Flow cell with flexible connections

Abstract

The present disclosure relates to a flow cell with a flexible connection. The instrument includes a reagent management system. The reagent management system includes a plurality of reagent wells, each reagent well being operable to accommodate one of a plurality of reagents located therein. The reagent management system is operable to select a reagent flow from one of the plurality of reagents. The flexible connection includes a laminated stack and includes a first flexible channel in fluid communication with the reagent management system. The first flexible channel is operable to route a reagent flow through the first flexible channel. The flow cell includes a flow channel in fluid communication with the first flexible channel. The flow channel is operable to route a reagent flow through an analyte located in the flow channel. The flexible connection enables the flow cell to be moved by the instrument relative to a fixed reference point in the instrument.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a non-provisional application of U.S. Provisional Application No. 62 / 671,481, filed on May 15, 2018, entitled “Flow Cell with Flexible Connection”, and claims the benefit of the filing date of the provisional application, the contents of which are incorporated herein by reference. This application also claims priority to Netherlands Patent Application No. 2021147, filed on June 18, 2018, entitled “Flow Cell with Flexible Connection”, the contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to flow cells having flexible connections. Background Art

[0004] Many instruments using microfluidic devices can include a reagent management system (RMS) that can select multiple reagents and route multiple reagents to a flow cell, wherein the RMS and flow cell can be rigidly connected (i.e., connected so that the positions of the RMS and flow cell remain substantially fixed relative to each other). For example, the reagent management system can include multiple reagent wells (wells) that accommodate various reagents, wherein each reagent well can be connected to a rotary selection valve. The rotary valve is aligned with each reagent well to select any one of the reagents. A common pipeline is then used to route the selected reagent from the rotary valve to the inlet of the flow cell.

[0005] Analytes (such as DNA fragments, nucleic acid strands, etc.) can be positioned in the flow channel. Selected reagents can flow through the flow cell to perform various controlled chemical reactions on the analyte. The chemical reactions may affect certain detectable properties associated with the analyte. For example, one such detectable property can be photons of light emitted from the analyte.

[0006] A detection module (e.g., an imaging module) may be located within the instrument. The detection module may be operable to scan the flow cell to detect detectable properties. Device circuitry within the instrument may then process and transmit data signals derived from those detected properties. The data signals may then be analyzed to reveal the properties of the analyte.

[0007] However, the flow cells in many instruments are very sensitive to vibrations during the detection process. In addition, in order to detect small features in the flow cell (e.g., photons of light from the analyte), the detection module can often be positioned relative to the flow cell with micron accuracy (e.g., plus or minus 100 microns or less).

[0008] Because the RMS and flow cell can be rigidly connected and can not move within the instrument, it can move relative to the flow cell when the detection module scans the flow cell. However, the detection module may be several orders of magnitude heavier and larger than the flow cell. Therefore, it may be difficult to accurately position the detection module. In addition, the relatively large processing equipment required to position the detection module may inadvertently vibrate the flow cell. In addition, due to the size of the detection module and its associated processing equipment, it is expensive and time-consuming to scan several positions across the entire flow cell. Summary of the invention

[0009] The present disclosure provides advantages and alternatives over the prior art by providing a flexible connection for a flow cell that is connected to a reagent management system (RMS) in a fluid communication manner. The flexible connection enables the flow cell to move relative to a reference point on the instrument while the RMS is fixed relative to the reference point. Therefore, the flow cell can move relative to a detection module of the instrument while the detection module also remains stationary relative to the reference point. In addition, because the flow cell is not rigidly coupled to the RMS, the flow cell may be more accurately positioned relative to a fixed reference point on the instrument than the RMS or the detection module.

[0010] The RMS and flow cell may be included in a cartridge removable from the instrument, wherein the flow cell may or may not be removable from the cartridge. Alternatively, the RMS may be rigidly attached to the instrument, while the flow cell is removable from the instrument.

[0011] In addition, the flow cell and the flexible connection can be assembled together and included in a flexible connection module. The flexible connection module can be connected to a box or instrument. The module may or may not be operable to be detachably connected to the RMS in the box or instrument.

[0012] Because the flow cell is much lighter and smaller than the detection module, moving the flow cell may involve smaller and less expensive processing equipment than moving the detection module may involve. In addition, movement of the flow cell rather than the detection module reduces vibrations that may affect the accuracy of detection of photons of light or other forms of detectable properties associated with the analyte located in the flow cell. In addition, the flow cell can be moved to various positions faster than the speed at which the detection module can be moved to scan and detect the detectable properties.

[0013] Furthermore, even if the detection module is mobile relative to the reference point of the instrument and the flow cell is fixed, the flexible connection can advantageously reduce vibrations transmitted by the RMS to the flow cell. This is because the flexible connection can attenuate the vibrations generated by the RMS as they are transmitted through the flexible connection.

[0014] An instrument according to one or more aspects of the present disclosure includes a reagent management system (RMS) operable to be positioned in the instrument. The RMS includes a plurality of reagent wells, each reagent well operable to accommodate one of a plurality of reagents located therein. The RMS is operable to select a reagent flow from one of a plurality of reagents. A flexible connection is also operable to be positioned in the instrument. The flexible connection includes a first flexible channel in fluid communication with the RMS. The first flexible channel is operable to route a reagent flow through it. A flow cell is also operable to be positioned in the instrument. The flow cell includes a flow channel in fluid communication with the first flexible channel. The flow channel is operable to route a reagent flow through an analyte located in the flow channel. The flexible connection enables the flow cell to be moved by the instrument relative to a fixed reference point in the instrument.

[0015] The box of the instrument according to one or more aspects of the present disclosure includes a reagent management system (RMS) that is operable to select a reagent flow from one of a plurality of reagents contained in the RMS. A flexible connection is operable to be positioned in the box. The flexible connection includes a first flexible channel in fluid communication with the RMS. The first flexible channel is operable to route the reagent flow through it. A flow cell is operable to be positioned in the box. The flow cell includes a flow channel in fluid communication with the first flexible channel. The flow channel is operable to route the reagent flow through an analyte located in the flow channel. When the box is engaged with the instrument, the flexible connection enables the flow cell to be moved by the instrument relative to a fixed reference point in the instrument.

[0016] The flexible connection module according to one or more aspects of the present disclosure includes a flexible connection and a flow cell. The flexible connection includes a first channel inlet via, a first channel outlet via and a first flexible channel in fluid communication therebetween. The first channel inlet via includes a fluid seal that is operable to be connected to the RMS outlet and enables a reagent stream to pass through it. The flow cell includes an inlet, an outlet and a flow channel in fluid communication therebetween. The inlet is in fluid communication with the first channel outlet via of the flexible connection. The flow channel is operable to allow a reagent stream to be transmitted through an analyte located in the flow channel along a prescribed route. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The present disclosure will be more fully understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

[0018] Figure 1 depicts an example of a schematic block diagram of an apparatus according to aspects disclosed herein;

[0019] Figure 2 depicts an example of a schematic block diagram of an apparatus having a cartridge according to aspects disclosed herein;

[0020] Figure 3Describes aspects of the present disclosure Figure 2 Examples of more detailed schematic diagrams of instruments;

[0021] Figure 4 Describes aspects of the present disclosure Figure 3 Examples of schematic block diagrams of instruments;

[0022] Figure 5A depicts an example of a simplified perspective view of a flexible connection module and a portion of an RMS to which the module is operable to connect according to aspects disclosed herein;

[0023] Figure 5B Describes aspects of the present disclosure Figure 5A An example of a cross-sectional side view of a flexible connection module;

[0024] Figure 6 depicts an example of an exploded view of a flexible connection having a top layer, a bottom layer, and a middle layer according to aspects disclosed herein;

[0025] Fig. 7A Describes aspects of the present disclosure Figure 6 An example of a perspective view of a flexible connection;

[0026] Figure 7B Describes aspects of the present disclosure Figure 6 Example of a front side view of a flexible connection;

[0027] Figure 8 depicts an example of a curve of burst pressure versus the ratio of wall width to channel width according to aspects disclosed herein;

[0028] Fig. 9A depicts an example of a front side view of a flexible connection having an intermediate stack of sub-layers according to aspects disclosed herein, wherein 50% of the volume of the sub-layers is adhesive;

[0029] Fig. 9B depicts an example of a front side view of a flexible connection having an intermediate stack of sub-layers according to aspects disclosed herein, wherein 25% of the volume of the sub-layers is adhesive;

[0030] Fig.10 depicts an example of a pair of force versus displacement curves for a straight flexible connection without a slit and a straight flexible connection with a slit, respectively, according to aspects disclosed herein;

[0031] Fig.11 depicts an example of a pair of force versus displacement curves for a straight line flexible connection and an S-curve flexible connection, respectively, according to aspects disclosed herein;

[0032] Fig. 12Adepicts an example of a pair of force versus displacement curves for a laser bonded flexible connection and an adhesive bonded flexible connection, respectively, according to aspects disclosed herein;

[0033] Fig. 12B Describes aspects of the present disclosure Fig. 12A An exploded perspective view of a laser bonded flexible connection;

[0034] Fig. 12C Describes aspects of the present disclosure Fig. 12A An exploded perspective view of an adhesive bonded flexible connection;

[0035] Fig.13A depicts a top view of an example of a mechanical strain relief element fixedly coupled to a flexible connection according to aspects disclosed herein, wherein the strain relief element is configured as an epoxy bead;

[0036] Fig. 13B Describes aspects of the present disclosure Fig.13A A side view of an example of a mechanical strain relief element;

[0037] Fig. 13C Describes aspects of the present disclosure Fig.13A A perspective bottom view of an example of a mechanical strain relief element;

[0038] Fig.14A depicts a top view of an example of a mechanical strain relief element fixedly coupled to a flexible connection according to aspects disclosed herein, wherein the strain relief element is configured as a slot;

[0039] Fig. 14B Describes aspects of the present disclosure Fig.14A A side view of an example of a mechanical strain relief element;

[0040] Fig. 14C Describes aspects of the present disclosure Fig.14A A perspective view of an example of a mechanical strain relief element;

[0041] Fig.15A depicts a top view of an example of a mechanical strain relief element fixedly coupled to a flexible connection according to aspects disclosed herein, wherein the strain relief element is configured as a solid part having a first adhesive and a second adhesive bonded thereon;

[0042] Fig. 15B Describes aspects of the present disclosure Fig.15A a side view of an example of a mechanical strain relief element; and

[0043] Fig. 15C Describes aspects of the present disclosure Fig.15A A perspective view of an example of a mechanical strain relief element. DETAILED DESCRIPTION

[0044] Certain examples will now be described to provide a comprehensive understanding of the principles of the structure, function, manufacture and use of the methods, systems and devices disclosed herein. One or more examples are shown in the accompanying drawings. It will be understood by those skilled in the art that the methods, systems and devices particularly described herein and shown in the accompanying drawings are non-limiting examples, and the scope of the present disclosure is limited only by the claims. The features shown or described in conjunction with an example may be combined with the features of other examples. Such modifications and variations are defined to be included within the scope of the present disclosure.

[0045] The terms "substantially," "approximately," "about," "relatively," or other such similar terms that may be used throughout this disclosure, including the claims, are used to describe and take into account small fluctuations from a reference or parameter, for example, due to variations in processing. Such small fluctuations also include zero fluctuations from a reference or parameter. For example, they may refer to less than or equal to ±10%, such as less than or equal to ±5%, such as less than or equal to ±2%, such as less than or equal to ±1%, such as less than or equal to ±0.5%, such as less than or equal to ±0.2%, such as less than or equal to ±0.1%, such as less than or equal to ±0.05%.

