Capillary array manufacturing method

Abstract

A capillary array assembly is manufactured by inserting capillaries into corresponding grooves of a substrate and fixing the capillaries to the substrate. The capillaries are secured by applying heat and force to the substrate, along with a defined displacement of the substrate material and for a defined period of time, so that the heated portion of the substrate is spread over the capillaries. After application of heat and force, capillary tubes are at least partially embedded by the substrate and may be at least partially exposed to the top outer surface of the substrate through the respective slots. The capillary array assembly may be used in a sample analyzer, such as a capillary electrophoresis (CE) instrument.

Description

Technical Field

[0001] This invention relates to capillary array assemblies and methods for manufacturing such capillary array assemblies. The invention also relates to devices, systems, etc., that include or operate in conjunction with such capillary array assemblies. Capillary array assemblies can, for example, be used as part of analytical techniques such as capillary electrophoresis (CE). Background Technology

[0002] Analytical instruments typically utilize capillaries (i.e., tubes with micron-sized internal pores) to contain and transport fluids (in liquid or gas phase) containing samples for various purposes. In some analytical instruments, capillaries can be configured to separate analytes (i.e., target sample components, such as chemical or biological compounds) in a sample based on different properties or attributes (such as molecular size, molecular composition, charge, etc.). For this purpose, the capillary may contain a separation medium within its internal pores. The separation medium can be a stationary phase permanently or semi-permanently located within the capillary. A semi-permanent phase can be a separation medium that requires periodic replacement or regeneration during the capillary's lifespan. Depending on the analytical technique, the stationary phase can be a polymer gel, bead packing material, a monolithic material with gaps allowing fluid flow, a liner or membrane on the inner surface of the capillary that defines its internal pores. Alternatively, the separation medium can be a dynamic phase, which may require more frequent replacement or regeneration, such as after each analytical run or even during the same analytical run. In use, the sample is carried by a fluid (i.e., the mobile phase) through a capillary and comes into contact with the separation medium. As the sample migrates through the separation medium, the different analytes in the sample separate from each other, thus facilitating the detection / measurement of the analytes by the analytical instrument. Examples of analytical separation techniques include capillary electrophoresis (CE, such as capillary gel electrophoresis or CGE, capillary zone electrophoresis or CZE, etc.), liquid chromatography (LC), and gas chromatography (GC).

[0003] In some analytical instruments, a capillary (or at least the optically transparent portion of the capillary, referred to as a capillary window) can be used as a sample detection cell. In this case, the analytical instrument is configured to perform optical-based measurements (e.g., fluorescence, absorbance, imaging, etc.) of the sample analyte contained in the capillary by reading the electromagnetic energy emitted by the sample. This emission can be due to the analytical instrument's electromagnetic radiation source irradiating the capillary window with an electromagnetic energy beam, thereby irradiating the sample. This type of detection / measurement, referred to as capillary detection, is performed after the analyte has separated in the capillary but remains there. Alternatively, the outlet end of the capillary can extend into a flow cell, from which a fluid containing the separated analyte is emitted. In the latter case, detection optics (e.g., electromagnetic energy source and detector) may interact with the analyte-containing fluid emitted from the capillary.

[0004] Operating multiple capillaries in parallel within the same analytical run can enhance sample analysis (i.e., analytical separation and detection / measurement). Besides increasing analytical throughput, multi-capillary systems can significantly improve the flexibility and versatility of analytical strategy development. For example, different samples can be loaded into different capillaries, and different analytes can be positioned in different capillaries. Furthermore, the optical system can simultaneously or sequentially illuminate multiple capillaries and collect detection / measurement signals from them, depending on the specific method development requirements.

[0005] Multiple capillaries or capillary arrays have been used in analytical instruments. For example, see U.S. Patents 11,442,038 and 7,473,342, the entire contents of which are incorporated herein by reference. Known methods employ capillary clamps, i.e., structures configured to hold capillary arrays in place relative to each other and / or relative to other components (e.g., electrodes coaxial with the capillaries, components of the analytical instrument, etc.). Known methods have some drawbacks. For example, holding capillary arrays typically requires the use of adhesives (glues), such as adhesive tapes or curing adhesive compounds, and / or the use of components with different compositions and therefore different properties. These methods can lead to issues such as adhesive / glue component venting, contaminating samples or components of analytical instruments; unwanted fluorescence from the adhesive (e.g., autofluorescence), increasing background noise in analytical instrument detection / measurement signals; problems arising from differences in the coefficients of thermal expansion between the adhesive and other materials; adhesive viscosity limiting capillary packing density; adhesive degradation due to incident electromagnetic radiation from optical detection / measurement systems; adhesive swelling; uneven chemical resistance between the adhesive and other materials; increased space requirements for adhesive use, etc. Furthermore, these methods require significant time, cost, operator / user training, and a large number of components needed to assemble the capillary clamp. Additionally, the reliance on adhesives limits the types of materials or material coatings that can be used in the capillary clamp and imposes stringent requirements on the surface quality and cleanliness of the capillary clamp components. As in other examples, during adhesive curing, the capillary may be displaced from its intended position within the assembled clamp. Some known methods embed the capillary between two or more sheets of material laminated together. See, for example, U.S. Patent No. 6,562,214. Such methods typically rely on lamination using adhesives and suffer from one or more of the same disadvantages described above. In addition, laminating devices may easily delaminate over time.

[0006] Therefore, there is still a need to provide capillary arrays that can overcome the above problems. Summary of the Invention

[0007] In order to address all or part of the problems described above and / or other problems that may have been observed by those skilled in the art, this disclosure provides methods, processes, systems, apparatuses, instruments and / or devices, as illustrated by way of example in the embodiments set forth below.

[0008] According to one embodiment of this disclosure, a method for manufacturing a capillary array assembly includes the following steps: providing a substrate made of a thermoplastic material, the substrate including a substrate length, a substrate width, a substrate height, a top outer surface, and a plurality of grooves, wherein the plurality of grooves extend along at least a portion of the substrate length, extend from the top outer surface along the substrate height into the substrate, and are spaced apart from each other along the substrate width; inserting a plurality of capillaries into the grooves respectively; and fixing the capillaries to the substrate by the following steps: applying heat and force to the substrate for a fixed time, the fixed time being sufficient to displace a portion of the substrate to cover the capillaries; and after the fixed time, removing the heat and force to stop the displacement; wherein, after fixing, the displaced portion of the substrate hardens and at least partially covers the capillaries, such that the substrate at least partially embeds the capillaries.

[0009] In one embodiment, the step of providing the substrate includes forming the groove.

[0010] In one embodiment, the substrate has a configuration according to at least one of the following: the substrate is a monolithic body; the substrate is a non-laminated body.

[0011] In one embodiment, the fixing step is performed according to at least one of the following: the fixing step is performed without adding additional material to the substrate; the fixing step is performed without adding additional material to the capillary; the fixing step is performed without using adhesive.

[0012] In one embodiment, each capillary includes an outermost capillary surface, and after the fixing step, the substrate directly contacts the outermost capillary surface.

[0013] In an embodiment, for each capillary, the outermost capillary surface is defined by one of the following: an exposed outer surface of the capillary; an outer protective layer that coaxially surrounds at least a segment of the capillary; an additional outer layer that coaxially surrounds at least a segment of the capillary, wherein the additional outer layer comprises a conductive or thermally conductive material; or an additional outer layer that coaxially surrounds at least a segment of the capillary, wherein the additional outer layer comprises a thermally conductive non-stick material.

