position 132, third position 134, and fourth position 136. Also shown in Figure 45 are tape 104, thermal unit 210, and heated pressure chamber 212.
[0275] Strip 104 includes an array of wells that contain a biological sample and reagent mixture. Tape 104 is fed into tape path assembly 118 and then advances to first position 130. A tape cutter is positioned below first position 130. Tape cutter can be actuated upward to cut tape 104 if wanted. Tape 104 can also advance along tape path assembly 118 without being cut. Tape 104 advances from first position 130 to second position 132 along tape path assembly 118. At cut position 132, biological sample and reagent mixture are dispensed onto tape 104 with dispensing assembly 114 (not shown). The biological sample and reagent mixture are mixed in the array of strip wells 104 to create the biological sample and reagent mixture. The biological sample and reagent mixture in strip 104 can be heated or cooled in second position 132 with a thermal unit that is positioned below second position 132. Seal 106 can also be placed over strip 104 well array to seal the biological sample and the reagent mixture in the well array when the strip 104 is in the second position 132. After dispensing and sealing, the strip 104 advances to the third position 134. The biological sample and the reagent mixture in the strip 104 can be heated or cooled in the third position 134 with a thermal unit that is positioned below the third position 134. The strip 104 can wait in the third position 134 until the instrument 100 is prepared to analyze the biological sample and the reagent mixture on the strip 104 .
[0276] When instrument 100 is ready to amplify and analyze the biological sample and reagent mixture, the strip 104 can advance to the fourth position 136. Positioned below the fourth position 136 is the thermal unit 210 to control the temperature of the biological sample and reagent mixture on strip 104. Positioned above fourth position 136 is heated pressure chamber 212 to create a constant pressure across the top of strip 104. Thermal unit 210 can be used to heat the biological sample and reagent mixture in a constant temperature or cycle the biological sample and reagent mixture through multiple temperatures. The heated pressure chamber 212 can be sealed from the ambient air surrounding the heated pressure chamber 212. The heated pressure chamber 212 pressurizes and heats the area above the fourth position 136 so that the biological sample and reagent mixture on the tape 104 can be analyzed. The heated pressure chamber 212 further heats the biological sample and reagent mixture and prevents condensation on the seal 106 covering the strip well array 104 to ensure accurate analysis. After or during heating, the biological sample and reagent mixture can be analyzed using a camera that is positioned above the fourth position 136.
[0277] The thermal unit 210 and the heated pressure chamber 212 can also be used to improve the application and adhesion of a bottom side of the seal 106 to a top side of the tape 104 when the tape 104 is to be used externally to the instrument 100. In one embodiment, this use of tape 104 can be thermal cycling of tape 104 in a water bath. To improve the application and adhesion of seal 106 to tape 104, tape 104 is advanced to fourth position 136, thermal unit 210 is raised, heat and pressure are applied to an enclosure of heated pressure chamber 212, and allowed to an amount of time elapses. In one mode, this time can be 60 seconds. In other modalities, any reasonable amount of time can be used. When operation is complete, thermal unit 210 is lowered, heated pressure chamber 212 is raised, and tape 104 can be advanced for use external to instrument 100.
[0278] In this modality, the adhesive between the seal 106 and the tape 104 is ideally applied at a temperature higher than room temperature. Furthermore, the force applied to the seal 106 by pressurizing the enclosure and thus pressing the seal 106 against the tape 104 is uniform across the entirety of the seal 106. This force helps to ensure that a bottom side of the seal 106 of the tape 104 that is not immediately over a concavity of the tape 104 is in contact with a top side of the tape 104. Therefore, the application of heat and pressure over time can greatly improve the adhesion of the seal 106 to the tape 104.
[0279] Figure 45A is a perspective view of the thermal unit 210 and the heated pressure chamber 212, with the heated pressure chamber 212 in a closed position. Figure 45B is a perspective view of the thermal unit 210 and the heated pressure chamber 212, with the heated pressure chamber 212 in an open position. Figure 45C is an exploded view of thermal unit 210 and heated pressure chamber 212. Also shown in Figure 45C are tape 104 and seal 106. Figure 45D is an exploded view of thermal unit 210. Figure 45E is a view explosion from heated pressure chamber 212.
[0280] The thermal unit 210 is used to control the temperature of the biological sample and the reagent mixing in the well array of the strip 104. The strip 104 can be positioned on a top side of the thermal unit 210. The thermal unit 210 includes cavities that are configured to receive the array of tape wells 104. The wells of the thermal unit 210 are slightly smaller than or the same size as the wells of the tape 104 in order to form solid contact between the surface of the wells of the thermal unit 210 and the outer surface of the wells of tape 104. Thermal unit 210 can be used to heat and cool the biological sample and reagent mixture on ribbon 104. Thermal unit 210 can heat the biological sample and reagent mixture at a constant temperature or thermal unit 210 can cycle the biological sample and reagent mixture through multiple temperatures.
[0281] Positioned above the thermal unit 210 and the tape 104 is the heated pressure chamber 212. When the thermal unit 210 heats a mixture in the tape 104, the vapor pressure in the wells of the tape 104 can cause the seal 106 to delaminate from the tape 104. The heated pressure chamber 212 pressurizes the space above the seal 106 of the tape 104 to create a pushing force against the seal 106. The pressure keeps the seal 106 in contact with the tape 104 and also presses against the well array of the tape. tape 104 in the wells of the thermal unit 210 in order to provide better heat transfer between the thermal unit 210 and the biological sample and reagent mixture in the well array of the tape 104. The heated pressure chamber 212 also heats the area above the tape 104 to prevent condensation from forming on the seal 106 so that accurate detection can occur. During or after the biological sample and reagent mixture is heated with the thermal unit 210, a camera, such as a CCD camera, positioned above the heated pressure chamber 212 can analyze the biological sample and the reagent mixture in the well array on tape 104.
[0282] Thermal unit 210 includes first housing portion 1002, second housing portion 1004, gasket 1006, mounting feature 1008, entry ports 1010, exit ports 1012, recess 1014, heat block 1020, wells 1022, path fluid path 1052 (not shown in Figures 45A through 45E), and fluid path 1054 (not shown in Figures 45A through 45E). Thermal block 1020 includes first plate 1030, first plate 1032, second plate 1034, second plate 1036, thermoelectric modules (TEMs) 1038, heat transfer compound 1040 (not shown in Figures 45A to 45E), and temperature sensor 1042 Thermal unit 210 will be discussed in more detail below in Figures 46A through 49.