[0046] refer to Figure 1 , depicts an example of a schematic block diagram of an instrument 100 according to aspects disclosed herein. The instrument 100 may be a sequencing instrument or other instrument utilizing microfluidic devices.

[0047] The instrument 100 includes a flow cell 102 in fluid communication with a reagent management system (RMS) 104, wherein the RMS 104 and the flow cell 102 are mechanically and flexibly connected together by a flexible connection 106. The RMS 104 is capable of selecting a plurality of reagents 108, 109, 110, 111, 112, 114, 116, 118 (herein 108-118) (in Figure 3 ) and routes these reagents to the flow cell 102. For purposes herein, the term "flexible" and its derivatives include the ability to be turned, bent, or twisted without damage or loss of function.

[0048] The flow cell 102 includes an inlet 120 and an outlet 122 connected by a flow channel 124 therebetween (in Figure 3 Analyte 140 (in Figure 3 (e.g., DNA fragments, nucleic acid chains, etc.) can be located in flow channel 124.

[0049] The selected reagents 108-118 can flow through the flow channel 124 of the flow cell 102 and be routed through the analyte 140 so as to perform various controlled chemical reactions on the analyte with the reagents 108-118 of the predetermined sequence. An example of a chemical reaction between the reagents and the analyte in the flow cell is one in which the reagents transport an identifiable tag (e.g., a fluorescently labeled nucleotide molecule, etc.) that can be used to label the analyte. Thereafter, the excitation light can be radiated through the top layer of the flow cell (or any other part of the flow cell) and reach the analyte, causing the fluorescent tag labeled to the analyte to fluoresce the emitted light photons. The emitted light photons can be scanned and / or detected by the detection module 126 (e.g., an imaging module) of the instrument 100 during the detection process.

[0050] During the detection process, the detection module 126 may or may not move relative to a fixed reference point on the instrument 100. For example, the detection module 126 may move relative to the reference point while the flow cell 102 remains fixed, so as to scan the flow channel 124 for emitted light photons. Alternatively, as an example, the detection module 126 may remain fixed relative to a reference point of the instrument while the flow cell 102 moves, so as to scan the flow channel 124 of the flow cell 102.

[0051] Device circuitry within the instrument 100 may then process and transmit data signals derived from those detected photons. The data signals may then be analyzed to reveal properties of the analyte 140.

[0052] Although the detection module 126 is shown in this example as an imaging module for detecting photons of light, other forms of detection modules 126 and detection schemes can be used to detect other forms of detectable properties associated with the analyte 140. For example, the detectable properties associated with the analyte 140 can include photons of light, electrical charge, magnetic field, electrochemical properties, pH changes, etc. In addition, the detection module 126 can include, without limitation, a sensing device that can be embedded in the flow cell 102, mounted in the instrument 100 external to the flow cell 102, or mounted in any combination of these two ways. The chemical reaction between the reagents 108-118 and the analyte 140 induces the analyte to affect the detectable property.

[0053] For purposes herein, the term "affecting a detectable property" and its derivatives include causing such a detectable property to be induced or altered in such a manner that its initiation or alteration is detectable by the detection module 126. For example, affecting a detectable property may include causing a fluorescent tag tagged to the analyte 140 to fluoresce emitted light photons, altering or inducing an electromagnetic field, changing pH, etc.

[0054] The detection module 126 may be equipped with all cameras and / or sensors suitable and / or required to detect the affected detectable property. Alternatively, some sensors may be embedded in the flow cell itself, wherein the sensors communicate with the detection module 126.

[0055] The flexible connection 106 enables the flow cell 102 to move relative to a fixed reference point 128 in the instrument 100 while the detection module 126 remains stationary relative to the reference point 128 to detect photons of light or other forms of detectable properties. Alternatively, the flow cell 102 can remain stationary relative to the reference point 128 while the detection module 126 moves to detect the detectable properties. In some implementations, both the flow cell 102 and the detection module 126 can move relative to the reference point 128. More specifically, the flow channel 124 of the flow cell 102 is moved through the focus area of ​​the sensing device and / or camera of the detection module 126 to allow the detection module 126 to scan the flow channel 124 for photons of light or other forms of detectable properties associated with the analyte 140.

[0056] The flow cell 102 can move in any of the three directions (as indicated by the X, Y, and Z arrows) relative to the reference point 128. In addition, the flow cell 102 can move so that it can rotate with any one or any combination of axes (i.e., X, Y, and Z) as the axis of rotation. In this example, the flow cell 102 can move in three-dimensional space with 6 degrees of freedom (i.e., any combination of linear motion in the X, Y, and Z directions plus any combination of rotational motion around the X, Y, and Z axes). However, it is important to note that no matter which direction the flow cell 102 moves, the flow cell 102 can be positioned in each of the three directions (i.e., in the X direction, the Y direction, or the Z direction) relative to the reference point 128 within a precise tolerance range (e.g., within a range of plus or minus 100 microns or less).

[0057] The reference point 128 may be any fixed structure or any number of fixed structures on the instrument 100. For example, the reference point 128 may be one or more mechanical registration holes or protrusions located throughout the instrument 100. Furthermore, the reference point 128 may include a single or multiple reference points to which one or more of the RMS 104, flow cell 102, and / or detection module 126 are aligned or positioned relative thereto, wherein the single reference points 128 may be aligned with a common reference point.

[0058] For purposes herein, various reference points 128 or groups of reference points 128 may be referred to as one or more registration systems. Additionally, positioning or aligning a component, such as flow cell 102, RMS 104, and / or detection module 126 relative to a registration system may be referred to herein as registering the component.

[0059] In addition, the flow cell 102 can be indirectly positioned relative to the reference point 128. For example, the detection module 126 can be positioned relative to the reference point 128, and the flow cell 102 can be positioned relative to a fixed reference point on the detection module 126. Alternatively, as an example, the detection module 126 can be positioned relative to the reference point 128, and then the detection module 126 can be used to detect the relative position of the flow cell 102 to the detection module 126.

[0060] The flow cell 102 moves relative to the detection module 126 so that the detection module 126 scans and detects photons of light or other forms of detectable properties affected by the analyte 140 located on the area of ​​the flow channel 124. Advantageously, the flow cell 102 is lighter and smaller than the detection module 126 by at least one order of magnitude. Therefore, compared to such positioning of the detection module 126 relative to the flow cell 102, the precise positioning of the flow cell 102 relative to the detection module 126 can be completed with smaller processing equipment, lower cost and in less time. In addition, the movement of the flow cell 102 can cause less vibration than the movement of the detection module 126.

[0061] Additionally, even though the detection module 126 is mobile relative to the reference point 128 of the instrument 100 and the flow cell 102 is fixed, the flexible connection 106 can advantageously reduce vibrations transmitted from the RMS 104 to the flow cell 102. This is because the flexible connection 106 separates the RMS 104 from the flow cell 102 and can therefore attenuate any vibrations generated by the RMS 104 that may be transmitted through the flexible connection 106.

[0062] In addition, whether the detection module 126 is movable or fixed, the flexible connection 106 advantageously enables independent registration (i.e., positioning) of the RMS 104 and the flow cell 102 with separate registration systems (i.e., separate reference points). Therefore, both the RMS 104 and the flow cell 102 can be more accurately registered to their associated reference points.

[0063] For example, the reference points 128 may include a first reference point of the RMS 104 and a second reference point of the flow cell 102. Thus, the RMS 104 may be positioned relative to the first reference point, and the flow cell 102 may be positioned relative to the second reference point. The respective positioning of the RMS 104 and the flow cell 102 relative to their respective first reference point and second reference point may be independent of each other.

[0064] refer to Figure 2, depicts an example of a schematic block diagram of a cartridge-based instrument according to aspects disclosed herein, wherein the instrument 100 includes a cartridge 130. The cartridge 130 includes a flow cell 102, an RMS 104, and a flexible connection 106. In addition, the cartridge 130 may be detachable from the instrument 100. In addition, the flow cell 102 may or may not be detachable from the cartridge 130. When the cartridge 130 is engaged with the instrument 100 and the flow cell 102 is engaged with the cartridge 130, the RMS 104 is fixed relative to a reference point 128 of the instrument 100, while the flow cell 102 is movable relative to the reference point 128 of the instrument 100.

[0065] During the engagement process of the box 130 with the instrument 100, the tolerance ranges of the positioning requirements (i.e., the registration requirements) of the RMS 104 and the flow cell 102 may be very different. More specifically, in order to engage the box 130 with the instrument 100, the RMS 104 can be positioned within a first tolerance range approximately predetermined relative to the reference point 128. This first tolerance range can be within a millimeter range, such as plus or minus 2 millimeters or less. On the other hand, when the flow cell 102 is aligned and / or moved to a predetermined position in the instrument 100 relative to the detection module 126 so as to be scanned by the detection module 126, the position of the flow cell can be positioned within a second predetermined tolerance range approximately relative to the reference point 128. This second tolerance range can be within a micrometer range, such as plus or minus 100 microns or less. Therefore, the first tolerance range can be at least 10 times larger than the second tolerance range.

[0066] This is because the RMS 104 may be aligned with certain mechanical components, such as valves and drive motors, for operation by the instrument 100. On the other hand, the flow cell 102 may be more precisely positioned relative to the detection module 126 to be optically scanned across the surface of the flow channel 124.

[0067] If the RMS 104 is rigidly connected to the flow cell 102 (i.e., connected so that the positions of the RMS 104 and the flow cell 102 remain substantially fixed relative to each other), then both the RMS 104 and the flow cell 102 may have to be positioned within the smaller of the two tolerance ranges (i.e., the second tolerance range of the flow cell 102). However, the flexible connection 106 decouples the positioning requirements of the RMS 104 and the flow cell 102. Therefore, by allowing separable alignment to engage the box 130 to the instrument 100 and position the flow cell 102 relative to the detection module 126, the RMS 104 and the flow cell 102 can be independently aligned according to their separate positioning requirements.

[0068] Even if the Figure 2The example shows a cartridge-based instrument 100 having an RMS 104 and a flow cell 102 contained in a cartridge 130, other instruments 100 may not include such a cartridge-based system. More specifically, in some instruments 100, the components of the RMS 104 may be integrally and rigidly mounted within the instrument 100, and only the flow cell 102 may be detachable from the instrument 100. However, even in such non-cartridge-based instruments 100, the flexible connection 106 still advantageously facilitates precise positioning of the flow cell 102 relative to the detection module 126 during the detection process.

[0069] refer to Figure 3 , depicting a device having a cartridge 130 engaged therein Figure 2 1 is an example of a more detailed schematic diagram of a cartridge-based instrument 100. The cartridge 130 includes a flow cell 102 and an RMS 104 connected with a flexible connection 106 therebetween.

[0070] The RMS includes a plurality of reagent wells 132. Each reagent well 132 is operable to receive one of the plurality of reagents 108-118 therein. The RMS 104 is operable to select a reagent stream 134 from one of the plurality of reagents 108-118.

[0071] The reagents 108-118 may be any of several types or combinations of reagents, depending on the type and sequence of chemical reactions to be performed at the flow cell. For example, the reagents 108-118 may be of the following types:

[0072] • Reagents 108 and 109 can be different formulations of a spike-in mixture, which is a mixture of chemicals that will spike the fluorescently labeled nucleotides into the DNA strand.

[0073] • Reagents 110 and 111 can be different formulations of a scan mix, which is a mixture of chemicals that stabilize the DNA strands during the detection process.