[0014] In one embodiment, each groove has a bottom groove surface, each groove has an initial groove height defined between the bottom groove surface and the top outer surface prior to the fixing step, and the initial groove height is greater than the outer diameter of the capillary.

[0015] In one embodiment, the initial groove height is in the range of 125% to 200% of the outer diameter of the capillary.

[0016] In one embodiment, the substrate includes a plurality of groove partitions defining the groove, the step of applying heat and force includes applying heat and force to at least a portion of the groove partitions, and the displaced portion of the substrate that at least partially covers the capillary includes at least a portion of the groove partitions.

[0017] In one embodiment, the step of applying heat and force includes: pressing a heated mold onto the top outer surface.

[0018] In one embodiment, the top outer surface includes a non-flat shape, and the heated mold includes a contact surface whose shape conforms to the non-flat shape.

[0019] In one embodiment, the method further includes placing a sheet between the heated mold and the top outer surface prior to the pressing step, wherein the sheet is made of a thermally conductive non-stick material sufficient to transfer heat and force from the heated mold to the top outer surface. The method may further include removing the sheet after the pressing step.

[0020] In one embodiment, the outer diameter of each capillary is in the range of 50µm to 400µm, and the inner diameter of each capillary is in the range of 0.5µm to 200µm.

[0021] In one embodiment, after the fixing step, the capillaries are spaced apart from each other along the width of the substrate by a capillary spacing, the capillary spacing being according to at least one of the following: the outer diameter of the capillary plus 30 μm, wherein the outer diameter is in the range of 50 μm to 400 μm; the outer diameter of the capillary plus 30 μm or greater, wherein the outer diameter of the capillary is in the range of 50 μm to 400 μm; in the range of 10 μm to 9000 μm; and in the range of 100 μm to 600 μm.

[0022] In one embodiment, the fixing step forms a plurality of slots extending along at least a portion of the length of the substrate, and the capillaries are exposed to the top outer surface through the slots.

[0023] In one embodiment, each slot has a slot width along the width of the substrate, and the slot width depends on at least one of the following: the slot width is less than the outer diameter of the capillary; the slot width is greater than the inner diameter of the capillary and closer to the inner diameter of the capillary than the outer diameter of the capillary; the slot width is equal to or less than the inner diameter of the capillary; the slot width is in the range of 0µm to 300µm; or the slot width is in the range of 0µm to 300µm and less than the outer diameter of the capillary.

[0024] In one embodiment, each capillary has a lower capillary half and an upper capillary half, the lower capillary half and the upper capillary half defining the cross-section of the capillary in a cross-section defined by the width and height of the substrate; after the fixing step, the lower capillary half is completely embedded in the substrate; after the fixing step, the upper capillary half is at least partially embedded in the substrate.

[0025] In one embodiment, the upper half of the capillary is defined by an outer surface region; the upper half of the capillary is partially embedded by the substrate in such a way that it covers the outer surface region by a certain percentage; the percentage is in the range of 0% to 80%.

[0026] In one embodiment, the plurality of capillaries each include a capillary window; the plurality of capillaries are covered by an outer protective layer except at the capillary window; and the plurality of capillary windows are positioned aligned with each other in the substrate and exposed on the top outer surface of the substrate.

[0027] In one embodiment, after the fixing, the displaced portion completely covers the capillary along at least a portion of the length of the substrate, such that the substrate completely embeds the capillary.

[0028] According to another embodiment, a capillary array assembly is manufactured according to any of the above embodiments.

[0029] According to another embodiment, the capillary array assembly is manufactured according to any of the methods disclosed herein.

[0030] According to another embodiment, the capillary array assembly includes one or more features of the embodiments mentioned above.

[0031] According to another embodiment, the capillary array assembly includes one or more features of any of the methods disclosed herein.

[0032] Other devices, apparatuses, systems, methods, features, and advantages of the present invention will be apparent to those skilled in the art upon reading the following drawings and detailed description. All such additional systems, methods, features, and advantages are to be included in this specification, fall within the scope of the invention, and are protected by the appended claims. Attached Figure Description

[0033] The invention can be better understood by referring to the following accompanying drawings. The components in the drawings are not necessarily drawn to scale; rather, the focus is on illustrating the principles of the invention. In the drawings, the same reference numerals denote corresponding components throughout different views.

[0034] Figure 1 This is a perspective view of an example of a capillary array assembly according to one embodiment of the present disclosure.

[0035] Figure 2 This is a perspective view of an example of a porous plate that can be used with a capillary array assembly, as disclosed herein.

[0036] Figure 3A This is a cross-sectional or end view of an example of a capillary that may be part of a capillary array assembly according to one embodiment of the present disclosure.

[0037] Figure 3B yes Figure 3A The diagram shows a three-dimensional representation of a capillary.

[0038] Figure 4A This is a cross-sectional or end view of another example of a capillary according to one embodiment of the present disclosure.

[0039] Figure 4B yes Figure 4A A three-dimensional diagram of a capillary tube is shown.

[0040] Figure 5A This is a perspective view of an example of a capillary array assembly (or a portion thereof) according to another embodiment of the present disclosure.

[0041] Figure 5B yes Figure 5A A top view of the capillary array assembly shown.

[0042] Figure 5C yes Figure 5A The cross-sectional elevation view or end view of the capillary array assembly shown.

[0043] Figure 5D yes Figure 5C An enlarged cross-sectional elevation view or end view of a portion of the capillary array assembly shown.

[0044] Figure 6AThis is a cross-sectional elevation view or end view of a blank substrate according to one embodiment of the present disclosure.

[0045] Figure 6B This is a cross-sectional elevation view or end view of an intermediate structured substrate according to an embodiment of the present disclosure, wherein in Figure 6A The blank substrate shown has grooves formed in it.

[0046] Figure 6C This is according to one embodiment of the present disclosure. Figure 6B The intermediate structured substrate shown is a cross-sectional elevation view or end view after the addition of capillaries.

[0047] Figure 6D This is according to one embodiment of the present disclosure. Figure 6C The diagram shows a cross-sectional elevation view or end view of an intermediate structured substrate subjected to heat and force.

[0048] Figure 7 This is a top view of an example of a capillary array assembly (or a portion thereof) according to another embodiment of this disclosure.

[0049] Unless otherwise expressly stated, all illustrations in the accompanying figures are to be considered schematic diagrams. Detailed Implementation

[0050] In this disclosure, all described "aspects," "examples," "embodiments," and "implementations" are considered non-limiting and non-exclusive. Therefore, the specific "aspect," "example," "embodiment," or "implementation" expressly described herein does not exclude other "aspects," "examples," "embodiments," and "implementations" falling within the scope of this disclosure, even if such content is not explicitly described. In this disclosure, the terms "aspect," "example," "embodiment," and "implementation" are used interchangeably; that is, they are considered to have interchangeable meanings.

[0051] In this disclosure, the terms “substantially,” “approximately,” or “about” when modifying a particular numerical value are understood to cover a range of values ​​including ±10% of that value.

[0052] Figure 1 This is a perspective view of an example of a capillary array assembly 100 according to an embodiment of the present disclosure. For simplicity, the capillary array assembly disclosed herein will be described primarily in the context of capillary electrophoresis (CE), and it should be understood that the capillary array assembly can also be used in applications other than CE.