[0283] The 990 stationary frame connects to the tape path assembly 118. The 992 movable frame connects to the 990 stationary frame with 994 pivot pins. The 990 stationary frame connects to the 996 actuator with 998 vertical mounts. The 996 actuator is connected to movable frame 992 with pin 1000. Interface mount 1058 of heated pressure chamber 212 connects heated pressure chamber 212 to movable frame 992. In the embodiment shown, actuator 996 is an air cylinder. In alternative embodiments, the 996 actuator can be another type of actuator, such as a pneumatic, hydraulic, solenoid, or electromagnetic actuator. Actuator 996 moves heated pressure chamber 212 from a closed position (Figure 45A) to an open position (Figure 45B) by rotating movable frame 992 around pivot pins 994.
[0284] The heated pressure chamber 212 includes interface support 1058, clamp 1060, housing 1062, dowels 1064, glass cover plate 1066, gasket 1068, gasket 1070, insulating plate 1071, gasket 1072, gasket 1073, closed space 1074 (not shown in Figures 45A to 45B), heater plenum 1076 with air distribution holes 1077, heating element 1078, compressed air fitting 1080, electrical connection 1082 (not shown in Figures 45A to 45E), mask 1084 (not shown in Figures 45A to 45E), 1086 air pump fitting, 1087 air pump fitting, 1088 air pump fitting, 1089 air pump fitting, 1090 air pump fitting, 1092 air pump fitting, pump air supply 1094 (not shown in Figures 45A through 45E), compressed air source 1096 (not shown in Figures 45A through 45E), and temperature sensor 1098 (not shown in Figures 45A through 45E). The heated pressure chamber 212 will be discussed in more detail below in Figures 50 to 52.
[0285] Figure 46A is a perspective view of the thermal unit 210. Figure 46B is a perspective view of the bottom of the thermal unit 210. Figure 46C is a top view of the thermal unit 210. Figure 46D is an isometric view of a tape array 104 in thermal unit 210. Thermal unit 210 includes first housing portion 1002, second housing portion 1004, gasket 1006, mounting feature 1008, input ports 1010, output ports 1012, recess 1014, thermal block 1020, and cavities 1022. Also shown in Figure 46D is tape 104.
[0286] Thermal unit 210 is positioned along tape path assembly 118 on instrument 100. Thermal unit 210 includes first housing portion 1002 positioned above second housing portion 1004. Gasket 1006 is positioned between first housing portion 1004. housing portion 1002 and second housing portion 1004. Mounting feature 1008 is positioned around second housing portion 1004. Second housing portion 1004 includes mounting feature 1008, which can be used to mount thermal unit 210 in the tape path assembly 118.
[0287] The thermal unit 210 also includes two 1010 inlet ports and two 1012 outlet ports. The 1010 inlet ports are positioned on a first end of the thermal unit 210 and can receive a fluid. That fluid can flow through a thermal management system in the first housing portion 1002. The outlet ports 1012 are positioned at a second end of the thermal unit 210 and can expel fluid from the thermal management system in the first housing portion 1002. Thermal unit 210 additionally includes recess 1014. Recess 1014 is positioned on a first side of first housing portion 1002 and extends into first housing portion 1002.
[0288] The thermal unit 210 additionally includes the thermal block 1020. The thermal block 1020 is positioned in the recess 1014 and does not directly contact the first housing portion 1002. The thermal block 1020 includes a heat pump that can be used to heat or cool a biological sample and reagent mixture in an array of strip wells 104. Thermal block 1020 additionally includes wells 1022. Wells 1022 are configured to receive array of strip wells 104. Each well 1022 is sized slightly smaller or the same size as a concavity in strip 104. This allows an outer surface of each of the wells in the strip 104 well array to form a solid contact with an inner surface of a cavity 1022. The formation of a solid contact between an inner surface of each cavity 1022 and an outer surface of one of the wells in the strip well array 104 provides better heat transfer. Solid contact between each cavity 1022 in thermal block 1020 with a concavity in the strip well matrix 104 provides better heat transfer between the heat pump in thermal block 1020 and the biological sample and reagent mixture in the strip well matrix 104. Improved heat transfer allows for more accurate control of the temperature of the biological sample and the reagent mix in the strip 104 well array.
[0289] As seen in the embodiment shown in Figures 46A to 46C, the thermal unit 210 includes 768 cavities 1022. The 768 cavities 1022 include two arrays of 384 cavities 1022 that are arranged in an interlaced and offset pattern. This allows wells 1022 to receive tape 104 which has a matrix of 768 wells. In alternative embodiments, thermal unit 210 can include a number of cavities 1022 and cavities 1022 can be arranged in any suitable pattern.
[0290] Figure 47A is a cross-sectional side view of the thermal unit 210. Figure 47B is a cut-away side cross-sectional view of the thermal unit 210. Figure 47C is a schematic cross-sectional view of the thermal unit 210. Thermal unit 210 includes first housing portion 1002, second housing portion 1004, gasket 1006, mounting feature 1008, inlet ports 1010, outlet ports 1012, recess 1014, thermal block 1020, and cavities 1022. Thermal block 1020 includes first plate 1030, first sheet 1032, second plate 1034, second sheet 1036, TEMs 1038, and heat transfer compound 1040.
[0291] Thermal unit 210 includes first housing portion 1002 which is connected to second housing portion 1004 with gasket 1006. Mounting feature 1008 is part of second housing portion 1004 and can be used to mount second portion of housing 1004 on the tape path assembly 118. Input ports 1010 are connected to a first end of thermal unit 210 and output ports 1012 are connected to a second end of thermal unit 210 so that a fluid can be routed. through thermal unit 210. Recess 1014 is positioned on a first side of first housing portion 1002. Thermal unit 210 further includes thermal block 1020 positioned in recess 1014 of first housing portion 1002. Thermal block 1020 includes a plurality of wells 1022 that are configured to receive an array of tape wells 104.
[0292] Thermal block 1020 includes first plate 1030, first plate 1032, second plate 1034, second plate 1036, TEMs 1038 and heat transfer compound 1040. First plate 1030 is an aluminum plate that is configured to spread across the first board 1030 in the mode shown. In alternative embodiments, the first plate 1030 can be composed of any material that has the ability to transfer and spread heat. The first 1030 plate is between 1 millimeter (0.039 inch) and 10 millimeter (0.394 inch) thick. More preferably, first plate 1030 is between 1 millimeter (0.039 inches) and 3 millimeters (0.118 inches) thick. The first plate 1030 contains cavities 1022 of the thermal block 1020. The cavities 1022 are cavities that extend a distance within the first plate 1030.