[0074] • Reagent 112 may be a cleave mix, which is a mixture of chemicals that enzymatically cleave fluorescently labeled nucleotides from a DNA strand.

[0075] • Reagents 114 and 116 can be different formulations of wash buffer, which is a mixture of wash reagents that remove active reagents from the flow cell.

[0076] • The reagent 118 may be air.

[0077] The flexible connection 106 includes a first flexible channel 136 in fluid communication with the RMS 104 through the RMS outlet 156. The first flexible channel 136 is operable to route a reagent stream 134 through the inlet 120 of the flow cell 102 and into the flow channel 124. The flexible connection 106 also includes a second flexible channel 138 in fluid communication with the flow channel 124 through the outlet 122 of the flow cell 102. The second flexible channel 138 is operable to route a reagent stream 134 from the flow cell 102 through the RMS inlet 158 ​​and back into the RMS 104 after the reagent stream 134 passes through the flow channel 124.

[0078] although Figure 3 The example in FIG. 1 shows a flexible connection 106 having a first flexible channel 136 and a second flexible channel 138 to route a reagent to and from the flow cell 102, but other configurations of flexible connections having any number of flexible channels may also be utilized. For example, the flexible connection 106 may include a first and a second flexible connection, wherein the first flexible connection has only a single flexible channel to route a reagent flow from the RMS 104 toward the flow cell 102, and the second flexible connection has only a single flexible channel to route a reagent flow from the flow cell 102 toward the RMS 104. Also as an example, the flexible connection 106 may include multiple flexible channels for routing a reagent flow toward the flow cell 102 and multiple flexible channels for routing a reagent flow from the flow cell 102.

[0079] The flow cell 102 of the cartridge 130 includes a flow channel 124 in fluid communication with a first flexible channel 136 through an inlet 120 and in fluid communication with a second flexible channel 138 through an outlet 122. The flow channel 124 is operable to perform various chemical reactions between various reagent streams 134 from the plurality of reagents 108-118 and analytes 140 located in the flow channel 124. The flexible connection 106 enables the flow cell 102 to move relative to a fixed reference point 128 in the instrument 100.

[0080] although Figure 3 The example of the flow cell 102 shown has a single inlet 120 and a single outlet 122, but other configurations of the flow cell can also be utilized. For example, the flow cell 102 can include multiple inlets 120 for receiving reagent flows from multiple flexible channels of the flexible connection 106. Also as an example, the flow cell can include multiple outlets 122 for routing reagent flows to multiple flexible channels of the flexible connection 106.

[0081] In this implementation, the fixed reference point 128 is a registration hole. However, the reference point 128 can be any number of fixed structures in the instrument 100. For example, the reference point 128 can be a plurality of registration pegs or holes located at different locations on the fixed frame of the instrument 100.

[0082] In this example, the cartridge 130 includes a rotary valve 142 for selecting reagents 108-118. The rotary valve 142 has an internal rotary valve body 144. The valve body 144 includes a central port 146 and a rotatable port 148 connected by a rotary channel 150. The valve body 144 pivots around the central port 146 to move the rotatable port 148.

[0083] A plurality of reagent wells 132 containing reagents 108-118 may be arranged around the periphery of the rotary valve 142 or otherwise remote from the rotary valve 142. Each reagent well 132 is in fluid communication with a corresponding well channel 152. Each well channel 152 includes a well channel port 154 with which the rotatable port 148 of the rotary valve 142 may be aligned to receive a reagent stream 134 from any given reagent well 132.

[0084] When the rotatable port 148 is aligned with one of the well channel ports 154, a flow path for the reagent stream 134 is established that allows the reagent stream 134 to flow from the selected well 132, through the well channel 152, through the rotary valve 142, through the common line 155, and out the RMS outlet 156. The reagent stream 134 then continues through the first flexible channel 136, into the inlet 120 of the flow cell 102, and through the flow channel 124, where a selected reagent from the plurality of reagents 108-118 can react with the analyte 140.

[0085] Unreacted reagents and / or byproducts of the reaction may flow out of the outlet 122 of the flow cell 102 and through the second flexible channel 138. The reagent stream 134 may then re-enter the RMS 104 through the RMS inlet 158.

[0086] The RMS inlet 158 ​​of the RMS 104 is in fluid communication with a first pinch valve 160. The first pinch valve 160 is in fluid communication with a second pinch valve 162. The first pinch valve 160 and the second pinch valve 162 include a resilient center portion that can be mechanically or pneumatically actuated to pinch or release the reagent flow 134 through the pinch valves 160, 162. Furthermore, while the pinch valves 160, 162 are shown in this example, other types of valves can be utilized to perform the same function. For example, the valves 160, 162 can be rotary valves.

[0087] An onboard pump 164 (e.g., a syringe pump or the like) is also disposed on the RMS 104. Even though the onboard pump 164 may be another type of pump, it will be referred to herein as a syringe pump 164. The syringe pump 164 is connected in a tee formation between the first pinch valve 160 and the second pinch valve 162. Both pinch valves 160, 162 are opened and closed by the instrument 100 to engage or disengage the syringe pump 164 with the flow cell 102 and / or the waste tank 172.

[0088] The syringe pump 164 includes a reciprocating plunger 166 disposed in a cylinder 168 having a cylinder bore 170. The plunger 166 is received in the cylinder bore 170 to form a plunger-cylinder bore seal. The plunger 166 is driven by the instrument 100 to reciprocate in the cylinder bore 170 and pump the reagents 108-118 from the reagent well 132 to a waste tank 172.

[0089] The instrument 100 also includes a detection module 126 operable to detect photons of light or other forms of detectable properties when a chemical reaction caused by the reagents 108-118 induces an analyte 140 to affect such detectable properties. The flexible connection 106 enables the flow cell 102 to move relative to a fixed reference point 128 in the instrument 100 while the detection module 126 remains stationary relative to the reference point 128 to facilitate detection of the detectable property.

[0090] Alternatively, the detection module 126 can be movable relative to a fixed reference point 128 while the flow cell 102 remains fixed relative to the reference point 128. Thus, the flexible connection 106 can enable the flow cell 102 to be more precisely positioned relative to the reference point 128 than a flow cell rigidly connected to the RMS 104. In some implementations, both the detection module 126 and the flow cell 102 can be movable relative to each other and / or the RMS 104.

[0091] Furthermore, even though the detection module 126 is movable relative to the reference point 128 while the flow cell 102 remains fixed, vibrations transmitted from the RMS 104 to the flow cell 102 can be advantageously reduced. This is because the flexible connection 106 separates the RMS 104 from the flow cell 102 and thus vibrations generated by the RMS 104 that can be transmitted through the flexible connection 106 can be attenuated.

[0092] In addition, because the flexible connection 106 separates the RMS 104 from the flow cell 102, the flexible connection 106 enables independent registration (i.e., positioning) of the RMS 104 and the flow cell 102 with separate registration systems (i.e., separate reference points). Therefore, both the RMS 104 and the flow cell 102 can be more accurately registered to their associated reference points.

[0093] although Figure 3 The illustrated implementation is that of an instrument 100 that utilizes a rotary valve 142 that routes the various reagents 108-118 through a common line 155 and into the flow cell 102, but other instruments 100 may not utilize a rotary valve 142. For example, the well channel 152 from each reagent well 132 may extend directly to one of a plurality of individual RMS outlets 156.

[0094] In this case, the well channels 152 may each include a valve (not shown) to control the reagent flow 134 from each reagent well 132. In addition, the first flexible channel 136 may be a plurality of first flexible channels, each of which is used to receive a corresponding reagent flow 134 from a corresponding RMS outlet 156. In addition, the inlet 120 of the flow cell 102 may be a plurality of inlets 120 to receive a variety of reagent flows 134 from each of the plurality of first flexible channels 136.

[0095] refer to Figure 4 , depicting Figure 3 The instrument 100 includes a docking station 174 to receive the cartridge 130. Various electrical and mechanical components within the instrument 100 interact with the cartridge 130 to operate the cartridge during microfluidic analysis operations of various chemical reactions performed in the flow cell 102.

[0096] The instrument 100 may include, among other things, one or more processors 176 that execute program instructions stored in a memory 178 to perform microfluidic analysis operations. The processor is in electronic communication with a rotary valve drive assembly 180, a syringe pump drive assembly 182, a pinch valve drive assembly 184, a detection module 126, and a movable temperature adjustment assembly 206.

[0097] A user interface 186 is provided for a user to control and monitor the operation of the instrument 100. A communications interface 188 may transfer data and other information between the instrument 100 and a remote computer, network, or the like.

[0098] The rotary valve drive assembly 180 includes a drive shaft 190 mechanically coupled to a rotary valve docking bracket 192. The rotary valve docking bracket 192 selectively mechanically couples to the rotary valve 142 of the cassette 130. The rotary valve drive assembly 180 includes a rotary motor 194 and, in some implementations, a translation motor 196. The translation motor 196 can move the drive shaft 190 in a translation direction between an engaged state and a disengaged state with the rotary valve 142. The rotary motor 194 manages the rotation of the rotary valve body 144 of the rotary valve 142.

[0099] The rotary valve drive assembly 180 also includes a position encoder 198 that monitors the position of the drive shaft 190. The encoder 198 provides position data to the processor 176.

[0100] The syringe pump drive assembly 182 includes a syringe pump motor 200 coupled to an extendable shaft 202. The shaft 202 is driven by the syringe pump motor 200 between an extended position and a retracted position to reciprocate the plunger 166 within the cylinder bore 170 of the cylinder 168 on the syringe pump 164.

[0101] The pinch valve drive assembly 184 includes a set of two pneumatically driven pinch valve drive motors 204. The two pinch valve drive motors 204 are mechanically coupled to corresponding pinch valves in the first pinch valve 160 and the second pinch valve 162. The pinch valve drive motors 204 can use air pressure to pinch or release the elastic center portion of the first pinch valve 160 and / or the second pinch valve 162 to pneumatically open and close the first pinch valve 160 and / or the second pinch valve 162. Alternatively, the pinch valve drive motors 204 can be electrically driven.

[0102] The detection module 126 may include all cameras and / or detection sensors suitable and / or required to achieve the detection of emitted light photons or other forms of detectable properties associated with the analytes 140 in the flow cell 102. Device circuitry (not shown) within the instrument 100 may then process and transmit data signals resulting from those detected emissions. The data signals may then be analyzed to reveal properties of the analytes 140.

[0103] A temperature regulation assembly 206 (or other environmental control device) may also be included in the instrument 100. The temperature regulation assembly 206 may be used to provide temperature control of the flow cell 102 during various chemical reactions. More specifically, the temperature regulation assembly 206 may provide heating and cooling of the flow cell 102, thereby achieving thermal cycling of the flow cell 102. The environmental control device may control or regulate parameters other than just temperature (e.g., pressure). As will be described in Figure 5A and Figure 5B As seen in more detail in , the temperature regulation assembly 206 can be movable relative to the reference point 128 and can provide a platform on which the flow cell 102 can be positioned to facilitate movement of the flow cell 102 relative to the detection module 126.

[0104] refer to Figure 5A and Figure 5B , depicts an example of a flexible connection module 300. More specifically, Figure 5A Depicted is an example of a simplified perspective view of a flexible connection module 300 and a portion of an RMS 104 to which the module 300 is operative to connect. Figure 5BAn example of a cross-sectional side view of a flexible connection module 300 connected in fluid communication to a portion of the RMS 104 is depicted, wherein the cross-sectional side view is taken along the first flexible channel 136 of the flexible connection 106 .