[0053] Typically, the capillary array assembly 100 includes a plurality of capillaries 104 and one or more capillary clamps 108 for securing the capillaries 104. The following will combine... Figures 5A-5DAn example of a clamp 108 is described in more detail. Each clamp 108 is configured to securely hold or fix capillary 104 in a linear (one-dimensional or 1D) array, such as a single row (or single column) of capillary 104. In this document, “securely hold” or “fixed” means that the capillary 104 cannot be removed from a given clamp 108 when used in its normal and intended manner (e.g., storage, transport or carrying, installation and removal in a CE instrument, operation with a CE instrument under cyclic operating conditions such as temperature, pressure, electric field application, etc.). For example, the force required to pull any capillary 104 from the clamp 108 is considered excessive compared to the normal intended use of the capillary 104, and such excessive force may be sufficient or insufficient to cause damage to the capillary 104 and / or the clamp 108.

[0054] Figure 1 Four capillaries 104 and three clamps 108A, 108B and 108C are shown only as examples. Typically, any number of capillaries 104 and clamps 108A, 108B and 108C can be arranged depending on the application (e.g., purpose and function). Multiple clamps 108A, 108B and 108C may be spaced apart from each other along the length of the capillaries 104.

[0055] Each capillary 104 has a capillary inlet end (or first end) 112, a capillary outlet end (or second end) 116, and a capillary length defined between and extending from the capillary inlet end 112 and the capillary outlet end 116. Thus, the capillary array assembly 100 as a whole has an inlet end corresponding to the capillary inlet end 112 and an outlet end corresponding to the capillary outlet end 116. In this document, the terms “inlet” and “outlet” are used as relative terms to distinguish between two opposing capillary ends. For ease of description, the capillary inlet end 112 is considered as the inlet end for drawing (loading) a sample (e.g., a sample solution) into the capillary 104 for CE testing. However, in some applications or at some stages of an application, liquid may be drawn into the capillary outlet end 116. Each capillary 104 may have a considerably long capillary length relative to its outer diameter (OD). As an example, the length of a capillary tube may be on the order of centimeters (cm), such as ranging from 20 cm to 300 cm. The capillary length may be long enough that the capillary 104 needs to occupy a considerable two-dimensional (2D) or three-dimensional (3D) space. For example, the capillary 104 may be installed in the internal cavity of a CE instrument. To reduce the overall two-dimensional or three-dimensional space (or shape factor) occupied by the capillary 104, the capillary 104 may be bent at one or more points along its length, for example... Figure 1 The bends (bend positions) shown are 120A, 120B, 120C, and 120D.

[0056] In CE applications, capillary inlet 112 may extend to an inlet-side liquid reservoir (not shown), and capillary outlet 116 may extend to an outlet-side liquid reservoir (not shown). Capillary inlet 112 may be immersed in the liquid in the inlet-side liquid reservoir, and capillary outlet 116 may be immersed in the liquid in the outlet-side liquid reservoir. The inlet-side reservoir may include multiple inlet electrodes, for example, one inlet electrode corresponding to each capillary inlet 112. The inlet electrodes may be arranged parallel or coaxially with the capillary inlet 112. The outlet-side reservoir may include at least one outlet electrode, which is typically grounded relative to the inlet electrodes. The inlet and outlet electrodes are electrically connected to a high-voltage (HV) circuit. In CE applications, buffer solutions are contained within the inlet-side reservoir, the outlet-side reservoir, and the inner bore of capillary 104. The buffer solutions are formulated to provide ions for electrolytic activity. Thus, a complete circuit is formed between the contents of capillary 104 and the high-voltage circuit. During operation, the high-voltage circuit applies a voltage (e.g., 15 kV) or a sequence of voltage pulses with predetermined parameters (pulse width, pulse shape, etc.) along the length of capillary 104 to cause electrophoretic separation of different analytes in the sample within capillary 104. Prior to electrophoretic separation, the high-voltage circuit can also be used to inject the sample into capillary 104, such as by applying appropriate voltage pulses to draw the sample from the corresponding sample container (located at the inlet-side liquid reservoir) to the corresponding capillary inlet 112. This sample injection can be referred to as electrodynamic injection or electrophoretic injection. Alternatively, the sample can also be hydraulically injected by creating a pressure differential between the sample container and the corresponding capillary 104.

[0057] Each clamp 108 is configured to fix the spacing between capillaries 104, also referred to herein as the capillary spacing S, such as Figure 5D As shown. In one embodiment, the given clamp 108 is configured to hold a plurality of capillaries 104 in parallel. However, in other embodiments, the given clamp 108 may be configured to hold the plurality of capillaries 104 in a non-parallel spatial relationship. For example, the clamp 108 may be configured to hold the plurality of capillaries 104 such that the plurality of capillaries converge with each other (or, depending on a sense of direction, diverge from each other). In another example, the clamp 108 may be configured to hold the plurality of capillaries 104 such that the plurality of capillaries pass through one or more bends or turns within the clamp 108.

[0058] like Figure 1As shown, the capillary spacing may vary in different clamps 108 (e.g., clamps 108A, 108B, and / or 108C). In this case, the different clamps 108A, 108B, and 108C may have different dimensions (dimensions). However, outside of clamps 108A, 108B, and 108C, the spacing between freely suspended (or unfixed) capillaries 104 may vary along the length of the capillary array assembly 100. For example, the capillary spacing (and overall positional relationship in two-dimensional or three-dimensional space) may be non-uniform at and near one or more bends 120A, 120B, 120C, and 120D. As another example, the capillaries 104 may converge (or diverge, depending on orientation) at one or more portions of the capillary array assembly 100, for example at... Figure 1 The converging (or diverging) portions 124A and 124B are shown. One or more clamps 108A, 108B and / or 108C can be used to set or restore a linear array of capillaries 104 with uniform capillary spacing, for example along portions with non-uniform positional spacing (e.g., bends 120A, 120B, 120C and 120D, converging portions 124A and 124B, etc.).

[0059] In addition to securely holding the capillary 104 in a fixed spatial position, the given clamp 108 can be configured to provide one or more other functions. For example, the capillary array assembly 100 can be mounted on a capillary support (not shown) that holds the capillary array assembly 100 in a desired two-dimensional or three-dimensional arrangement. Such a capillary support facilitates the transport or handling of the capillary array assembly 100, facilitating travel to and from the capillary electrophoresis apparatus. Alternatively, or additionally, the capillary support can be mounted together with the capillary array assembly 100 within the internal cavity of the capillary electrophoresis apparatus to support the capillary array assembly 100 during operation. The given clamp 108 may include one or more mounting features (e.g., bosses, protrusions, pins, recesses, holes, fastening components, locking components, threads, etc.) configured to engage with corresponding mounting components of the capillary support. Optionally or additionally, a given clamp 108 may include one or more mounting components configured to engage with corresponding mounting features (e.g., walls or other structures) of the internal cavity of the CE instrument.

[0060] In use, the inlet end 112 of the capillary 104 can be immersed in the liquid contained in the inlet-side liquid reservoir as described above. Depending on the application or stage of application, the liquid can be, for example: a buffer solution for providing electrolytically active ions, a solution for providing a compound for forming an inner coating (or liner) on the inner surface defining the inner pore (or cavity) of the capillary 104, a solution for providing an electrophoretic separation medium (e.g., gel) in the inner pore, or a sample solution containing a sample to be loaded into the capillary 104 and separated into different analytes by electrophoresis for detection / measurement. In one embodiment, a clamp 108 (e.g., clamp 108A) located at or near the inlet end can be configured to position the capillary 104 relative to the inlet-side liquid reservoir such that the inlet end 112 can be immersed in the liquid. When the inlet-side liquid reservoir is used as a sample source, the inlet-side liquid reservoir can include multiple sample containers to facilitate loading the sample in each sample container into the corresponding capillary 104. In this configuration, clamp 108A can be configured to position capillary 104 such that the inlet end 112 of the capillary is aligned with the corresponding sample container.