[0293] A bottom side of the first plate 1030 is affixed to a top side of the first sheet 1032. A bottom side of the first sheet 1032 is fixed to a top side of the second sheet 1034. In this embodiment, the first sheet 1032 is a sheet of pyrolytic graphite that is used to fix and conduct heat between the first plate 1030 and the second plate 1034. In other embodiments, the first sheet 1032 can be a heat transfer compound or any other heat transfer medium.
[0294] The second plate 1034 is a copper plate that is configured to transfer heat in the mode shown. In alternative embodiments, the second plate 1034 can be composed of any material that has the ability to transfer and spread heat. Second plate 1034 is between 0.5 millimeters (0.019 inches) and 5 millimeters (0.197 inches) thick. More preferably, second plate 1034 is between 0.5 (0.019 inch) millimeter and 2 millimeter (0.079 inch) thick. A bottom side of second sheet 1034 is attached to a top side of second sheet 1036. A bottom side of second sheet 1036 is attached to a top side of TEMs 1038. In this embodiment, second sheet 1036 is a sheet of pyrolytic graphite which is used to fix and conduct heat between the second plate 1034 and the TEMs 1038. In other embodiments, the second sheet 1036 can be a heat transfer paste or any other suitable heat transfer medium.
[0295] The 1038 TEMs are positioned below the 1030 first plate and the 1034 second plate. The 1038 TEMs make up the 1020 heat block heat pump. The 1038 TEMs generate heat that can be transferred and spread through the second 1034 plate and the first plate 1030 in a biological sample and reagent mixture retained in an array of wells on strip 104. In alternative embodiments, any suitable heat pump can be used in place of 1038 TEMs.
[0296] The heat transfer compound 1040 is used to secure a bottom side of the TEMs 1038 to the first housing portion 1002. A portion of a thermal management system is positioned in a lower half of the first housing portion 1002 below the cavity which retains the 1020 thermal block. The thermal management system portion is used to exchange heat with the 1038 TEMs. In the embodiment shown, the 1040 heat transfer compound is a silicon-based compound used to improve heat transfer between the thermal management system portion and the TEMs 1038. In alternative embodiments, heat transfer compound 1040 may be a sheet of pyrolytic graphite or any other suitable heat transfer medium.
[0297] The thermal unit 210 is advantageous in that it is the compact system that has the ability to be placed within the tape path assembly 118 on the instrument 100. Additionally, the configuration of the thermal unit 210 with multiple layers of plates allows different materials to be used to ensure that the heat transfer and spread of the 1038 TEMs through the 1020 thermal block is efficient and effective. Using copper, which has a superior thermal conductivity relative to aluminum, to the second 1034 plate allows heat from the 1038 TEMs to spread and transfer evenly through the second 1034 plate to the first 1030 plate. , which has a lower density than copper, for the first plate 1030 increases the rate of temperature change in the first plate 1030 and second plate 1034 for the same amount of energy as the TEMs 1038. Combined, the materials used in the first plate 1030, first sheet 1032, second plate 1034, and second sheet 1036 ensure that heat is transferred and spread throughout the first plate 1030 to quickly and uniformly heat or cool the biological sample and reagent mixture in the well array of strip 104 positioned over the thermal unit 210. Uniformly heating and cooling the biological sample and reagent mixture is necessary to obtain consistent and accurate results when analyzing the aa shows biological and reagent mixture. In this context, heating or cooling should be understood as inclusive of thermal cycling. Figure 48 is a top-side clear plan view of thermal unit 210. Thermal unit 210 includes first housing portion 1002, thermal block 1020, and cavities 1022. Thermal block 1020 includes TEMs 1038 and sensor. temperature 1042.
[0298] The first housing portion 1002 of the thermal unit 210 houses the thermal block 1020. The cavities 1022 are positioned on a top side of the thermal block 1020 and are configured to receive an array of tape wells 104. The thermal block 1020 includes 1038 TEMs. In the embodiment shown in Figure 48, thermal block 1020 includes six different 1038 TEMs. In alternative embodiments, thermal block 1020 can include a number of TEMs 1038. Additionally, TEMs 1038 can be any heat source that has the ability to heat and cool a biological sample and a reagent.
[0299] The 1038 TEMs are arranged to uniformly heat or cool the 1020 thermal block. As seen in the embodiment shown in Figure 48, three 1038 TEMs are positioned on a first side of the 210 thermal unit and the remaining three 1038 TEMs are positioned on a second side of the thermal unit 210. The heat that is generated in the TEMs 1038 can transfer through the thermal block 1020 to heat or cool a biological sample and reagent mixture in the array of strip wells 104 that are positioned in the wells 1022 of the thermal unit 210. The 1042 temperature sensor measures the temperature of the 1020 thermal unit block. In the modality shown, the 1042 temperature sensor is a resistance temperature detector that monitors the temperature of the 1020 thermal block and provides feedback to the control system of instrument 100 so that the control system heats, cools, or maintains a 1020 thermal block setpoint temperature.
[0300] Figure 49 is a bottom transparent plan view of thermal unit 210. Thermal unit 210 includes first housing portion 1002, fluid path 1052, and fluid path 1054. Fluid path 1052 and fluid path 1054 are positioned in a lower half of the first housing portion 1002.
[0301] Fluid path 1052 is a cavity that runs from a first end of thermal unit 210 to a second end of thermal unit 210. Fluid path 1052 will snake back and forth between the first end and the second end of thermal unit 210 on a first side of thermal unit 210. A fluid may travel through fluid path 1052 to exchange heat with thermal block 1020. Fluid flows through an inlet port (see Figures 45A to 45B) on a first end of thermal unit 210, through fluid path 1052, and out of an outlet port (see Figures 45A through 45B) into a second end of thermal unit 210.
[0302] Fluid path 1054 is a cavity that runs from a first end of thermal unit 210 to a second end of thermal unit 210. Fluid path 1054 will meander back and forth between the first end and the second end of thermal unit 210 on a second side of thermal unit 210. A fluid may travel through fluid path 1054 to exchange heat with thermal block 1020. Fluid flows through an inlet port (see Figures 45A through 45B) on a first end of thermal unit 210, through fluid path 1054, and out of an outlet port (see Figures 45A through 45B) into a second end of thermal unit 210.