[0105] The flexible connection module 300 includes the flexible connection 106, the flow cell 102, and the support fixture 302. The flexible connection 106 is assembled to be in fluid communication with the flow cell 102, wherein the assembly of the flexible connection 106 and the flow cell 102 is framed and supported by the support fixture 302. The flexible connection module 300 can be connected to the RMS 104 within the instrument 100 or the cartridge 130.

[0106] The flexible connection 106 of the flexible connection module 300 includes a first channel inlet through-hole 304, a first channel outlet through-hole 306 and a first flexible channel 136 in fluid communication therebetween. The first flexible channel 136 is operable to route the reagent flow 134 from the RMS outlet 156 of the RMS 104 to the inlet 120 of the flow cell 102.

[0107] The flexible connection 106 also includes a second channel inlet through-hole 308, a second channel outlet through-hole 310, and a second flexible channel 138 in fluid communication therebetween. The second flexible channel 138 is operable to route the reagent flow 134 from the outlet 122 of the flow cell 102 to the RMS inlet 158 ​​of the RMS 104.

[0108] The first channel inlet through-hole 304 and the second channel outlet through-hole 310 may each include a fluid seal 312. The fluid seal 312 of the first channel inlet through-hole 304 is operable to connect to the RMS outlet 156 of the RMS 104 and enable the reagent flow 134 to pass through the fluid seal so that the reagent flow 134 is transferred from the RMS 104 to the first flexible channel 136. The fluid seal 312 of the second channel outlet through-hole 310 is operable to connect to the RMS inlet 158 ​​of the RMS 104 and enable the reagent flow 134 to pass through the fluid seal so that the reagent flow 134 is transferred from the second flexible channel 138 back into the RMS 104.

[0109] exist Figure 5A and Figure 5B The fluid seal 312 in the implementation shown in is a removable O-ring. However, other forms of removable fluid seals 312 can be utilized. For example, various elastic gaskets can be used to provide a removable fluid seal.

[0110] In addition, the fluid seal 312 can be non-detachably connected to the RMS 104 of the box and / or instrument. For example, the fluid seal 312 can be an adhesive layer bonded to the RMS 104, or the fluid seal 312 can be formed by laser bonding, which forms a permanent bond to the RMS 104.

[0111] The flow cell 102 of the flexible connection module 300 includes an inlet 120, an outlet 122, and a flow channel 124 in fluid communication therebetween. The flow channel 124 is operable to route a reagent flow 134 through an analyte 140 located in the flow channel 124.

[0112] The first channel outlet through-hole 306 is connected in fluid communication with the inlet 120 of the flow cell 102. In addition, the second channel inlet through-hole 308 is connected in fluid communication with the outlet 122 of the flow cell 102. The fluid connections from the first channel outlet through-hole 306 to the inlet 120 and from the second channel inlet through-hole 308 to the outlet 122 can be made with an adhesive layer 314 (at Figure 5B The adhesive layer 314 forms a permanent bond between the first channel outlet through-hole 306 and the inlet 120 and between the second channel inlet through-hole 308 and the outlet 122.

[0113] Adhesive layer 314 can be composed of several different materials that are suitable for processing application parameters, including application temperature, application pressure, and chemical compatibility with the reagents. For example, adhesive layer 314 can be composed of acrylic-based adhesives, silicone-based adhesives, heat-activated adhesives, pressure-activated adhesives, light-activated adhesives, epoxy adhesives, and the like, or combinations thereof.

[0114] Alternatively, other forms of bonding can be used to seal the connection between the first channel outlet through hole 306 and the inlet 120 and between the second channel inlet through hole 308 and the outlet 122. For example, the through hole and the port can be laser bonded together. In addition, the through hole and the port can be detachably connected with a detachable fluid seal (such as with an O-ring or an elastic gasket).

[0115] although Figure 5A and Figure 5BThe implementation shown in shows a flexible connection 106 having a first channel inlet through-hole 304, a first channel outlet through-hole 306, a second channel inlet through-hole 308, and a second channel outlet through-hole 310, but other configurations of flexible connections having any number of channels with any number of inlet through-holes and / or outlet through-holes may also be utilized. For example, the flexible connection 106 may be utilized only for reagent flow into the flow cell 102, wherein the flexible connection 106 may have only one inlet through-hole from the RMS 104, wherein multiple flexible channels fan out from the single inlet through-hole to multiple outlet through-holes to the flow cell 102. Alternatively, the flexible connection 106 may be utilized only for reagent flow into the flow cell 102, wherein the flexible connection 106 may have multiple flexible channels, each having a single inlet through-hole from the RMS 104 and a single outlet through-hole to the flow cell 102. Alternatively, the flexible connection 106 may be utilized only for reagent flow from the flow cell 102 into the RMS 104, wherein the flexible connection may have only one inlet through-hole from the flow cell 102, wherein multiple flexible channels fan out from the single inlet through-hole to multiple outlet through-holes to the RMS 104. The flexible connection 106 may be utilized only for reagent flow from the flow cell 102 into the RMS 104, wherein the flexible connection 106 may have multiple flexible channels, each having a single inlet through-hole from the flow cell 102 and a single outlet through-hole to the RMS 104. In yet other implementations, the flexible connection 106 may be utilized for both reagent flow into the flow cell 102 and out of the flow cell 102 from the same end or opposite end of the flow cell 102. In such implementations, the flexible connection 106 may include only one inlet through-hole, wherein multiple flexible channels fan out from the single inlet through-hole to multiple outlet through-holes, or may include multiple flexible channels, each having a single inlet through-hole and a single outlet through-hole. Configurations of additional flexible connections 106 may include a first flexible connection for reagent flow into the flow cell 102 and a second flexible connection for reagent flow out of the flow cell 102, wherein both the first and second flexible connections may include various configurations of inlet through-holes, outlet through-holes, and flexible channels connected therebetween.

[0116] The support fixture 302 of the flexible connection module 300 includes an inner boundary 316 surrounding the flow cell 102. The support fixture 302 is operable to contain the flow cell 102 within the inner boundary 316. The support fixture 302 can enable the flow cell 102 to move laterally in the Y direction and longitudinally in the X direction within the support fixture 302. In addition, the support fixture 302 can also allow the flow cell 102 to move vertically in the Z direction relative to the support fixture 302.

[0117] One way that the support fixture 302 can provide such movement in the X, Y, and Z directions while containing the flow cell 102 within the inner boundary 316 is to use a plurality of support fingers 318 arranged on the upper surface 320 and / or the lower surface 322 of the support fixture 302. The support fingers 318 can extend inwardly from the inner boundary 316 and partially cross the top surface and / or the bottom surface of the flow cell 102. For the support fingers 318 arranged on the upper surface 320, such support fingers 318 can be sized so that they do not extend across the flow channel 124 of the flow cell 102 so as not to interfere with the detection module 126 on the flow channel 124 during the detection process. The support fingers 318 can prevent the flow cell 102 and the flexible connection 106 from being significantly displaced or completely removed from the inner boundary 316 of the support fixture 302 during shipping of the flexible connection module 300 and / or during operation of the instrument 100.

[0118] Additionally, the support fingers 318 can allow the flow cell 102 to move laterally (in the Y direction) and longitudinally (in the X direction) within the inner boundary 316. In some implementations, the support fingers 318 can be disposed on a bottom surface 322 of the support fixture 302, and the support fingers 318 can be disposed on a top surface 320 of the support fixture 302 and can be spaced apart to allow the flow cell 102 to move a predetermined amount in the vertical (Z) direction while still maintaining the flow cell 102 within the inner boundary 316 of the support fixture 302.

[0119] although Figure 5A and Figure 5B The implementation in FIG. 1 shows a support fixture 302 having support fingers 318 for holding the flow cell 102, but other configurations of the support fixture 302 may also be utilized. For example, the support fixture 302 may be designed as a carrier plate that does not include any support fingers 318, and the flow cell 102 may be bonded to the top surface of the support fixture 302. In addition, even if Figure 5A and Figure 5B The implementation in FIG. 3 shows a support fixture 302 extending along the entire combined length of the flow cell 102 and the flexible connection 106 , other configurations of the support fixture 302 may also have the flexible connection 106 extending beyond the outer perimeter of the support fixture 302 .

[0120] During operation, the flexible connection module 300 may be assembled to the RMS 104 (at Figure 5B). Thereafter, the support fixture 302 may be clamped to the RMS 104 such that the fluid seal 312 is sandwiched between the support fixture 302 and the RMS 104. This may be accomplished with any number of clamping techniques, such as by bolting or by using a C-clamp or various other forms of clamping devices. In yet other implementations, the fluid seal 312 and the flexible connection module 300 may be attached via other attachment features, such as snap-in connectors, etc. Such attachment may be independent of the support fixture 302.

[0121] In the illustrated implementation, once the RMS 104 is in fluid communication with the flexible connection module 300, the flow cell 102 can be connected to the movable temperature adjustment assembly 206 (at Figure 5B 102). In some implementations, the support fingers 318 can be arranged on the lower surface 322 of the support fixture 302 to extend only partially across the bottom surface of the flow cell 102, thereby allowing the flow cell 102 to engage with the movable temperature adjustment assembly 206. Thus, sufficient bottom surface of the flow cell 102 can be exposed to the surface of the temperature adjustment assembly 206 to be engaged with the flow cell 102. Such engagement can allow the flow cell 102 to move longitudinally and laterally within the inner boundary 316 of the support fixture 302 when engaged with the temperature adjustment assembly 206.

[0122] The temperature adjustment assembly 206 can be operable to position the flow cell 102 within a few microns in the vertical (i.e., Z) direction relative to the position of the detection module 126. In addition, the temperature adjustment assembly 206 can move the flow cell 102 in one or both of the X and / or Y directions to enable the detection module 126 to scan the flow channel 124 of the flow cell 102 during the detection process.

[0123] Optionally, even if the detection module 126 moves relative to the reference point 128 while the flow cell 102 remains fixed during a scan of the flow cell 102, the temperature adjustment assembly 206 can still accurately position the flow cell 102 relative to the detection module 126 before starting the scan. This is because the flexible connection 106 decouples some of the movement of the flow cell 102 from the movement of the RMS 104. Therefore, the initial starting position of the flow cell 102 relative to the detection module 126 before scanning can be accurately maintained by moving the flow cell 102. If the flow cell 102 is not connected to the flexible connection 106 and is rigidly connected to the RMS 104, then parts of the flow cell 102 and / or the RMS 104 must all be moved, making such precise positioning of the flow cell 102 relative to the detection module 126 more difficult.

[0124] In addition, whether the detection module 126 is movable or fixed relative to the reference point, the flexible connection 106 separates the RMS 104 from the flow cell 102. Therefore, the flexible connection 106 enables independent registration (i.e., positioning) of the RMS 104 and the flow cell 102 with separate registration systems (i.e., separate reference points). Therefore, both the RMS 104 and the flow cell 102 can be more accurately registered to their associated reference points.

[0125] refer to Figure 6 , depicts an example of an exploded view of the flexible connection 106 having a top layer 210, a bottom layer 212, and a middle layer 214. An adhesive 216 is used to bond the top layer 210, the bottom layer 212, and the middle layer 214 together to form a laminate stack or lamination 218.

[0126] The first flexible channel 136 and the second flexible channel 138 are cut into the middle layer 214 using, for example, a laser cutting process. Thus, the middle layer 214 defines the geometry of the flexible channels 136, 138. More specifically, the middle layer 214 defines the wall width 220 and the channel width 222 (in Fig. 7A and Figure 7B best seen in ).