[0061] The outlet end 116 of capillary 104 can be immersed in the liquid in the outlet-side liquid reservoir as described above. Depending on the specific application or stage of application, the liquid can be one of the solutions described above regarding the inlet-side reservoir, but does not include the sample solution (in other words, in...). Figure 1 In the illustrated embodiment, the sample source is associated with the inlet-side reservoir. The outlet-side reservoir can also be used as a collection container to receive liquid flowing from the outlet end 116. In some embodiments, the portion of the capillary 104 closest to and terminating at the outlet end 116 can be collected and tightly bundled together, particularly when capillary detection is performed upstream of the outlet end 116. For this purpose, the capillary array assembly 100 may include a capillary outlet manifold 128 located at or near the outlet end 116. As shown, the outlet manifold 128 may be cylindrical with a circular orifice. Alternatively, the cross-section of the orifice in the outlet manifold 128 may be square, linear, elliptical, racetrack-shaped, etc.

[0062] In one embodiment, the clamp 108 described herein can be used instead. Figure 1 The capillary outlet manifold 128 is shown. This implementation may be necessary, for example, in situations where, as an alternative to detection on the capillary, the outlet-side liquid reservoir is configured as a flow cell for detecting / measuring analytes that have been electrophoretically separated in the capillary 104. For example, the optical detection system of a CE instrument may be positioned such that the excitation beam interacts (e.g., parallel) with the sample stream emitted from the outlet end 116 of the capillary 104 extending to the outlet-side liquid reservoir.

[0063] In some embodiments, the inlet-side liquid reservoir described above may have a 2D array of sample containers. As an example, Figure 2 This is a perspective view of an inlet-side liquid reservoir in the form of a perforated plate 236. The perforated plate 236 includes a support structure 240 and a two-dimensional (2D) array (i.e., defined by rows and columns) of holes 244, which are typically integrally formed with the support structure 240. The perforated plate 236 may also include a barcode 246 for identification and tracking. The 2D array of holes 244 can be a 2:3 rectangular array, for example... Figure 2 The image shows a 96-hole array (8 rows and 12 columns). 2D arrays can have more than... Figure 2 The diagram shows more holes (e.g., 384, 1536, etc.) or fewer holes (e.g., 24, 54, etc.). Alternatively, the 2D array can be a square array, such as a 4x4 array with 16 holes or an 8x8 array with 64 holes. In one embodiment, the porous plate 236 has a uniform pitch P between adjacent holes 244 in each row and each column of the array. For example, the pitch P can be the distance between the centers of two adjacent holes 244 (i.e., center-to-center distance). In one embodiment, the format of the porous plate 236 (including the size and shape of the holes 244) conforms to a standard format known to a standard (e.g., the prevailing American National Standards Institute / Laboratory Automation and Screening Association (ANSI / SLAS) Porous Plate Standard at the time of this disclosure). For example, the pitch P can be specified according to ANSI / SLAS4-2004 (R2012): Microplates – Hole Positioning. Therefore, for an array of 96 holes 244, the pitch P can be 9.0 mm, for an array of 384 holes 244, the pitch P can be 4.5 mm, or for an array of 1536 holes 244, the pitch P can be 2.25 mm.

[0064] In using such Figure 2 In the embodiment of the two-dimensional sample container array (e.g., well 244) shown, Figure 1 The inlet ends 112 of the shown capillary 104 can be arranged in a 2D array that matches the 2D array of the sample container in terms of row-to-column ratio. Furthermore, the spacing or pitch between the capillary 104 (along each row and between adjacent rows) can match the spacing or pitch of the sample container, for example... Figure 2 The pitch P between the holes 244 is shown. Furthermore, the total number of capillaries 104 can be matched with the total number of sample containers, such that each capillary 104 is associated with a corresponding sample container, allowing samples from all sample containers to be simultaneously injected into the corresponding capillary 104 as needed. In this embodiment, in Figure 1In the diagram, the linear array of four capillaries 104 closest to and terminating at the inlet end 112 may represent only one row of a 2D array defined by two or more rows of capillaries 104, while other rows of capillaries 104... Figure 1 Not visible in the image. The two-dimensional arrangement of the capillary 104 and sample containers (e.g., orifice 244) facilitates the insertion of each capillary 104 (and the corresponding inlet electrode as described above) into the respective sample container. In one embodiment, a plurality of clamps 108A may be provided to support multiple rows of capillary 104 at or near the inlet end 112, respectively. These clamps 108A may be placed in parallel and spaced apart from each other in a suitable manner. For example, the clamps 108A may engage with a suitable support structure (not shown) configured to set the relative and relative positions of the clamps 108A (and the rows of capillary 104 respectively secured by the clamps 108A).

[0065] In one embodiment, another clamp 108 (e.g., clamp 108B) may be configured to convert (or transition) the array of 2D capillaries 104 located at the inlet end into a single linear array comprising all the side-by-side capillaries 104. For this purpose, the dimensions (e.g., width) of clamp 108B may be (relative to) Figure 1 (Compared to other objects shown) significantly larger Figure 1 The dimensions are schematically shown. Alternatively, the conversion or transition from the 2D array to a single 1D array of capillaries 104 can be achieved in two or more stages. For example, two or more jigs (not shown) can be located between jigs 108A and jigs 108B. Each intermediate jig can convert a subset of the 2D array of capillaries 104 into a corresponding linear array, thereby producing two or more linear arrays, which are then combined by jig 108B into a single linear array containing all capillaries 104.

[0066] In one embodiment, another fixture (e.g., fixture 108C) may be configured as a detection cell on the capillary or a portion thereof. As described in the background section above, such a detection cell is defined by an optically transparent portion or capillary window of capillary 104. An example of capillary window 374 is shown below. Figure 3BAs shown, it will be described below. In this case, the capillary array assembly 100 is mounted in the capillary electrophoresis apparatus by positioning the capillary window 374 in a manner that is optically aligned with the optical detection system of the capillary electrophoresis apparatus. Typically, the optical detection system includes a light source configured to emit excitation light and a photodetector configured to receive the emitted light. Herein, "optical alignment" refers to the position of the capillary window 374 relative to the optical detection system such that the excitation light can be successfully incident on the capillary window 374 (e.g., simultaneously on all capillary windows), and the emitted light emitted from the capillary window 374 can be successfully collected or captured by the photodetector, thereby enabling the generation of data (e.g., electrophoresis maps) related to the electrophoretically separated analytes to be analyzed. In this embodiment, the portion of the capillary 104 containing the capillary window 374 is held by a clamp 108C.

[0067] Figure 3A This is a cross-sectional view (or end view) of an example capillary 104. Figure 3B yes Figure 3A The diagram shows a perspective view of the capillary 104, or a perspective view of at least a portion of the length of the capillary 104. For reference and descriptive purposes, Figure 3A and one Some of the other figures include an arbitrarily positioned Cartesian coordinate (xyz) frame. The x-axis, y-axis, and z-axis may also be referred to herein as the longitudinal axis, transverse axis, and elevation axis, respectively. The terms "x-direction," "y-direction," and "z-direction" may also be used to refer to the x-axis, y-axis, and z-axis, respectively. Dimensions along the x-axis, y-axis, and z-axis represent length, width, and height (or thickness), respectively. The capillary 104 has a central axis or capillary axis C along which it extends. In the straight segments of the capillary 104, the capillary axis C is considered to coincide with or be parallel to the x-axis. The yz plane is referred to herein as the transverse plane. The cross-sectional view in Figure 3 is taken in the transverse plane.