[0303] Fluid path 1052 and fluid path 1054 are part of a thermal management system in instrument 100. The thermal management system is a closed loop system and fluid that flows through fluid path 1052 and fluid path 1054 fluid flows through a radiator (not shown in Figure 49) to be cooled or heated as needed. That fluid can then flow through fluid path 1052 and fluid path 1054 again to exchange heat with thermal unit 210. The thermal management system is advantageous as it is a compact and effective way to control block temperature thermal 1020 in thermal unit 210.
[0304] Figure 50 is a cross-sectional view of tape 104 with seal 106 sealed between the thermal unit 210 and the heated pressure chamber 212. The heated pressure chamber 212 includes interface support 1058, clamp 1060, housing 1062, pegs 1064, glass cover plate 1066, gasket 1068, gasket 1070, insulator plate 1071, gasket 1072, gasket 1073, enclosed space 1074, heater plenum 1076 with manifold 1077, heating element 1078, compressed air fitting 1080 , and multi-pin 1082 electrical connector (see Figure 51). Clamp 1060 may be produced from aluminum and is connected to housing 1062 with pegs 1064. Housing 1062 may be a thermoplastic polymer of low thermal conductivity such as poly(ether ether ketone) (PEEK) so that the housing 1062 does not absorb heat generated within enclosed space 1074. In alternative embodiments, housing 1062 can be any heat resistant material or material with low thermal conductivity.
[0305] Glass cover plate 1066 is clamped between gasket 1068 and gasket 1070. Clamp 1060 holds glass cover plate 1066 in place so that glass cover plate 1066 does not move when pressure is applied. is applied to glass cover plate 1066. Gasket 1068 creates a seal between glass cover plate 1066 and clamp 1060. Gasket 1070 creates a seal between glass cover plate 1066 and housing 1062. The gaskets 1068 and 1070 prevent crushing and cracking of glass cover plate 1066 and facilitate uniform pressure distribution across glass cover plate 1066. Gasket 1072 creates a seal between housing 1062 and tape 104.
[0306] Clamp 1060, housing 1062, dowels 1064, glass cover plate 1066, gasket 1068, gasket 1070, and gasket 1072 create enclosed space 1074. Enclosed space 1074 is an enclosed space and sealed above the tape 104 and the seal 106 which can be heated and pressurized. Insulator plate 1071, gasket 1073, heater plenum 1076, and heating element 1078 are located within enclosed space 1074. Insulator plate 1071 insulates heating element 1078 and heater plenum 1076, minimizing loss of heat from the enclosed space 1074. The heating element 1078 heats the enclosed space 1074 to prevent condensation at the seal 106 in the tape wells 104. The plenum of heater 1076 includes air distribution holes 1077 which circulate air within the enclosed space 1074 to facilitate even heat distribution within enclosed space 1074. Gasket 1073 creates a seal between heater plenum 1076 and housing 1062. Heater plenum 1076 may be aluminum. In alternative embodiments, heater plenum 1076 can be any other suitable material with high thermal conductivity, such as stainless steel. Compressed air fitting 1080 is affixed to housing 1062 and can be connected to a source of compressed air to supply compressed air to pressurize enclosed space 1074. Multi-pin electrical connector 1082 is affixed to housing 1062 and powers the heating element 1078.
[0307] In order to amplify and analyze a mixture of reagent and biological sample, tape 104 with seal 106 is positioned between thermal unit 210 and heated pressure chamber 212 so that an array of tape wells 104 is aligned with the thermal unit well array 210. Thermal unit 210 is raised and heated pressure chamber 212 is lowered so that tape 104 is pressed against gasket 1072 and tape well array 104 is pressed into the well array of thermal unit 210. The heated pressure chamber 212 is sealed by raising the erected load to which the thermal unit 210 is affixed, which in turn causes a top surface of the first housing portion 1002 of the thermal unit 210 contact a tape bottom surface 104. This pushes a tape top surface 104 against a gasket bottom surface 1072 of the heated pressure chamber 212. Compressed air is fed through the compressed air fitting 1080 in enclosure 1074 above tape 104 and seal 106. Compressed air pressurizes enclosure 1074 to between 0.03 and 0.14 MPa (5 psi and 20 psi). Heating element 1078 heats the air in enclosed space 1074. Depending on the temperature of thermal unit 210 during amplification, the air temperature within enclosed space 1074 can be between 70 and 120 degrees Celsius. Heater plenum 1076 with air distribution holes 1077 accelerates heating and facilitates even heat distribution within enclosed space 1074.
[0308] A desired pressure and temperature are maintained in enclosed space 1074 while a mixture of reagent and biological sample is amplified and detected in the array of tape wells 104. When amplification and detection are complete, thermal unit 210 is lowered, the The heated pressure chamber 212 is raised, and the tape 104 advances along the tape path 118 so that a new array of tape wells 104 is positioned between the thermal unit 210 and the heated pressure chamber 212. Figure 51 is an isometric view of heated pressure chamber 212. Heated pressure chamber 212 includes interface holder 1058, clamp 1060, housing 1062, heater plenum 1076 with air distribution holes 1077, glass cover plate 1066 with 1084 mask, 1080 compressed air fitting, 1082 multi-pin electrical connector, and 1086 air pump fittings. 1086 air pump fittings can be connected to an air pump to pump air to the plows in and out of enclosed space 1074 to facilitate uniform temperature distribution within enclosed space 1074.
[0309] The 1066 glass cover plate with mask 1084 allows for accurate detection of mixture in the array of tape wells 104. The mask 1084 is two dots on the 1066 glass cover plate and allows instrument 100 to recognize an array of tape 104 is present in thermal unit 210. Mask 1084 may be marked or printed onto a bottom surface of glass cover plate 1066. Glass cover plate 1066 may be a ten anti-reflection coated glass cover plate with ten millimeters thick to allow the camera to view the entire array of wells during detection.
[0310] Figure 52 is a top view of heated pressure chamber 212. Heated pressure chamber 212 includes clamp 1060, dowels 1064, glass cover plate 1066 with mask 1084, heater plenum 1076 (shown in Figures 50 to 51), heating element 1078 (shown in Figure 50), compressed air fitting 1080, multi-pin electrical connector 1082, air pump fitting 1086, air pump fitting 1087, 1088 air pump fitting, 1089 air pump fitting, 1090 air pump fitting and 1092 air pump fitting, 1094 air pump, 1096 compressed air source, and 1098 temperature sensor. Compressed air source 1096 pumps compressed air into enclosed space 1074 through compressed air fitting 1080 to pressurize enclosed space 1074.
[0311] The 1086 air pump fitting, the 1087 air pump fitting, the 1088 air pump fitting, the 1089 air pump fitting, the 1090 air pump fitting and the 1092 air pump fitting are connected to the 1094 air pump, forming a closed air flow circuit. Air flows out of air pump 1094, through air pump fittings 1086, 1087, 1088, and 1089, through enclosed space 1074, out of air pump fittings 1090 and 1092, and back to the pump of 1094 air. The closed air flow circuit moves the air at approximately four liters per minute within the 1074 enclosed space to facilitate uniform temperature distribution within the 1074 enclosed space. In alternative embodiments, air may flow to either four air pump fittings 1086, 1087, 1088, 1089, 1090, and 1092 and outward any one of the two air pump fittings 1086, 1087, 1088, 1089, 1090, and 1092.