[0127] The top layer 210 defines a top portion 224 of the first flexible channel 136 and the second flexible channel 138 (at Fig. 7A and Figure 7B The bottom layer defines the bottom 226 of the first flexible channel 136 and the second flexible channel 138 (in Fig. 7A and Figure 7B best seen in ).

[0128] The first through hole 228 and the second through hole 230 are located in the bottom layer 212 of the flexible connection 106. The first through hole 228 and the second through hole 230 are in fluid communication with the first proximal end 232 and the first distal end 234 of the first flexible channel 136 in the middle layer 214. In addition, the third through hole 236 and the fourth through hole 238 are located in the bottom layer 212 of the flexible connection 106. The third through hole 236 and the fourth through hole 238 are in fluid communication with the second proximal end 240 and the distal end 242 of the second flexible channel 138 in the middle layer 214. Although the first through hole 228, the second through hole 230, the third through hole 236 and the fourth through hole 238 are located in the bottom layer 212 of the flexible connection 106, the third through hole 236 and the fourth through hole 238 are in fluid communication with the second proximal end 240 and the distal end 242 of the second flexible channel 138 in the middle layer 214. Figure 6 210, one or more through holes may be located in the top layer 210 and / or in both the top layer 210 and the bottom layer 212. More specifically, the first through hole 228 and the third through hole 236 may be located together in the bottom layer 212 or the top layer 210. In addition, the second through hole 230 and the fourth through hole 238 may also be located together in the bottom layer 212 or the top layer 210.

[0129] The first through-hole 228 can be coupled to the RMS outlet 156 of the RMS 104 to route the reagent flow 134 from the RMS 104 to the first flexible channel 136 (and thus the first through-hole 228 can be considered an inlet through-hole of the first flexible channel 136). The second through-hole 230 can be coupled to the inlet 120 of the flow cell 102 to route the reagent flow 134 from the first flexible channel 136 to the flow channel 124 (and thus the second through-hole 230 can be considered an outlet through-hole of the first flexible channel 136). The fourth through-hole 238 can be coupled to the outlet 122 of the flow cell 102 to route the reagent flow 134 from the flow cell 102 to the second flexible channel 138 (and thus the fourth through-hole 238 can be considered an inlet through-hole of the second flexible channel 138). The third through-hole 236 may be coupled to the RMS inlet 158 ​​of the RMS 104 to route the reagent flow 134 from the second flexible channel 138 back into the RMS 104 (and thus the third through-hole 236 may be considered an outlet through-hole of the second flexible channel 138 ).

[0130] The top layer 210, the bottom layer 212, and the middle layer 214 can be composed of several different materials that are suitable for the processing application parameters, including application temperature, application pressure, and chemical compatibility with the reagents. For example, the top layer 210, the bottom layer 212, and the middle layer 214 can be composed of polyethylene terephthalate, polyimide, cyclic olefin copolymer, polycarbonate, polypropylene, etc.

[0131] In addition, an additive of carbon black can be added to a material such as polyethylene terephthalate to provide black polyethylene terephthalate or the like. The material to which the carbon black additive is added can have relatively low autofluorescence properties. In addition, the carbon black additive can promote laser bonding of the top layer 210, the bottom layer 212, and the middle layer 214.

[0132] Adhesive 216 can be composed of several different materials that are suitable for processing application parameters, including application temperature, application pressure, and chemical compatibility with reagents. For example, adhesive 216 can be composed of acrylic-based adhesives, silicone-based adhesives, heat-activated adhesives, pressure-activated adhesives, light-activated adhesives, epoxy adhesives, and the like, or combinations thereof. Such adhesive 216 can be used to bond top layer 210, bottom layer 212, and middle layer 214 together.

[0133] In addition to adhesively bonding the top layer 210, the bottom layer 212, and the middle layer 214 together using the adhesive 216, the top layer 210, the bottom layer 212, and the middle layer 214 may also be bonded together in other ways. For example, a direct bonding technique such as heat (melt) bonding or laser bonding may be used to bond the top layer 210, the bottom layer 212, and the middle layer 214 together. In addition, any combination of adhesive bonding or direct bonding techniques may be used to bond the top layer 210, the bottom layer 212, and the middle layer 214 together.

[0134] In addition, with respect to adhesive bonding or direct bonding techniques, surface treatment of the top layer 210, the bottom layer 212, and the middle layer 214 can be used to enhance the strength of the various bonds. Such surface treatments can include, for example, chemical surface treatments, plasma surface treatments, and the like.

[0135] A simplified manufacturing method for constructing the flexible connection 106 can be to start by cutting each of the top layer 210, the bottom layer 212, and the middle layer 214 to predetermined specifications using, for example, a laser cutting process. The method can continue by aligning the top layer 210, the bottom layer 212, and the middle layer 214 together and bonding them with only manual pressure to make the layers stick together and form the stack 218. Thereafter, the stack 218 can be passed through a laminator to activate the adhesive 216 by applying a predetermined pressure. Thereafter, the stack 218 can be heated to a predetermined temperature (e.g., above about 50° C. or above about 90° C.) for a predetermined amount of time (e.g., about 2 hours or more) to fully form the flexible connection 106.

[0136] Additionally, the manufacturing process may include specific steps to reduce the number of air pockets that may be trapped between the top layer 210, the bottom layer 212, and the middle layer 214 during assembly. For example, positive pressure (e.g., about 100, 125, 150 psi or greater) or negative vacuum pressure (e.g., about -10, -12, -14 psi or less) may be applied for a predetermined amount of time to reduce the number of air pockets that may be trapped between the top layer 210, the bottom layer 212, and the middle layer 214. This process of applying pressure to reduce trapped air pockets may or may not be combined with elevated temperatures (e.g., greater than about 50° C. or greater than about 90° C.).

[0137] Thereafter, a bottom liner (not shown) that may be disposed on the adhesive 216 of the bottom layer 212 is removed to expose the adhesive 216. The flexible connection 106 is then bonded to the RMS 104 and the flow cell 102 by applying an appropriate force to the flexible connection 106 so as to activate the adhesive 216 disposed on the bottom of the flexible connection 106.

[0138] refer to Fig. 7A and Figure 7B , depicting Figure 6 A perspective view of the flexible connection 106 ( Fig. 7A ) and front and side views ( Figure 7B ). For purposes of clarity, in this particular example, only the first flexible channel 136 is shown.

[0139] The top layer 210, the bottom layer 212, and the middle layer 214 are combined together to form a laminate 218. The top layer 210, the bottom layer 212, and the middle layer 214 are thin, for example, from about 10 microns to about 1000 microns per layer in some cases. Therefore, the laminate 218 is flexible.

[0140] The stack height (or flexible connection height) 244 can range, for example, from about 30 microns to about 3000 microns. The channel height 246 is the distance between the top 224 and the bottom 226 of the first flexible channel 136. The channel height can range, for example, from about 10 microns to about 1000 microns. The channel width 222 is the distance between the two opposing inner walls 248, 250. The wall width 220 can be any practical size, depending on the design parameters. For example, the wall width 220 can range from about 250 microns to about 650 microns. As will be described in detail in the drawings, Figure 8 As discussed in more detail in , the ratio of wall width 220 to channel width 222 can be designed to be approximately 2.5 or greater.

[0141] refer to Figure 8 , depicts an example of a graph 252 of burst pressure 256 versus a ratio 254 of wall width 220 to channel width 222. The ratio 254 of wall width 220 to channel width 222 is shown on the horizontal axis of the graph 252. The burst pressure 256 (in pounds per square inch gauge (psig)) is shown on the vertical axis. Each plotted point 258 represents an intersection of the burst pressure 256 for a given ratio 254. Note that 1 pound per square inch (imperial units) is equal to approximately 0.069 bar (metric units).

[0142] The ratio 254 of the wall width 220 to the channel width 222 is a parameter that affects the burst pressure 256 of the flexible channel (e.g., the first flexible channel 136 or the second flexible channel 138) in the flexible connection 106. The larger the ratio 254, the higher the burst pressure 256 tends to be. In this case, the burst pressure 256 means the pressure at which leakage will occur in the flexible channels 136, 138.

[0143] The desired burst pressure 256 for an application may vary depending on the application parameters. However, a burst pressure 256 of 40 psig or greater in the first passage 136 and the second passage 138 is generally sufficient for most reagent stream 134 applications. From the plotted points 258 on the graph 252, it can be seen that a ratio 254 of about 2.5 or greater can result in a burst pressure 256 of about 40 psig or greater.

[0144] refer to Fig. 9A , depicting an example of a front-side view of a flexible connection with an intermediate stack of sublayers. Fig. 9A In the embodiment of the present invention, 50% of the volume of the sub-layer is adhesive.

[0145] refer to Fig. 9B , also depicted is an example of a front-side view of a flexible connection with an intermediate stack of sublayers. Fig. 9B In the embodiment of the present invention, 25% by volume of the sub-layer is adhesive.

[0146] Fig. 9A and Fig. 9B The flexible connection 106 of FIG. 1 includes a top layer 210 , a bottom layer 212 , and a middle layer 214 . However, the middle layer 214 is a plurality of middle sub-layers 260 bonded together by adhesive 262 .

[0147] exist Fig. 9A In the embodiment, the adhesive 262 has a volume of about 50% relative to the total volume of the adhesive 262 plus the intermediate sublayer 260, and the intermediate sublayer 260 may be composed of, for example, polyimide. Fig. 9B In the embodiment shown in FIG. 1 , there is only about 25% by volume of adhesive 262 relative to the total volume of adhesive 262 plus the intermediate sub-layer 260 composed of the same material (eg, polyimide).

[0148] The percentage by volume of adhesive 262 (eg, pressure sensitive adhesive) relative to the total of adhesive 262 plus intermediate sublayer 260 is also a parameter that affects the burst pressure. The smaller the percentage, the greater the burst pressure tends to be. Fig. 9A and Fig. 9B In the specific case of , the only difference between the two structures of the flexible connection 106 is the percentage by volume of adhesive 262 relative to the total of adhesive 262 and intermediate sublayer 260. Fig. 9A In , the percentage is 50%, and the burst pressure is 50 psig. Fig. 9B In the example, the ratio is 25% and the burst pressure is 130 psig.

[0149] refer to Fig.10, depicts an example of a pair of curves 264 and 266 of force (in Newtons) versus displacement (in millimeters) for a corresponding pair of linear flexible connections 106A, 106B. In curve 264, the associated flexible connection 106A includes only the first flexible channel 136 and the second flexible channel 138 disposed therein. In curve 266, the associated flexible connection 106B includes the first flexible channel 136 and the second flexible channel 138, but additionally includes a slit 268 disposed between the flexible channels 136, 138.

[0150] The separation of the reagent management system (RMS) 104 from the flow cell 102 may occur at the expense of applying additional mechanical stress to the RMS 104 and the flow cell 102. This is because the RMS 104 and the flow cell 102 can now move relative to each other due to the bending of the flexible connection 106. However, there are a variety of ways to mitigate this additional mechanical stress. One such way to reduce this stress (i.e., the forces involved in moving or displacing the flow cell 102 and / or the flexible connection 106) is to position a slit 268 between the first flexible channel 136 and the second flexible channel 138.

[0151] As shown in a comparison of curves 264 and 266, the slit 268 reduces the force involved in moving the flexible connection 106B relative to the force involved in moving the flexible connection 106A. More specifically, the first distal ends 263 of the flexible connections 106A and 106B are anchored, and the second distal ends 265 of the flexible connections 106A and 106B are moved toward the first distal ends 263 in the X direction by a predetermined distance (e.g., about 1% to 20% of the total length of the flexible connection). Thereafter, the second distal ends 265 are moved in a direction perpendicular to the X direction (i.e., the Y direction), and the force (in Newtons) required to move a given displacement (in millimeters) in the Y direction is then measured to plot curves 264 and 266.