[0068] Capillary 104 has a hollow cylindrical (tubular) capillary body 350. Typically, the capillary body 350 has a circular or annular cross-section, as shown in the figure. The radial thickness of the capillary body 350 lies between the inner capillary surface 354 and the outer capillary surface 358. The inner capillary surface 354 defines (coaxially surrounds as a boundary) the inner bore (or lumen) of capillary 104 (also referred to herein as the capillary bore), and thus also defines the inner diameter (ID) of capillary 104, i.e., capillary ID. If capillary 104 is exposed (e.g., uncoated), or in an exposed portion of capillary 104, the outer capillary surface 358 defines the outer diameter (OD) of capillary 104, i.e., capillary OD. In one example, the capillary inner diameter can range from 0.5 μm to 200 μm, and the capillary outer diameter can range from 50 μm to 400 μm. The capillary 104 (or capillary body 350) can be considered to have a lower half (or bottom, or first half) 362 and an upper half (or top, or second half) 366, which are semi-cylindrical in shape and have a semi-circular cross-section. As described below, when the capillary 104 is assembled to the fixture 108, the lower half 362 can be completely embedded in the substrate material of the fixture 108, while the upper half 366 can be at least partially embedded in the substrate material of the fixture 108. In this document, "lower" and "upper" are relative terms used to distinguish between the lower half 362 and the upper half 366.

[0069] The capillary body 350 is made of an optically transparent material. In this document, "transparent" means a material that allows light propagating within a certain wavelength range to pass through, which includes at least one or more wavelengths of the excitation and emission light used in the capillary array assembly 100. Depending on the specific embodiment, the excitation and / or emission light may be ultraviolet, visible, or infrared light. Examples of materials for the capillary body 350 include, but are not limited to, silica, fused silica, fused quartz, doped (synthetic) fused silica, and polymers such as polytetrafluoroethylene (PTFE).

[0070] In one embodiment, capillary 104 may include an outer protective layer (or coating, film, etc.) 370 that contacts and coaxially surrounds the outer surface 358 of the capillary. The protective layer 370 is configured to protect capillary 104 from damage or breakage and to increase the strength or robustness of capillary 104 to allow it to bend to a certain extent (e.g., see...). Figure 1The protective layer 370 will not be damaged or broken. It also substantially blocks the transmission of light at least within the intended wavelength range of the excitation, emission, and stray light. The protective layer 370 can be made of a variety of materials suitable for this purpose, such as various polymers, examples of which include, but are not limited to, polyimide (PI), acrylates, silicone resins, and fluoropolymers. In one example, the transverse radial thickness of the protective layer 370 may range from 5 μm to 30 μm. When the protective layer 370 is present, the outer diameter (OD) specified for the capillary 104 may include (taking into account) the radial thickness of the protective layer 370.

[0071] Figure 3B An embodiment of capillary 104 including capillary window 374 is shown. Capillary window 374 can be formed using any suitable existing or subsequently developed technique. In one example, the manufacture of capillary 104 can be performed as follows: first, a capillary body 350 is formed; then, the entire length of the capillary body 350 is coated to form a protective layer 370; and then the protective layer 370 is peeled off from a selected longitudinal section of capillary 104 to form capillary window 374. As another example, a mask can be applied to the longitudinal section of capillary 104 where capillary window 374 is to be formed, then the capillary body 350 is coated with the material of the protective layer 370, and then the mask is removed. (As described above...) Figure 1 As described above, in the capillary array, all the corresponding capillary windows 374 can be positioned together to form the optical window of the detection cell.

[0072] Figure 4A This is a cross-sectional view (or end view) of another example of capillary 104. Figure 4B yes Figure 4A The diagram shows a perspective view of the capillary 104, or a perspective view of at least a portion of the length of the capillary 104. In this example, the capillary 104 includes one or more additional outer layers 378 that surround at least one longitudinal portion of the capillary 104. The additional outer layers 378 may be configured to perform various functions depending on the application. In one example, the additional outer layer 378 (or at least one of a plurality of additional outer layers 378 provided) may be made of a conductive material, i.e., one or more additional outer layers 378 may constitute electrodes. For example, as described above... Figure 1 As described, one or more additional outer layers 378 may be used as located at the inlet end 112 of the capillary 104 ( Figure 1 The coaxial inlet electrode is located at or near the point of contact. In this case, one or more conductive portions of the additional outer layer 378 can be electrically connected to the high-voltage (HV) circuitry of the CE instrument using any suitable technique.

[0073] In another example, the additional outer layer 378 (or at least one of the plurality of additional outer layers 378 provided) may be made of a thermally conductive material. The thermally conductive material may serve as a solid heat transfer medium for cooling or heating the capillary 104 or selected longitudinal portions of the capillary 104. For example, the thermally conductive material may serve as a heat sink and / or in thermal contact with a cooling device (e.g., a Peltier device) to remove Joule heat generated by the application of an HV field for electrophoretic separation. Another example is that the thermally conductive material may be used as part of a heating system for heating the capillary 104.

[0074] In all these cases, the additional outer layer 378 may be supported by the clamp 108 together with the corresponding capillary 104. The longitudinal portion of the capillary 104 containing one or more additional outer layers 378 (e.g., Figure 4B The portion 382 shown can be completely positioned within the fixture 108 or can extend partially outside the fixture 108.

[0075] The additional outer layer 378 can be made of any suitable conductive and / or thermally conductive material. Examples include, but are not limited to, various metals, metal alloys, conductive and / or thermally conductive polymers, etc.

[0076] Figure 4B One or more portions 382 of the additional outer layer 378 are shown. In the example shown, portion 382 extends only a portion of the length of capillary 104. Depending on the application (e.g., the function of the one or more additional outer layers 378), capillary 104 may include two or more portions 382, ​​which may be spaced apart from each other along the length of capillary 104. In another example, one or more additional outer layers 378 may extend to the entire length of capillary 104.

[0077] In various embodiments, capillary 104 may include Figures 3A-4B A combination of two or more features shown. For example, capillary 104 may include a protective layer 370, a capillary window 374, and / or one or more portions 382 of an additional outer layer 378.

[0078] exist Figures 3A to 4B In the illustrated embodiment, capillary 104 can be considered to have an outermost capillary surface that is in direct contact (direct engagement) with clamp 108. According to the embodiment, the outermost capillary surface may correspond to the outer surface 358 of the capillary (e.g., in the exposed portion of capillary 104), the outer surface of the protective layer 370, or the outermost surface of one or more additional outer layers 378 (e.g., the outer surface of a conductive or thermally conductive layer, or the outer surface of a protective layer that coaxially surrounds the conductive or thermally conductive layer).

[0079] Figures 5A to 5D An embodiment of the capillary array assembly 100 is shown. Figure 5A It is a three-dimensional view of the capillary array assembly 100 (or a part thereof). Figure 5B This is a top view of the capillary array assembly 100 in the xy plane. Figure 5C It is a cross-sectional view (or end view) of the capillary array assembly 100 in the yz (lateral) plane. Figure 5D yes Figure 5C An enlarged cross-sectional view (or end view) of a portion of the capillary array assembly 100 shown in the yz (lateral) plane.

[0080] The clamp 108 includes a structured substrate 502, that is, a substrate 502 that has been structured (or designed) to include structural features. In this embodiment, the clamp 108 may be primarily or entirely defined by the material body or substrate body 546 constituting the substrate 502. Therefore, in this embodiment, the terms "clamp" and "substrate" can refer to essentially the same structural component. However, in other embodiments, the clamp 108 may include other features that are considered to be related to... Figures 5A to 5D The features of the integral components of the substrate 502 (substrate body 546) shown are separate or different.