[0312] Heating element 1078 is embedded in heat-tolerant media and connected to heater plenum 1076 with an adhesive. In one embodiment, the heat tolerant media can be a polyamide. In an alternative embodiment, the heat tolerant media may be silicone rubber media. Heating element 1078 is connected to heater plenum 1076 with adhesive. The adhesive adheres to the heater plenum 1076 and the heat tolerant means in which the heating element 1078 is embedded. In one embodiment, heating element 1078 may be a copper-based resistive heater, such as a copper alloy heater. In alternative embodiments, heating element 1078 is a heater that fits within enclosure space constraints 1074. Heating element 1078 heats the air in enclosure 1074 to a desired temperature and heater plenum 1076 absorbs and transfers the heat to facilitate uniform temperature distribution within the enclosed space 1074.
[0313] The 1082 multi-pin electrical connector provides power to the 1078 heating element and potentiates the sensor values of the 1098 temperature sensor while maintaining a pressure-type connection to the 1062 housing. The 1098 temperature sensor senses the temperature of heater plenum 1076 so that the temperature within the enclosed space 1074 can be controlled. In one embodiment, heater plenum 1076 is maintained at 115 degrees Celsius so that the temperature in enclosed space 1074 is approximately 105 degrees Celsius. In alternative embodiments, heater plenum 1076 is maintained at a temperature such that the air temperature within enclosed space 1074 is maintained at a desired temperature between 70 and 120 degrees Celsius. ALTERNATIVE MODALITIES OF THE TOTAL INSTRUMENT
[0314] Figure 53A is a schematic view of instrument 100A. Figure 53B is a schematic view of instrument 100B. Instrument 100A and instrument 100B are alternative embodiments of instrument 100 seen in Figures 1 to 52. Instrument 100A includes tape path assembly 118A, which includes tape cutter station 1100, dispensing and sealing station 1102, hold station 1104, and a plurality of amplification and detection stations 1106 (including amplification and detection station 1106A, amplification and detection station 1106B, and amplification and detection station 1106C). Instrument 100B includes tape path assembly 118B, which includes tape cutter station 1110, dispensing and sealing station 1112, a plurality of waiting stations 1114 (which includes waiting station 1114A and waiting station 1114B), and a plurality of amplification and detection stations 1116 (which includes amplification and detection station 1116A, amplification and detection station 1116B, and amplification and detection station 1116C).
[0315] Tape path assemblies 118A and 118B extend through instruments 100A and 100B, respectively, and provide a path along which tape 104 has a plurality of wells that can advance. Tape 104 moves through instruments 100A and 100B from an inlet to an output of tape path assemblies 118A and 118B through the different stations in tape path assemblies 118A and 118B.
[0316] Instrument 100A includes tape cutter station 1100 which is positioned between a tape path mounting inlet 118A and dispensing and sealing station 1102; dispensing and sealing station 1102 is positioned between tape cutting station 1100 and holding station 1104; the waiting station 1104 is positioned between the dispensing and sealing station 1102 and the plurality of amplification and detection stations 1106; and the plurality of amplification and detection stations 1106 are positioned between the hold station 1104 and a tape path mounting output 118A. The plurality of amplification and detection stations 1106 includes three different amplification and detection stations in the embodiment shown in Figure 53A, but may include any number of amplification and detection stations in the alternative embodiments.
[0317] The amplification and detection stations 1106 are arranged parallel to each other in the instrument 100A. Tape 104 entering instrument 100A can be cut into a first tape segment with a single array of wells in tape cutter station 1100. The first tape segment can then move to dispensing and sealing station 1102 , wherein a biological sample and a reagent can be dispersed on the first strip segment to form a mixture of reagent and biological sample. The reagent and biological sample mixture can then be sealed onto the first tape segment in a dispensing and sealing station 1102. In addition, the first tape segment can be cooled to prevent the reagent and biological sample mixture from passing through a chemical reaction or heated to incubate the reagent and biological sample mixture in dispensing and sealing station 1102. The first strip segment can then move to waiting station 1104 where the first strip segment can be re-cooled to prevent Allow the reagent and biological sample mixture to undergo a chemical or heated reaction to incubate the reagent and biological sample mixture.
[0318] From the hold station 1104, the first tape segment can be routed to the amplification and detection station 1106A, the amplification and detection station 1106B, or the amplification and detection station 1106C. At any one of the plurality of amplification and detection stations 1106, the reagent and biological sample mixture may be thermally cycled or heated to a constant temperature. The reagent and biological sample mixture can also be analyzed in 1106 amplification and detection stations.
[0319] After the first segment of tape has moved from the dispensing and sealing station 1102 to the waiting station 1104, a second segment of tape can be cut from the tape 104 and moved to the dispensing and sealing station 1102. The second tape segment will undergo the same processing as the first tape segment, but may be moved to a different station among the plurality of amplification and detection stations 1106. In addition, a third tape segment may be cut from tape 104 and moved to the dispensing and sealing station 1102. The third tape segment will undergo the same processing as the first and second tape segments and move to the end station among the plurality of amplification and detection stations 1106. Have a plurality of amplification stations and detection 1106 allows instrument 100A to analyze multiple arrays of tape 104 at the same time. Amplification and detection stations 1106 can begin processing of tape 104 when tape 104 reaches each amplification and detection station 1106, or amplification and detection stations 1106 can be traversed at the same time. In an alternative embodiment, the waiting station 1104 may be eliminated and the tape segments may be passed from the dispensing and sealing station 1102 to one of the plurality of amplification and detection stations 1106.