[0152] The slits 268 reduce the force by at least about two times (as shown by curve 266) compared to the force involved in moving the flexible connection 106A without the slits 268 (as shown by curve 264). More specifically, the force applied to move the flexible connection 106A (and thus the flow cell 102) a distance of one millimeter without the slits 268 is greater than 0.2 Newtons (see curve 264), while the force applied to move the flexible connection 106B with the slits 268 is reduced to less than 0.1 Newtons (see curve 266). In addition, the force applied to move the flexible connection 106A a distance of four millimeters without the slits 268 is greater than 0.6 Newtons (see curve 264), while the force applied to move the flexible connection 106B with the slits 268 is reduced to less than 0.2 Newtons (see curve 266).

[0153] refer to Fig.11 , depicts an example of a pair of force versus displacement curves 270, 272 for a straight flexible connection 106C (curve 270) and an S-curve flexible connection 106D (curve 272). Another way to reduce the additional mechanical stress caused by separating the RMS 104 from the flow cell 102 via the flexible connection 106 is to design a sinuous shape into the flexible connection 106. In this particular example, the sinuous shape is an S-curve 274 of the flexible connection 106D designed as curve 272.

[0154] As shown in a comparison of curves 270 and 272, S-shaped curve 274 reduces the force involved in moving flexible connection 106D compared to the force involved in moving flexible connection 106C. More specifically, first distal ends 271 of flexible connections 106C and 106D are anchored, and second distal ends 273 of flexible connections 106C and 106D are moved toward first distal ends 271 in the X direction by a predetermined distance (e.g., approximately 1% to 20% of the total length of the flexible connection). Thereafter, second distal ends 273 are moved in a direction perpendicular to the X direction (i.e., the Y direction), and then the force (in Newtons) required to move a given displacement (in millimeters) in the Y direction is measured to plot curves 270 and 272.

[0155] The S-curve 274 reduces the force by at least about two times (as shown in curve 272) compared to the force involved in moving the flexible connection 106C without the S-curve 274 (as shown in curve 270). More specifically, the force applied to move the flexible connection 106C (and thus the flow cell 102) a distance of one millimeter without the S-curve 274 is greater than 0.2 Newtons (see curve 270), while the force applied to move the flexible connection 106D with the S-curve 274 is reduced to less than 0.1 Newtons (see curve 272). In addition, the force applied to move the flexible connection 106C a distance of 4 millimeters without the S-curve 274 is greater than 0.6 Newtons (see curve 270), while the force applied to move the flexible connection 106D with the S-curve is reduced to less than 0.1 Newtons (see curve 272).

[0156] refer to Fig. 12A , Fig. 12B and Fig. 12C , depicting a flexible connection 106E for laser bonding ( Fig. 12A and Fig. 12B Curve 276) and adhesive bonded flexible connection 106F ( Fig. 12A and Fig. 12C274). The flexible connections 106E and 106F both include an S-shaped curve 274.

[0157] Another way to reduce the additional mechanical stress caused by separating the RMS 104 from the flow cell 102 via the flexible connection 106 is in the choice of bonding process between the top layer 210, the bottom layer 212, and the middle layer 214. In this particular example, for each curve 276, 278, respectively, the only significant difference between the structure of the flexible connections 106E and 106F is the bonding process.

[0158] More specifically, the flexible connection 106E for curve 276 has been laser bonded. Fig. 12B As shown in the exploded perspective view of FIG. 27 , the top layer 210, bottom layer 212, and middle layer 214 of the flexible connection 106E are in direct contact with each other and do not include adhesive 216 therebetween. In contrast, the flexible connection 106F for curve 278 is bonded by adhesive. Fig. 12C As shown in the exploded perspective view of FIG. 1 , the top layer 210 , bottom layer 212 , and middle layer 214 of the flexible connection 106F include a layer of adhesive 216 (eg, a pressure sensitive adhesive) between the top layer 210 , bottom layer 212 , and middle layer 214 .

[0159] As shown in the comparison of curves 276 and 278, the adhesive bonding reduces the force involved in moving the flexible connection 106F. More specifically, the first distal ends 275 of the flexible connections 106E and 106F are anchored, and the second distal ends 277 of the flexible connections 106E and 106F are moved toward the first distal ends 275 in the X direction by a predetermined distance (e.g., about 1% to 20% of the total length of the flexible connection). Thereafter, the second distal ends 277 are moved in a direction perpendicular to the X direction (i.e., the Y direction), and then the force (in Newtons) required to move a given displacement (in millimeters) in the Y direction is measured to plot curves 276 and 278.

[0160] Adhesive bonding reduces the force involved in moving the flexible connection 106E that has been laser bonded (as shown in curve 276) by at least about 6 times (as shown in curve 278) compared to the force involved in moving the flexible connection 106F that has been adhesive bonded. More specifically, the force applied to move the flexible connection 106E (and thus the flow cell 102) a distance of one millimeter when laser bonded is greater than 0.6 Newtons (see curve 276), while the force applied to move the flexible connection 106F when adhesive bonded is reduced to less than 0.1 Newtons (see curve 278). In addition, the force applied to move the flexible connection 106E a distance of four millimeters when laser bonded is greater than 0.8 Newtons (see curve 276), while the force applied to move the flexible connection 106F when adhesive bonded is reduced to less than 0.1 Newtons (see curve 278).

[0161] refer to Fig.13A , Fig. 13B and Fig. 13C , depicts a top view of a mechanical strain relief element 400 fixedly coupled to a flexible connection 106 ( Fig.13A )、Side view( Fig. 13B ) and perspective bottom view ( Fig. 13C ). Fig.13A , Fig. 13B and Fig. 13C In the particular example shown, the strain relief element 400 is configured as an epoxy bead 402 .

[0162] The connection between the flexible connection 106 and the flow cell 102 may be strong enough to withstand the mechanical load (or mechanical stress) imposed on the flexible connection 106 during movement of the flow cell 102 and the stress due to temperature and pressure changes. If the connection is not strong enough, such stress may cause the connection between the flexible connection 106 and the flow cell 102 to sever. The strain relief element 400 can help relieve such stress.

[0163] In the case of the epoxy bead 402 configuration of the strain relief element 400, the epoxy bead 402 is primarily composed of epoxy that is placed along the corner 404 where the outer perimeter 406 of the flow cell 102 and the bottom surface 408 of the flexible connection 106 join. In this configuration of the strain relief element 400, at least some of the stress applied to the flexible connection 106 is redirected into the body of the flow cell 102 through the epoxy bead 402.

[0164] Any number of epoxies may be used, provided they have sufficient surface tension to form individual beads. For example, epoxy beads 402 may include an acrylic or silicone based adhesive, or may be a two-component UV curing epoxy.

[0165] refer to Fig.14A , Fig. 14B and Fig. 14C , depicts a top view of an example of a mechanical strain relief element 400 fixedly coupled to a flexible connection 106 ( Fig.14A )、Side view( Fig. 14B ) and perspective view ( Fig. 14C ), wherein the strain relief element 400 is configured as a slot 410. The slot 410 is located between the flexible connection 106 and the support fixture 302.

[0166] As shown, the groove 410 does not contact the flow cell 102. Thus, the groove transfers a portion of the stress (e.g., shear force) away from the connection between the flow cell 102 and the flexible connection 106 and redirects the stress into the support fixture 302 through the strain relief element 400. In other configurations, the groove 410 may include a positioning arm (not shown) that is used to align the groove 410 relative to the flow cell 102. However, the positioning arm may not be designed to transfer any significant amount of force into the flow cell 102.

[0167] The slot 410 includes a relief cut 412 located within a central portion of the slot 410. The relief cut 412 may penetrate the entire width 414 of the slot 410 from a top surface 416 (i.e., a surface that contacts the flexible connection 106) to a bottom surface 418 (i.e., a surface that contacts the support fixture 302). The relief cut 412 forms a mold to contain and shape the epoxy deposited into the relief cut 412 so as to bond the flexible connection 106 to the support fixture 302.

[0168] The walls 420 of the relief cutout 412 taper outwardly from the top surface 416 to the bottom surface 418 of the slot 410. That is, a cross-sectional view of the relief cutout 412 appears to be trapezoidal in shape, wherein the area of ​​the relief cutout 412 at the top surface 416 is less than the area of ​​the relief cutout 412 at the bottom surface 418. By providing a larger area at the bottom surface 418, a larger area of ​​epoxy contacts the support fixture 302 than would be the case if the walls 420 were not tapered. This larger area of ​​epoxy can provide a stronger bond between the support fixture 302 and the slot 410.

[0169] Despite Fig.14A , Fig. 14B and Fig. 14C In the illustrated example, the wall 420 is shown tapering outwardly, but other configurations of the wall may also be utilized. For example, the wall 420 may taper inwardly, or the wall 420 may be vertical.

[0170] A plurality of adhesive support rims 422 are positioned around the outer perimeter of the top surface 416 of the relief cutout 412. The adhesive support rims 422 protrude upward from the top surface 416. In this example, the adhesive support rims 422 protrude upward to approximately the level of the top surface of the flexible connection 106.

[0171] The adhesive support flange 422 can enable the epoxy to create surface tension contact with the adhesive support flange 422 so that the top of the epoxy can extend above the top surface 416 of the groove 410. Therefore, the epoxy can more easily encapsulate the flexible connection 106 to provide a stronger bond between the epoxy within the groove 410 and the flexible connection 106.

[0172] Although in this implementation the adhesive support flange 422 protrudes upward to the level of the top surface of the flexible connection 106, the adhesive support flange 422 may alternatively be designed to protrude upward to a different level. This is because the height of the adhesive support flange 422 may be due in part to the type of epoxy used in order to provide the best surface tension contact for the epoxy.

[0173] The fiducials (or through holes) 424 are located on and / or in the slots 410 to support automated pick and place manufacturing. More specifically, during manufacturing, a three-axis pick and place machine can grab the slots 410 and then can use a camera to view the fiducials 424 one by one to correctly position the slots 410 on the support fixture 302.

[0174] The tank 410 may be made of a plastic such as polycarbonate or any other plastic compatible with injection molding. The tank 410 may be manufactured as an injection molded part.

[0175] refer to Fig.15A , Fig. 15B and Fig. 15C , depicts a top view of an example of a mechanical strain relief element 400 fixedly coupled to a flexible connection 106 ( Fig.15A )、Side view( Fig. 15B ) and perspective view ( Fig. 15C ), wherein the strain relief element 400 is configured as a solid portion 430 having a first adhesive 432 (such as a pressure sensitive adhesive) and a second adhesive 434 (such as a pressure sensitive adhesive) bonded thereto. The solid portion 430 is located between the flexible connection 106 and the support fixture 302.

[0176] As shown, the solid portion 430 having the first adhesive 432 and the second adhesive 434 does not contact the flow cell 102. Thus, the solid portion 430 transfers a portion of the stress (e.g., shear force) away from the flow cell 102 and redirects the stress into the support fixture 302. In other configurations, the solid portion 430 may include a positioning arm (not shown) that is used to align the solid portion 430 relative to the flow cell 102. However, the positioning arm may not be designed to transfer any significant amount of force into the flow cell 102.