[0081] Typically, substrate 502 (substrate body 546) can be made of any rigid (hard) material capable of effectively and reliably fixing capillary 104 in the manner described herein. Therefore, substrate materials can be selected from various metals (e.g., aluminum), metal alloys (e.g., stainless steel), quasi-metals (e.g., silicon), ceramics (e.g., glass), and polymers. In one embodiment, the substrate material can be a thermoplastic (e.g., "engineering thermoplastic"). Suitable thermoplastics include, but are not limited to, acrylic resins, acrylonitrile-butadiene-styrene copolymer (ABS), nylon, polycarbonate (PC), polyethersulfone (PES), polyoxymethylene (POM), polyetheretherketone (PEEK), polyetherimide (PEI), polyethylene (PE), polyphenylene ether (PPO), polyphenylene sulfide (PPS), polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene fluoride (PVDF), polytetrafluoroethylene (PTFE), etc.

[0082] In one embodiment, the substrate body 546 is a single sheet (or monolithic) material. In other words, in this embodiment, the substrate body 546 does not include (or is not composed of) multiple layers of interconnected materials. For example, the substrate body 546 may be a non-laminated material, i.e., it does not include two or more layers of material laminated together.

[0083] The substrate 502 has a substrate length in the x-direction, a substrate width in the y-direction, and a substrate height in the z-direction. According to a specific embodiment, any one dimension (length, width, and height) of the substrate 502 may be greater than, less than, or equal to one or both of the other two dimensions. In this embodiment, the dimensions of the substrate 502 may substantially correspond to the overall dimensions of the entire fixture 108. A plurality of capillaries 104 extend along the substrate length direction and are spaced apart from each other along the substrate width direction. Typically (but not necessarily), the plurality of capillaries 104 are at the same height (or horizontal height) relative to the substrate height. As described above, the plurality of capillaries 104 may be parallel to each other along the entire substrate length direction, or they may not be parallel along part or all of the substrate length direction.

[0084] In this embodiment, the substrate 502 has a three-dimensional linear shape, which may also be referred to as prism-shaped, box-shaped, plate-shaped, etc. Therefore, the substrate 502 has six outer surfaces: a top outer surface 506, a bottom outer surface 510 spaced apart from the top outer surface 506 along the z-direction, and four lateral outer surfaces 514 adjacent to the top outer surface 506 and the bottom outer surface 510. The top outer surface 506, the bottom outer surface 510, and the lateral outer surfaces 514 can be completely flat as shown. Alternatively, one or more of these outer surfaces may have one or more geometric features, such as curves or arcs, additional angles or edges, etc., depending on the embodiment. More generally, the substrate 502 has a shape capable of effectively securing the capillary 104 or providing additional functionality in the manner described herein.

[0085] As an example of structural features, substrate 502 includes a plurality of capillary channels 518 and a plurality of slots 522. The capillary channels 518 and slots 522 extend along the length of substrate 502. Each capillary 104 is located in a corresponding capillary channel 518. Each slot 552 is located above a corresponding capillary channel 518 and extends downward from the top outer surface 506 to the capillary outer surface 358 of the capillary channel 518 and the corresponding capillary 104. With this configuration, the spatial relationship (e.g., relative position and orientation) of the capillary 104 is determined by the spacing between the capillary channels 518. Furthermore, in this embodiment, the capillary 104 is embedded (or closed) by the capillary channels 518 except at the location of the slot 552. That is, at the slot 552, the capillary 104 is exposed to the environment outside substrate 502.

[0086] refer to Figure 5DA close-up view shows that the substrate 502 has a capillary spacing S between each pair of adjacent capillaries 104. Typically, the capillary spacing S is defined as the height (or horizontal height) of the capillary axis C. Furthermore, as shown, the capillary spacing S can be defined as the distance between the capillary axes C of two adjacent capillaries 104, i.e., the center-to-center distance. In one example, the capillary spacing S can be the capillary outer diameter plus 30 μm, or it can be the capillary outer diameter plus 30 μm or greater (e.g., capillary outer diameter plus 35 μm, capillary outer diameter plus 40 μm, capillary outer diameter plus 50 μm, etc.). In other examples, the capillary spacing S can range from 100 μm to 600 μm. In further examples, the capillary spacing S can be 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, or 600 μm. Alternatively, the capillary spacing S can be defined as the closest distance between two adjacent capillaries 104, which is located at the height of the capillary axis C. Typically, the capillary spacing S can be set to suit clamps 108 located at different positions along the length of the capillary array assembly 100, and thus may depend on the function / purpose of a particular clamp 108 at a particular location. When a clamp 108 is used as a detection cell on a capillary or as part of it, all or part of the range specified herein may apply. For a detection cell, the acceptable range of capillary spacing may depend on factors such as crosstalk between capillaries 104 and other unwanted optical effects. However, the capillary spacing S may be larger or smaller than the range specified above, depending on the function / purpose of the clamp 108. For example, when the clamp 108 is used in or near an inlet-side liquid reservoir, the capillary spacing S may be larger. In this case, as described above... Figure 2 The capillary spacing S can be set to match the spacing P of the sample source sample container. In other examples, when the clamp 108 is used for or near the outlet-side liquid reservoir, for example, if it is necessary to tightly bind the capillaries 104 together at the outlet end of the capillary array assembly 100, the capillary spacing S may be smaller. As a more general example, the capillary spacing S can range from 10 μm to 9000 μm. The fabrication method disclosed herein is flexible enough to achieve any range just specified.

[0087] like Figure 5DFurther, for ease of description, substrate 502 can be considered to include a substrate base (part or region) 526 and a capillary spacer (or spacer / embedded portion or region) 530. (From a transverse plane perspective) The substrate base 526 is the portion or region of substrate 502 located below the capillary 104 and not occupied by the capillary 104. The substrate base 526 may span the entire width of the substrate and thus may include the entire bottom outer surface 510. The substrate base 526 extends upward from the bottom outer surface 510 to the capillary channel 518. The dimensions (dimensions) of the substrate base 526 may vary depending on the specific embodiment of the clamp 108. For example, the dimensions of the substrate base 526 may be designed to accommodate the aforementioned mounting features or other additional features. In another example, the dimensions of the substrate base 526 may be designed to function as a heat sink, effectively absorbing heat energy generated by the capillary 104 during use (e.g., Joule heating), or as a solid heat transfer medium, effectively conducting heat energy in the capillary 104 to an external structure or cooling device (not shown). (The following is a continuation of the previous paragraph.) Figures 6A to 6D The substrate 526 can be sized to function as a heat sink during a heat-based capillary fixation process.