[0320] Each of the plurality of amplification and detection stations 1106 may include the same means for analysis or different means for analysis. For example, the 1106 amplification and detection stations can analyze the reagent and biological sample mixture using polymerization chain reaction analysis. Alternatively, the amplification and detection station 1106A can analyze the mixture of reagent and biological sample with the use of polymerization chain reaction analysis, the amplification and detection station 1106B can analyze the mixture of reagent and biological sample with the use of casting curve analysis, and 1106C amplification and detection station can analyze the reagent mixture and biological sample with the use of isothermal amplification analysis. Having different means of analysis in each amplification and detection station 1106 allows a sample to be subjected to different analysis at the same time.
[0321] Instrument 100B includes tape cutting station 1110 which is positioned between a tape path mounting inlet 118B and dispensing and sealing station 1112; dispensing and sealing station 1112 is positioned between tape cutting station 1110 and holding station 1114A; waiting station 1114A is positioned between dispensing and sealing station 1112 and waiting station 1114B; the hold station 1114B is positioned between the hold station 1114A and the amplification and detection station 1116A; amplification and detection station 1116A is positioned between standby station 1114B and amplification and detection station 1116B; amplification and detection station 1116B is positioned between amplification and detection station 1116A and amplification and detection station 1116C; and amplification and detection station 1116C is positioned between amplification and detection stations 1116B and a tape path mounting output 118A. The plurality of amplification and detection stations 1116 includes three different amplification and detection stations in the embodiment shown in Figure 53B, but may include any number of amplification and detection stations in the alternative embodiments.
[0322] The amplification and detection stations 1116 are arranged in series with respect to one another in the instrument 100B. Tape 104 entering instrument 100B can be cut into a first tape segment with a single array of wells at tape cutter station 1100 or tape 104 can advance as a mat through tape cutter station 1110 without being cut. . A first tape array 104 can then move to the dispensing and sealing station 1112, where a biological sample and a reagent can be dispersed on the first tape array 104 to form a mixture of reagent and biological sample. The mixture of reagent and biological sample can then be sealed in the first array of tape 104 at dispensing and sealing station 1112. In addition, the first array of tape 104 can be cooled to prevent the mixture of reagent and biological sample from passing through. by a chemical or heated reaction to incubate the reagent and biological sample mixture in the dispensing and sealing station 1112. The first tape array 104 can then move to the waiting station 1114A where the first tape array 104 can be recooled to prevent the reagent and biological sample mixture from undergoing a chemical reaction, or heated to incubate the reagent and biological sample mixture.
[0323] When the first array of tape 104 advances to the waiting station 1114A, a second array of tape 104 can move to the dispensing and sealing station 1112. The second array of tape 104 can then undergo the same processing of the first tape array 104 in the dispensing and sealing station 1112. Thereafter, the first tape array 104 can move to the waiting station 1114B and the second tape array 104 can move to the waiting station 1114A. Both 1114A and 1114B waiting stations can cool or heat the reagent and biological sample mixture. A third array of tape 104 can then move to the dispensing and sealing station 1112. The third array of tape 104 can then undergo the same processing as the first array of tape 104 in the dispensing and sealing station 1112. At this point, the tape 104 can move through the instrument 100B so that the first tape array 104 is positioned in the amplification and detection station 1116C, the second tape array 104 is positioned in the amplification and detection station 1116B, and the third tape array 104 is positioned in amplification and detection station 1116C. At any one of the plurality of amplification and detection stations 1116, the reagent and biological sample mixture may be thermally cycled or heated to a constant temperature. The reagent and biological sample mixture can also be analyzed in amplification and detection stations 1116. Having a plurality of amplification and detection stations 1116 allows the instrument 100B to analyze multiple arrays in a single time. In an alternative embodiment, wait stations 1114A and 1114B may be eliminated and tape 104 may move from dispensing and sealing station 1112 to the plurality of amplification and detection stations 1116.
[0324] Each of the plurality of amplification and detection stations 1116 may include the same means for analysis or different means for analysis. For example, the 1116 amplification and detection stations can analyze the reagent and biological sample mixture using polymerization chain reaction analysis. Alternatively, the 1116A amplification and detection station can analyze the mixture of reagent and biological sample using polymerization chain reaction analysis, the 1116B amplification and detection station can analyze the mixture of reagent and biological sample using Casting curve analysis, and 1116C amplification and detection station can analyze the reagent mixture and biological sample with the use of isothermal amplification analysis.
[0325] Instrument 100A and instrument 100B are exemplary alternative modalities of instrument 100. It should be noted that there can be any number of alternative modalities of instrument 100. For example, instrument 100 can include any number of amplification and detection stations arranged in series, parallel or both. In addition, instrument 100 can include any number of dispensing stations arranged in series, parallel, or both. Instrument 100 can also include any number of standby stations or no standby stations. Additionally, instrument 100 can also include any number of tape path assemblies. Having different means of analysis in each amplification and detection station 1116 allows a sample to be subjected to different analysis at the same time.
[0326] The foregoing description is a non-exclusive description of possible embodiments of the present disclosure. It is contemplated that the revealed elements can be combined in any way. The described instrument may optionally include, additionally and/or alternatively, any one or more of the features, configurations and/or components described in the foregoing description.
[0327] Although the invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes can be made and that equivalents can be replaced by elements thereof without departing from the scope of the invention. Additionally, many modifications can be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope of the invention. Therefore, the invention is not intended to be limited to the specific embodiments disclosed, however, the invention will include all embodiments falling within the scope of the appended claims.