[0177] A first adhesive 432 is placed between a top surface 436 of the solid portion 430 (i.e., the surface positioned closest to the flexible connection 106) and the flexible connection 106. A second adhesive 434 is placed between a bottom surface 438 of the solid portion 430 (i.e., the surface closest to the support fixture 302) and the support fixture 302. The first adhesive 432, the second adhesive 434, and the solid portion 430 form a configuration of the strain relief element 400, which is a laminate structure adhered to both the flexible connection 106 and the support fixture 302.

[0178] The fiducials (or through holes) 440 are located on the solid portion 430 to support automated pick and place manufacturing. More specifically, during manufacturing, a three-axis pick and place machine can grab the solid portion 430 and then can use a camera to view the fiducials 440 one by one to correctly position the solid portion 430 on the support fixture 302.

[0179] The solid portion 430 may be made of a plastic such as polycarbonate or any other plastic compatible with injection molding. The solid portion 430 may be manufactured as an injection molded part.

[0180] An implementation of an instrument according to one or more aspects of the present disclosure includes a reagent management system, a flexible connection, and a flow cell. The reagent management system is operable to be positioned in the instrument. The reagent management system includes a plurality of reagent wells. Each reagent well is operable to accommodate one of a plurality of reagents located therein. The reagent management system is operable to select a reagent flow from one of a plurality of reagents. The flexible connection is operable to be positioned in the instrument. The flexible connection includes a first flexible channel in fluid communication with the reagent management system. The first flexible channel is operable to route a reagent flow through the channel. The flow cell is operable to be positioned in the instrument. The flow cell includes a flow channel in fluid communication with the first flexible channel. The flow channel is operable to route a reagent flow through an analyte located in the flow channel. The flexible connection enables the flow cell to be moved by the instrument relative to a fixed reference point in the instrument.

[0181] In another implementation of the instrument, the flexible connection enables the flow cell to move relative to a fixed reference point in the instrument while the detection module of the instrument remains stationary relative to the reference point.

[0182] In another implementation of the instrument, the instrument includes a box. The box includes a reagent management system, a flow cell, and a flexible connection therebetween. When the box is engaged with the instrument and the flow cell is engaged with the box, the reagent management system is fixed relative to a reference point of the instrument, and the flow cell is movable relative to a reference point of the instrument.

[0183] In another implementation of the instrument, the reagent management system is positioned within approximately a predetermined first tolerance range relative to the reference point. The flow cell is positioned within approximately a second predetermined tolerance range relative to the reference point. The first tolerance range is at least 10 times greater than the second tolerance range.

[0184] In another implementation of the instrument, the flexible connection includes a second flexible channel in fluid communication with the flow channel of the flow cell. The second flexible channel is operable to route the reagent flow from the flow cell to the reagent management system after the reagent flow passes through the flow channel.

[0185] In another implementation of the instrument, the flexible connection includes a slit between the first and second flexible channels to reduce the forces involved in moving the flexible connection.

[0186] In another implementation of the instrument, the flexible connection has a curved shape to reduce the forces involved in moving the flexible connection.

[0187] In another implementation of the instrument, the flexible connection includes: a top layer defining a top of the first flexible channel, a bottom layer defining a bottom of the first flexible channel, and a middle layer defining a wall width and a channel width of the first flexible channel. The ratio of the wall width to the channel width is about 2.5 or greater.

[0188] In another embodiment of the instrument, the instrument includes a detection module. When the reagent flow is transmitted through the analyte according to the prescribed route, a chemical reaction between the reagent flow and the analyte is performed. The chemical reaction induces the analyte to affect a detectable property associated with the analyte. The detection module is operable to detect the detectable property when the flow cell moves relative to the detection module.

[0189] In another implementation of the apparatus, the intermediate layer is a plurality of sub-layers.

[0190] In another implementation of the apparatus, the top layer, the middle layer, and the bottom layer are bonded together using one of an adhesive bonding process, a thermal bonding process, and a direct laser bonding process.

[0191] The implementation of the box according to one or more aspects of the present disclosure includes a reagent management system, a flexible connection and a flow cell. The reagent management system is operable to select a reagent flow from one of a plurality of reagents contained in the reagent management system. The flexible connection is operable to be positioned in the box. The flexible connection includes a first flexible channel in fluid communication with the reagent management system. The first flexible channel is operable to route the reagent flow through the first flexible channel. The flow cell is operable to be positioned in the box. The flow cell includes a flow channel in fluid communication with the first flexible channel. The flow channel is operable to route the reagent flow through an analyte located in the flow channel. When the box is engaged with the instrument, the flexible connection enables the flow cell to be moved by the instrument relative to a fixed reference point in the instrument.

[0192] In another implementation of the cartridge, the flexible connection includes a second flexible channel in fluid communication with the flow channel of the flow cell. The second flexible channel is operable to route the reagent flow from the flow cell to the reagent management system after the reagent flow passes through the flow channel.

[0193] In another implementation of the cartridge, the flexible connection includes a slit between the first and second flexible channels to reduce the forces involved in moving the flexible connection.

[0194] In another implementation of the cartridge, the flexible connection has a curved shape to reduce the forces involved in moving the flexible connection.

[0195] In another implementation of the cartridge, the flexible connection comprises: a top layer defining a top of the first flexible channel, a bottom layer defining a bottom of the first flexible channel, and a middle layer defining a wall width and a channel width of the first flexible channel. The ratio of the wall width to the channel width is about 2.5 or greater.

[0196] The implementation of the flexible connection module according to one or more aspects of the present disclosure includes a flexible connection and a flow cell. The flexible connection includes a first channel inlet through hole, a first channel outlet through hole and a first flexible channel in fluid communication therebetween. The first channel inlet through hole includes a fluid seal that is operable to be connected to a reagent management system outlet and enables a reagent flow to pass therethrough. The flow cell includes an inlet, an outlet and a flow channel in fluid communication therebetween. The inlet is in fluid communication with the first channel outlet through hole of the flexible connection. The flow channel is operable to allow a reagent flow to be transmitted through an analyte located in the flow channel along a prescribed route.

[0197] In another implementation of the flexible connection module, the flexible connection includes a second channel inlet through hole, a second channel outlet through hole and a second flexible channel in fluid communication therebetween. The second channel inlet through hole is in fluid communication with the outlet of the flow cell. The second channel outlet through hole includes a fluid seal that is operable to be connected to the reagent management system inlet and enables reagent flow to pass through it.

[0198] In another implementation of the flexible connection module, the fluid seal is a removable fluid seal operable to removably connect to the reagent management system outlet and enable reagent flow therethrough.

[0199] In another implementation of the flexible connection module, the flexible connection module includes a support fixture. The support fixture includes an inner boundary surrounding the flow cell. The support fixture is operable to contain the flow cell within the boundary and enable the flow cell to move laterally and longitudinally therein.

[0200] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail herein (assuming such concepts are not mutually inconsistent) are contemplated as part of the inventive subject matter disclosed herein. In particular, all combinations of the claimed subject matter appearing at the end of this disclosure are contemplated as part of the inventive subject matter disclosed herein.

[0201] Although the foregoing disclosure is described by reference to specific examples, it should be understood that many changes can be made within the spirit and scope of the inventive concepts described. It is therefore intended that the disclosure not be limited to the examples described, but that it has the full scope defined by the language of the appended claims.

[0202] Aspects of the present disclosure may be implemented in one or more of the following embodiments:

[0203] 1) An apparatus comprising:

[0204] a reagent management system operable to be positioned in the instrument, the reagent management system comprising a plurality of reagent wells, each reagent well operable to receive one of a plurality of reagents positioned therein, the reagent management system operable to select a reagent flow from one of the plurality of reagent wells;

[0205] a flexible connection comprised of a laminated stack and operable to be positioned in the instrument, the flexible connection comprising a first flexible channel in fluid communication with the reagent management system, the first flexible channel operable to route the reagent flow through the first flexible channel; and

[0206] a flow cell operable to be positioned in the instrument, the flow cell comprising a flow channel in fluid communication with the first flexible channel, the flow channel operable to route the reagent flow past an analyte located in the flow channel; and

[0207] Detection module;

[0208] Wherein the flow cell is movable by the instrument relative to a fixed reference point in the instrument.

[0209] 2) An instrument according to 1), wherein the flow cell is movable relative to the fixed reference point in the instrument, while the detection module remains stationary relative to the fixed reference point.

[0210] 3) The apparatus according to 1), comprising:

[0211] a cartridge comprising the reagent management system, the flow cell, and the flexible connection;

[0212] Wherein, when the box is engaged with the instrument and the flow cell is engaged with the box, the reagent management system is fixed relative to the fixed reference point of the instrument, and the flow cell is movable relative to the fixed reference point of the instrument.

[0213] 4) The apparatus according to 1), wherein:

[0214] The reagent management system is positioned relative to the fixed reference point within approximately a predetermined first tolerance range; and the flow cell is positioned relative to the fixed reference point within approximately a second predetermined tolerance range, the first tolerance range being at least 10 times larger than the second predetermined tolerance range.

[0215] 5) An instrument according to 1), wherein the flexible connection includes a second flexible channel connected to the flow channel fluid of the flow pool, and the second flexible channel is capable of operating to transfer the reagent flow from the flow pool to the reagent management system in a prescribed manner after the reagent flow passes through the flow channel.

[0216] 6) The apparatus of 5) wherein the flexible connection comprises a slit between the first flexible channel and the second flexible channel.

[0217] 7) The apparatus according to 1), wherein the flexible connection comprises a curved shape.

[0218] 8) The apparatus according to 1), wherein the flexible connection comprises:

[0219] a top layer defining a top portion of said first flexible channel;

[0220] a bottom layer defining a bottom of the first flexible channel; and

[0221] a middle layer defining a wall width and a channel width of the first flexible channel;

[0222] Wherein a ratio of the wall width to the channel width is greater than about 2.5.

[0223] 9) The apparatus according to 8), wherein the intermediate layer is a plurality of sub-layers.

[0224] 10) The apparatus according to 8), wherein the top layer, the middle layer and the bottom layer are bonded together using one of an adhesive bonding process, a thermal bonding process or a direct laser bonding process.

[0225] 11) An instrument according to 1), wherein when the reagent flow is transported through the flow channel according to a prescribed route, a chemical reaction is performed between the reagent flow and the analyte, and the chemical reaction induces the analyte to affect a detectable property associated with the analyte; and wherein the detection module is capable of operating to detect the detectable property.

[0226] 12) The apparatus of 1) comprising a mechanical strain relief element fixedly coupled to the flexible connection.

[0227] 13) The apparatus according to 12), wherein the mechanical strain relief element is one of the following:

[0228] Epoxy beads,

[0229] slot, or

[0230] A solid piece having a first adhesive and a second adhesive bonded thereon.

[0231] 14) A box comprising:

[0232] a reagent management system operable to select a reagent flow from one of a plurality of reagents contained in the reagent management system;

[0233] a flexible connection formed from a laminate stack and comprising a first flexible channel in fluid communication with the reagent management system, the first flexible channel being operable to route the reagent flow through the first flexible channel; and

[0234] a flow cell including a flow channel in fluid communication with the first flexible channel, the flow channel being operable to route the reagent flow past an analyte located in the flow channel;

[0235] Wherein the flexible connection enables the flow cell to be moved relative to the reagent management system.

[0236] 15) A box according to 14), wherein the flexible connection includes a second flexible channel connected to the flow channel fluid of the flow pool, and the second flexible channel is capable of operating to transfer the reagent flow from the flow pool to the reagent management system in a prescribed manner after the reagent flow passes through the flow channel.

[0237] 16) The cartridge of 15), wherein the flexible connection comprises a slit between the first flexible channel and the second flexible channel.