[0088] The capillary spacer 530 is a portion or region of the substrate 502 located above the substrate base 526 and occupied by the capillary 104. Furthermore, the capillary spacer 530 defines the capillary spacing S and directly contacts and embeds the capillary 104. Therefore, the capillary spacer 530 (or at least a majority thereof) intersects with the capillary 104. Thus, the capillary spacer 530 (or at least a majority thereof) can be considered to include a plurality of different capillary spacers 530 (or different portions of the capillary spacer 530 region), wherein each individual capillary spacer 530 is adjacent to one or two capillary 104. Furthermore, the capillary spacer 530 (or each capillary spacer 530) can be considered to include a lower (or first) half 534 (or a lower (or first) half portion or region of the capillary spacer) and an upper (or second) half 538 (or an upper (or second) half portion or region of the capillary spacer). The lower half 534 of the capillary spacer is located within a plurality of capillaries 104 (particularly the lower half 362 of the plurality of capillaries). Figure 3A Below and completely embedding multiple capillary tubes 104 (particularly the lower half 362 of the multiple capillary tubes). The upper half 538 of the capillary spacer portion at least partially covers the multiple capillary tubes 104 (particularly the upper half 366 of the multiple capillary tubes), Figure 3A And thus at least partially embeds multiple capillaries 104 (particularly the upper halves 366 of the multiple capillaries). Therefore, as Figure 5DAs shown, each slot 522 is defined between the longitudinal edges (or adjacent upper halves 538 of capillary spacers) of the upper half 538 of the capillary spacer. With this configuration, the capillary spacers 530 provide an interference fit between each capillary 104 and the substrate 502 in one or more directions. The interference fit is particularly due to the direct (and tight) contact between the capillary spacers 530 and the outer surface 358 of the capillary, and the portion of the capillary spacers 530 covering the outer surface 358 of the capillary (i.e., one or more upper halves 538 of the capillary spacers). The interference fit prevents the capillary 104 from being removed from the substrate 502, for example, by pulling the capillary 104 in the longitudinal (x) or upward (z) direction.

[0089] exist Figure 5D In the diagram, dashed lines schematically distinguish the different parts or regions described for reference and explanation. Dashed lines do not necessarily represent physical boundaries or interfaces between different parts or regions. For example, when the substrate body 546 is a single-piece body, dashed lines can often indicate the transition points between different parts or regions.

[0090] Typically, the slot width of each slot 522 in the lateral direction (along the substrate width) is smaller than the capillary OD. The slot width is typically chosen to form an effective interference fit with the capillary 104 in the substrate height direction. When the fixture 108 is used for the detection cell, the slot width can also be chosen to accommodate the capillary window 358. Figure 3B (i.e., ensuring full exposure). In one example, the slot width is greater than the capillary inner diameter but smaller than the capillary OD. In another example, the slot width is greater than the capillary ID but closer to the capillary ID than the capillary OD. In yet another example, the slot width is equal to or (e.g., ... Figure 5D (As shown) is less than the capillary ID. In another example, the slot width ranges from 0µm to 300µm.

[0091] The extent to which the capillary spacer 530 embeds each capillary 104 can also be described as a percentage relative to the outer surface 358 of the capillary covered by the capillary spacer 530. As described above, the lower half 534 of the capillary spacer completely embeds each lower half 362 of the capillary. Figure 3A This covers (encloses) 100% of the outer surface (or outer surface area) of the lower half of the capillary 362. The upper half of the capillary spacer 538 may partially embed each upper half of the capillary 366. Figure 3AThis allows a certain percentage (fraction) of the entire outer surface (or outer surface area) of the upper half of the capillary 366 to be covered (enclosed). In one example, the percentage of the outer surface of the upper half of the capillary 366 covered by the capillary spacer 530 (particularly the upper half of the capillary spacer 538) can be in the range of 0% to 80%.

[0092] Figures 5A to 5D The capillary 104 shown may include Figure 3A and 3B The protective layer 370 shown (or the additional capillary window 374), and / or Figure 4A and 4B One or more portions 382 of one or more additional outer layers 378 are shown. Depending on the fixture 108, these features may be wholly or partially secured by the substrate 502. Therefore, the size and shape of the capillary channel 518 can be designed as needed to accommodate these features. Alternatively, these features may be located entirely outside the substrate 502.

[0093] In another embodiment, the capillary spacer 530 may completely or partially embed the upper capillary portion 366 of one or more capillaries 104 along the entire or partial length of the substrate. Figure 3A In these locations, the upper slot 522 does not exist.

[0094] A method for manufacturing such as Figures 5A to 5D The method of the capillary array assembly 100 shown, and see also Figures 6A to 6D These figures illustrate certain steps or results of the manufacturing method.

[0095] refer to Figure 6A A blank substrate (or workpiece) 642 is provided. The blank substrate 642 is "blank" because it has not yet been processed to form any features. However, the blank substrate 642 can be reduced to the required size before forming features or performing further steps in the manufacturing process. For example, Figure 6A The blank substrate 642 in the text can represent the substrate body 546 formed from a large block or volume of substrate material (e.g., cut, extruded, etc.). In this example of the manufacturing method, the substrate body 546 is a monolithic material. Furthermore, in this example, the monolithic substrate body 546 is made of a thermoplastic material (e.g., one of the examples described above). The blank substrate 642 (substrate body 546) includes a top outer surface 606 and other outer surfaces, which may be... Figures 5A to 5D The final (post-processed) substrate 502 shows the pre-processed form of the top outer surface 506 and other outer surfaces (or the form corresponding to the top outer surface 506 and other outer surfaces).

[0096] refer to Figure 6BAfter providing the blank substrate 642, the blank substrate 642 is processed to form desired features on or within the blank substrate 642, thereby obtaining an intermediate structured substrate 648. The intermediate structured substrate 648 is called "intermediate" because it will undergo further processing in one or more subsequent steps of the manufacturing method. Typically, any processing technique suitable for the selected thermoplastic material can be performed, such as injection molding, compression molding, calendering, extrusion, casting, stamping, embossing, machining, turning, milling, drilling, laser processing, rapid prototyping, additive manufacturing, 3D printing, subtractive manufacturing, etc., depending on the processing technique. Figure 6A The substrate raw materials, represented by the blank substrate 642, may be provided in granular or particulate form in preparation for a certain processing step, and as those skilled in the art will understand, may at some point be in the form of a heated, flowable viscous phase.

[0097] In this example, the features formed by this manufacturing method include a plurality of grooves 652. The size, number, and spatial arrangement (e.g., a linear array) of the grooves 652 are selected to accommodate capillary tubes 104 to be attached to the substrate body 546. In this example, the grooves 652 are formed such that the grooves 652 extend from the top outer surface 606 into the substrate thickness, and the grooves 652 are spaced apart from each other by intermediate regions of the substrate body 546, which are referred to herein as groove dividers (or groove divider walls or groove divider strips) 656. Each groove 652 has a groove inner surface 660 defined by the outer surface of the adjacent groove divider 656 and the lower portion of the substrate body 546. The bottom of each groove 652 includes a lowest point 664 of the groove 652 (and the groove inner surface 660). Figure 6B As shown, the bottom portion of each groove 652 may be semi-circular to conform to the circular cross-section of the capillary 104 to be added. Each groove 652 has an initial groove height GH, defined by the distance between the lowest point 664 and the top outer surface 606. Each groove 652 has an initial groove width GW, defined by the distance between adjacent groove separators 656. The initial groove height GH and groove width GW are referred to as "initial" because these dimensions may change with further processing.

[0098] Alternatively, the bottom of the groove 652 may have other types of circles (e.g., ellipses) without having to conform to the circular profile of the capillary 104. In addition, the bottom of the groove 652 may have polygonal shapes (e.g., straight, square, angled, trapezoidal, V-shaped, etc.).

[0099] In addition to the recess 652, additional features (not shown) such as those described herein (e.g., mounting features, etc.) may be formed on or within the blank substrate 642, thus serving as part of the intermediate structured substrate 648. Some features (such as the recess 652) are intermediate features because they are further processed in one or more subsequent steps of the method. Other features may be final features because they are further processed in... Figure 6B The manufacturing process shown at this stage is (basically) not further processed. For example, the mounting features formed at this stage may not require further processing.