权利要求:
Claims (16)
[0001]
1. Instrument for processing a biological sample, wherein the instrument is characterized in that it comprises: a tape path assembly that defines a tape path along which a tape with a well array can be advanced through the instrument ; a dispensing assembly for aspirating the biological sample and a reagent and for dispensing the biological sample and reagent into the array of strip wells to form a mixture of reagent and biological sample; a sealing assembly to seal the mixture of reagent and biological sample to the tape; an amplification and detection assembly for detecting a signal from the mixture of reagent and biological sample in the array of wells on the tape, the amplification and detection system including a thermal unit positioned on the tape path that is configured and arranged to control temperature the mixing of reagent and biological sample in the array of strip wells; wherein the thermal unit comprising a plurality of cavities configured to receive respective wells of the well array, each cavity sized so that the outer surface of a well forms solid contact with the inner surface of the cavity; and a pressure chamber mounted on the thermal unit in the tape path to pressurize an area over the tape.
[0002]
2. Instrument according to claim 1, characterized in that the thermal unit comprises: a heat pump; a first layer comprising a plurality of wells configured to receive respective wells of the well array; and a second layer positioned between the heat pump and the first layer such that heat can be exchanged between the heat pump and the biological sample and reactant mixture in the well matrix via the first and second layers.
[0003]
3. Instrument according to claim 2, characterized in that the first layer is an aluminum layer and the second layer is a copper layer.
[0004]
4. Instrument according to any one of claims 1 to 3, characterized in that it additionally comprises an analytical system to analyze data that are collected from the mixture of reagent and biological sample.
[0005]
5. Instrument according to any one of claims 1 to 4, characterized in that the instrument is capable of both isothermal amplification and polymerization of the chain reaction.
[0006]
6. Instrument according to any one of claims 1 to 5, characterized in that it further comprises the tape that includes a first array of wells and a second array of wells deviated from the first array of wells.
[0007]
7. An instrument according to any one of claims 1 to 6, characterized in that it further comprises a tape having a first array of wells and a second array of wells that are bypassed from and intertwined with the first array of wells.
[0008]
8. Instrument according to any one of claims 1 to 7, characterized in that the tape path assembly includes a portion that extends through the instrument and defines a tape path along which the tape with the matrix of wells can be automatically advanced or retracted.
[0009]
9. Instrument according to any one of claims 1 to 8, characterized in that the tape path assembly that extends through substantially the entire length of the instrument and defines a tape path along which the tape, with the well array, it can be automatically advanced or retracted.
[0010]
10. Instrument according to any one of claims 1 to 9, characterized in that it additionally comprises a plate shelf configured to fix one or more plates containing the biological samples or the reagent.
[0011]
11. Instrument according to claim 10, characterized in that it further comprises a plate stacker which is configured to lift a plate off the plate shelf.
[0012]
12. Instrument according to claim 11, characterized in that it further comprises a plate shuttle, with a platform on which the plate forklift can position the plate from the plate shelf, wherein the plate shuttle is configured to position platform for vacuuming or dispensing.
[0013]
An instrument according to any one of claims 1 to 12, characterized in that it further comprises at least one dispensing assembly wash for washing portions of the dispensing assembly.
[0014]
14. Instrument according to any one of claims 1 to 13, characterized in that the tape path assembly comprises a drive mechanism to automatically advance the tape along the tape path.
[0015]
15. An instrument according to any one of claims 1 to 14, characterized in that the tape path assembly comprises a tape feed positioned adjacent a first end of the tape path to feed the tape to the instrument, and a tape cutter positioned near the first end of the tape path to cut the tape.
[0016]
16. Instrument according to any one of claims 1 to 15, characterized in that the pressure chamber comprises a heating element.