[0238] 17) A box according to 14), wherein the flexible connection includes a curved shape.

[0239] 18) The box according to 14), wherein the flexible connection includes:

[0240] a top layer defining a top portion of said first flexible channel;

[0241] a bottom layer defining a bottom of the first flexible channel; and

[0242] a middle layer defining a wall width and a channel width of the first flexible channel;

[0243] Wherein a ratio of the wall width to the channel width is greater than about 2.5.

[0244] 19) The box according to 14) includes a mechanical strain relief element fixedly coupled to the flexible connection.

[0245] 20) The cartridge according to 19), wherein the mechanical strain relief element is one of the following:

[0246] Epoxy beads,

[0247] slot, or

[0248] A solid piece having a first adhesive and a second adhesive bonded thereon.

[0249] 21) A flexible connection module, comprising:

[0250] a flexible connection formed from a laminate stack and comprising a first channel inlet through-hole, a first channel outlet through-hole, and a first flexible channel in fluid communication between the first channel inlet through-hole and the first channel outlet through-hole, wherein the first channel inlet through-hole comprises a fluid seal operable to connect to a reagent management system outlet and enable reagent flow therethrough; and

[0251] A flow cell comprising an inlet, an outlet and a flow channel in fluid communication between the inlet and the outlet, wherein the inlet is in fluid communication with the first channel outlet through-hole of the flexible connection, and the flow channel is operable to route the reagent flow through an analyte located in the flow channel.

[0252] 22) The flexible connection module according to 21), wherein the flexible connection comprises:

[0253] a second channel inlet through-hole, a second channel outlet through-hole, and a second flexible channel in fluid communication between the second channel inlet through-hole and the second channel outlet through-hole;

[0254] wherein the second channel inlet through-hole is in fluid communication with the outlet fluid of the flow cell; and

[0255] Wherein said second channel outlet through-hole comprises a fluid seal operable to connect to a reagent management system inlet and enable said reagent flow therethrough.

[0256] 23) The flexible connection module according to 21), wherein the fluid seal is a removable fluid seal operable to be removably connected to the reagent management system outlet and enable the reagent flow to pass therethrough.

[0257] 24) The flexible connection module according to 21), comprising:

[0258] A support fixture includes an inner boundary surrounding the flow cell, the support fixture being operable to contain the flow cell within the inner boundary and to enable the flow cell to move laterally and longitudinally therein.

[0259] 25) The flexible connection module according to 21), comprising a mechanical strain relief element fixedly coupled to the flexible connection.

[0260] 26) The flexible connection module according to 25), wherein the mechanical strain relief element is one of the following:

[0261] Epoxy beads,

[0262] slot, or

[0263] A solid piece having a first adhesive and a second adhesive bonded thereon.

Claims

1. An apparatus for managing reagents, comprising: a reagent management system operable to be positioned in the instrument, the reagent management system comprising a plurality of reagent wells, each reagent well operable to receive one of a plurality of reagents positioned therein, the reagent management system operable to select a reagent flow from one of the plurality of reagent wells; a flexible connection comprised of a laminated stack and operable to be positioned in the instrument, the flexible connection comprising a first channel inlet through-hole, a first channel outlet through-hole, and a first flexible channel in fluid communication between the first channel inlet through-hole and the first channel outlet through-hole, the first channel inlet through-hole being in fluid communication with the reagent management system, the first flexible channel operable to route the reagent flow through the first flexible channel; wherein the first flexible channel has a burst pressure of 40 psig or greater; wherein the burst pressure of the first flexible channel is the pressure at which a leak will occur in the first flexible channel; wherein the flexible connection comprises an S-shaped curved shape; wherein a first distal end of the flexible connection is anchored and a second distal end of the flexible connection is movable toward the first distal end in an X direction by 20% of a distance, and thereafter, the second distal end is movable in a direction perpendicular to the X direction by a force of less than 0.1 Newtons by a distance of four millimeters; and a flow cell operable to be positioned in the instrument, the flow cell comprising an inlet, an outlet, and a flow channel in fluid communication between the inlet and the outlet, wherein the inlet is in fluid communication with the first channel outlet through-hole of the flexible connection, the flow channel is in fluid communication with the first flexible channel, the flow channel being operable to route the reagent flow past an analyte located in the flow channel; Detection module; wherein the reagent management system and the flow cell are mechanically and flexibly connected together via the flexible connection; wherein the flow cell is movable by the instrument relative to a fixed reference point in the instrument, and the reagent management system is fixed relative to the reference point; and The flexible connection comprises: a top layer defining a top portion of said first flexible channel; a bottom layer defining a bottom of the first flexible channel; and a plurality of intermediate layers bonded together by an adhesive to define the wall width and channel width of the first flexible channel; Wherein a ratio of the wall width to the channel width is greater than about 2.

5.

2. An instrument according to claim 1, wherein the flow cell is movable relative to the fixed reference point in the instrument, while the detection module remains stationary relative to the fixed reference point.

3. The apparatus according to claim 1, comprising: a cartridge comprising the reagent management system, the flow cell, and the flexible connection; Wherein, when the box is engaged with the instrument and the flow cell is engaged with the box, the reagent management system is fixed relative to the fixed reference point of the instrument, and the flow cell is movable relative to the fixed reference point of the instrument.

4. The apparatus according to claim 1, wherein: The reagent management system is positioned within a predetermined first tolerance range relative to the fixed reference point; and the flow cell is positioned within a second predetermined tolerance range relative to the fixed reference point, the first tolerance range being at least 10 times larger than the second predetermined tolerance range.

5. An instrument according to claim 1, wherein the flexible connection includes a second flexible channel connected to the flow channel fluid of the flow pool, and the second flexible channel is capable of operating to transfer the reagent flow from the flow pool to the reagent management system in a prescribed manner after the reagent flow passes through the flow channel.

6. The apparatus of claim 5, wherein the flexible connection comprises a slit between the first flexible channel and the second flexible channel.

7. The apparatus of claim 1, wherein the top layer, the middle layer, and the bottom layer are bonded together using one of an adhesive bonding process, a thermal bonding process, or a direct laser bonding process.

8. The apparatus of claim 1 , wherein when the reagent stream is routed through the flow channel, a chemical reaction is performed between the reagent stream and the analyte, the chemical reaction inducing the analyte to affect a detectable property associated with the analyte; and in, The detection module is operable to detect the detectable property.

9. The apparatus of claim 1, comprising a mechanical strain relief element fixedly coupled to the flexible connection.

10. The apparatus of claim 9, wherein the mechanical strain relief element is one of: Epoxy beads, slot, or A solid piece having a first adhesive and a second adhesive bonded thereon.

11. A cartridge for reagent flow, comprising: a reagent management system operable to select a reagent flow from one of a plurality of reagents contained in the reagent management system; a flexible connection formed by a laminate stack and comprising a first channel inlet through-hole, a first channel outlet through-hole, and a first flexible channel in fluid communication between the first channel inlet through-hole and the first channel outlet through-hole, the first channel inlet through-hole being in fluid communication with the reagent management system, the first flexible channel being operable to route the reagent flow through the first flexible channel; wherein the first flexible channel has a burst pressure of 40 psig or greater; wherein the burst pressure of the first flexible channel is the pressure at which a leak will occur in the first flexible channel; wherein the flexible connection comprises an S-shaped curved shape; wherein the first distal end of the flexible connection is anchored and the second distal end of the flexible connection is movable toward the first distal end in an X direction by 20% of a distance, and thereafter, the second distal end is movable in a direction perpendicular to the X direction by a force of less than 0.1 Newtons by a distance of four millimeters; and a flow cell comprising an inlet, an outlet, and a flow channel in fluid communication between the inlet and the outlet, wherein the inlet is in fluid communication with the first channel outlet through-hole of the flexible connection, the flow channel is in fluid communication with the first flexible channel, the flow channel being operable to route the reagent flow past an analyte located in the flow channel; wherein the reagent management system and the flow cell are mechanically and flexibly connected together via the flexible connection; wherein the flexible connection enables the flow cell to be moved relative to the reagent management system while the reagent management system is fixed relative to a reference point; The flexible connection comprises: a top layer defining a top portion of said first flexible channel; a bottom layer defining a bottom of the first flexible channel; and a plurality of intermediate layers bonded together by an adhesive to define the wall width and channel width of the first flexible channel; Wherein a ratio of the wall width to the channel width is greater than about 2.

5.

12. A box according to claim 11, wherein the flexible connection includes a second flexible channel connected to the flow channel fluid of the flow pool, and the second flexible channel is capable of operating to transfer the reagent flow from the flow pool to the reagent management system in a prescribed manner after the reagent flow passes through the flow channel.

13. The cartridge of claim 12, wherein the flexible connection comprises a slit between the first flexible channel and the second flexible channel.

14. The cartridge of claim 11, comprising a mechanical strain relief element fixedly coupled to the flexible connection.

15. The cartridge of claim 14, wherein the mechanical strain relief element is one of: Epoxy beads, slot, or A solid piece having a first adhesive and a second adhesive bonded thereon.

16. A flexible connection module, comprising: a flexible connection formed by a laminate stack and comprising a first channel inlet through-hole, a first channel outlet through-hole, and a first flexible channel in fluid communication between the first channel inlet through-hole and the first channel outlet through-hole, wherein the first channel inlet through-hole comprises a fluid seal operable to connect to a reagent management system outlet and enable reagent flow through the fluid seal; wherein the first flexible channel has a burst pressure of 40 psig or greater; wherein the burst pressure of the first flexible channel is the pressure at which a leak will occur in the first flexible channel; wherein the flexible connection comprises an S-shaped curved shape; wherein a first distal end of the flexible connection is anchored and a second distal end of the flexible connection is movable toward the first distal end in an X direction by 20% of a distance, and thereafter, the second distal end is movable in a direction perpendicular to the X direction by a force of less than 0.1 Newtons by a distance of four millimeters; a flow cell comprising an inlet, an outlet, and a flow channel in fluid communication between the inlet and the outlet, wherein the inlet is in fluid communication with the first channel outlet through-hole of the flexible connection, the flow channel being operable to route the reagent flow past an analyte located in the flow channel; and The flexible connection comprises: a top layer defining a top portion of said first flexible channel; a bottom layer defining a bottom of the first flexible channel; and a plurality of intermediate layers bonded together by an adhesive to define the wall width and channel width of the first flexible channel; Wherein a ratio of the wall width to the channel width is greater than about 2.

5.

17. The flexible connection module according to claim 16, wherein the flexible connection comprises: a second channel inlet through-hole, a second channel outlet through-hole, and a second flexible channel in fluid communication between the second channel inlet through-hole and the second channel outlet through-hole; wherein the second channel inlet through-hole is in fluid communication with the outlet fluid of the flow cell; and Wherein said second channel outlet through-hole comprises a fluid seal operable to connect to a reagent management system inlet and enable said reagent flow therethrough.

18. The flexible connection module of claim 16, wherein the fluid seal is a removable fluid seal operable to removably connect to the reagent management system outlet and enable the reagent flow therethrough.

19. The flexible connection module according to claim 16, comprising: A support fixture includes an inner boundary surrounding the flow cell, the support fixture being operable to contain the flow cell within the inner boundary and to enable the flow cell to move laterally and longitudinally therein.

20. The flexible connection module of claim 16, comprising a mechanical strain relief element fixedly coupled to the flexible connection.

21. The flexible connection module of claim 20, wherein the mechanical strain relief element is one of the following: Epoxy beads, slot, or A solid piece having a first adhesive and a second adhesive bonded thereon.

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