类似技术:

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公开号 | 公开日 | 专利标题

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BR112017001873B1|2021-06-22|INSTRUMENT FOR ANALYZING BIOLOGICAL SAMPLES AND REAGENTS

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JPWO2015151738A1|2017-04-13|Analysis equipment

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同族专利:

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公开号 | 公开日

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CN107076770A|2017-08-18|

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EP3175247B1|2020-08-19|

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AU2015296723B2|2020-12-24|

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ES2822993T3|2021-05-05|

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JP2017523809A|2017-08-24|

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JP6746574B2|2020-08-26|

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EP3175247A1|2017-06-07|

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SG11201700483UA|2017-02-27|

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JP2020174680A|2020-10-29|

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RU2017106623A|2018-08-28|

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WO2016018910A1|2016-02-04|

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EP3709026A1|2020-09-16|

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EP3175247A4|2018-01-10|

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DK3175247T3|2020-09-14|

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RU2017106623A3|2018-12-06|

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CN107076770B|2019-07-12|

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RU2697877C2|2019-08-21|

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CA2955846A1|2016-02-04|

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US20200191808A1|2020-06-18|

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BR112017001873A2|2017-11-28|

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US10620226B2|2020-04-14|

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CL2017000235A1|2017-12-01|

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US20170219614A1|2017-08-03|

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NZ728582A|2020-06-26|

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AU2015296723A1|2017-02-16|

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US11231430B2|2022-01-25|

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ZA201700540B|2021-06-30|

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法律状态:
2018-06-05| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|

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2018-07-24| B08G| Application fees: restoration [chapter 8.7 patent gazette]|

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2020-02-04| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-08-04| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-02-09| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-04-06| B09W| Correction of the decision to grant [chapter 9.1.4 patent gazette]|Free format text: RETIFIQUE-SE, PARA CORRECAO DE ERROS MATERIAIS NO QUADRO REIVINDICATORIO. |

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2021-06-22| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/07/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201462029961P| true| 2014-07-28|2014-07-28|

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US201462029959P| true| 2014-07-28|2014-07-28|

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US201462029954P| true| 2014-07-28|2014-07-28|

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US201462029965P| true| 2014-07-28|2014-07-28|

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US201462029953P| true| 2014-07-28|2014-07-28|

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US201462029968P| true| 2014-07-28|2014-07-28|

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US62/029,954|2014-07-28|

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US62/029,961|2014-07-28|

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US62/029,953|2014-07-28|

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US62/029,968|2014-07-28|

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US62/029,959|2014-07-28|

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PCT/US2015/042471|WO2016018910A1|2014-07-28|2015-07-28|Instrument for analyzing biological samples and reagents|

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