[0100] refer to Figure 6C After forming the groove 652, the capillary 104 is inserted into the corresponding groove 652. If necessary, a suitable tool (not shown) can be used to assist in inserting the capillary 104. The capillary 104 can be inserted such that it contacts at least a portion of the bottom of the groove 652 along the entire length of the intermediate structured substrate 648. This ensures accurate alignment of the multiple capillary 104s with each other and facilitates a uniform and repeatable fixation process. Depending on the shape of the bottom, the capillary 104 can be inserted to make full contact with the bottom; the capillary may include contact with the lowest point 664. Initial groove width GW ( Figure 6B The initial groove width GW can be slightly larger than the capillary outer diameter (e.g., up to 20%) to accommodate the insertion and alignment of the capillary 104. Due to subsequent fixation processes, the initial groove width GW may "shrink to fit" the capillary outer diameter. In one example, the initial groove width GW could be approximately 200 µm to accommodate a capillary 104 with an outer diameter of 193 µm.

[0101] As described above, the bottom of the groove 652 may have a circular or polygonal shape that does not conform to the circular outline of the capillary 104. In this case, in some embodiments of the subsequent fixing process, the groove partition 656 and / or a portion of the substrate body 546 below it may at least partially shrink to conform to the outer surface of the lower half 362 of the capillary.

[0102] In this embodiment, the groove partition 656 serves as a substrate material source in subsequent method steps for at least partially embedding the upper half 366 of the capillary 104. Figure 3A For the purpose of providing a sufficient amount of substrate material, such as Figure 6C As shown, the initial height of the groove partition 656 (which can (substantially) correspond to the initial groove height GH) Figure 6BThe initial height of the groove partition 656 (or the initial groove height GH) can be greater than the outer diameter of the capillary 104. In one example, the initial height of the groove partition 656 (or the initial groove height GH) can be in the range of 125% to 200% of the OD of the capillary 104. In another example, the initial height of the groove partition 656 (or the initial groove height GH) can be greater than 200% of the OD of the capillary 104. Figure 5D When determining the capillary spacing S of the final (post-processed) substrate 502, the initial width of the recessed partition 656 can be considered, as the width (similar to the height) of the recessed partition 656 may change due to one or more subsequent method steps. The initial width of the recessed partition 656 can also be considered when determining the initial height of the recessed partition 656, or more generally, when determining the total amount of substrate material required to at least partially embed the upper half 366 of the capillary 104.

[0103] refer to Figure 6D After the capillary tube 104 is inserted, the intermediate structured substrate 648 is processed in a manner that secures the capillary tube 104 to the substrate body 646 (and within the substrate body). The intermediate structured substrate 648 can be securely positioned on a working surface. According to a specific embodiment, the intermediate structured substrate 648 can be placed in a structure having one or more walls adjacent to one or more sides of the intermediate structured substrate 648. In this embodiment, the capillary tube 104 is then secured by applying heat and (downward) force (or pressure) to the top outer surface 606. The process of applying heat and force (or pressure) can be considered a thermoforming process, such as a hot melt process. Applying heat and force (or pressure) causes plastic deformation of a portion of the thermoplastic material in the substrate body 546. The applied heat causes a portion of the thermoplastic material, particularly in the uppermost region of the recessed partition 656, to soften (or melt), thereby becoming flowable and movable. The applied force (or pressure) helps to move and guide the heat-softened thermoplastic material to flow in the desired direction. Specifically, the applied force (or pressure) helps to diffuse the heated thermoplastic material outward from the initial (pre-treatment) position of the groove partition 656 and into the upper half 366 of the capillary 104. Figure 3A If necessary, the extent of diffusion can be controlled using one or more tools and / or surfaces (not shown) outside the intermediate structured substrate 648, such as the structures described above with one or more walls (e.g., a box-like structure with a top opening), or other structures that can be understood by those skilled in the art. Heat and force (or pressure) are applied for a period of time, referred to herein as the settling time. After the settling time, the heat and force are removed to stop the diffusion of the thermoplastic material. After the heat and force are removed, the thermoplastic material cools and hardens in situ.

[0104] Therefore, after the fixation process is completed, the final (post-processed) fixture 108 and its associated capillary array assembly 100 (such as...) Figures 5A to 5D (As shown) This is thus formed. For example, the groove 652, the groove partition 656, and the substrate body 546 region located below the groove 652 can be considered as having been transformed into capillary channels 518, slots 522, capillary spacers 530, and substrate base 526. The manufacturing method may also include one or more post-fixing (or finishing) steps as needed. For example, excess substrate material that is not needed in the final product and has moved / deformed can be removed (e.g., trimmed off).

[0105] The development of the manufacturing method in this embodiment may involve considering combinations of parameters affecting the fixing process (fixing parameters), particularly the applied heat, applied force / pressure, amount of movement / diffusion, and fixing time. Generally, the selection of values ​​for the fixing parameters should effectively form... Figures 5A to 5D The final fixture 108 and its associated (post-processing) capillary array assembly 100 are shown. The following acceptable ranges can be specified: the rate of heat energy transferred to the intermediate structured substrate 648 (e.g., in watts, W), the force (e.g., in Newtons, N) and / or pressure (e.g., in megapascals, MPa) applied to the intermediate structured substrate 648, and the fixed time for applying heat and force / pressure (e.g., in seconds, sec, or minutes, min). Generally, the rate of heat energy applied, or the total heat applied considering the fixed time (e.g., in joules, J), should be sufficient to soften a sufficient amount of thermoplastic material to embed the capillaries 104, but not so large as to permanently (or plastically) deform other areas of the substrate body 646 that do not require softening (to make it flowable) and deformation / movement. Similarly, the amount of force / pressure applied should be sufficient to allow the heated portion of the thermoplastic material to diffuse onto the capillary 104, but not excessive, so as not to damage the capillary 104 or other areas of the substrate body 646. The duration of the fixing time can be determined based on a defined range of applied heat and force / pressure optimal for the fixing process. The fixing parameters may also vary depending on the fixture 108, for example, the fixture 108 may have different dimensions and / or features. For different fixtures 108, the values ​​of the fixing parameters can be determined empirically based on the needs of optimizing the manufacturing process.

[0106] As described above, the final capillary array assembly 100 includes at least one clamp 108, but may also include multiple clamps 108. In the latter case, it can be based on... Figures 6A to 6D The method described in the present description manufactures multiple jigs 108. For a given set of capillaries 104, multiple jigs 108 can be manufactured simultaneously or sequentially, depending on the specific manufacturing method.

[0107] The application of heat and force / pressure can be performed using various techniques. Figure 6D In the illustrated embodiment, a heated die 664 is used to apply heat, force, and movement of the heated material. Heated dies are generally well known to those skilled in the art, therefore only a brief description of the illustrated heated die 664 is provided herein. The heated die 664 can be configured for manual or robotic operation. The heated die 664 is made of a thermally conductive material, typically a metal or metal alloy, but may also be a polymer with suitable thermal stability (i.e., heat resistance that melts and degrades due to repeated heating cycles). The heated die 664 can be in thermal contact with a suitable heat source (e.g., a resistance heating element). Alternatively or additionally, all or part of the heated die 664 may also be conductive, such that the heated die 664 itself acts as a resistance heating element in response to applied electrical power (current or voltage).

[0108] In this embodiment, as Figure 6D As indicated by the arrows, heat and force / pressure are applied by pressing a heated mold 664 against the top outer surface 606 of the intermediate structured substrate 648 at specified fixed times. The heated mold 664 includes a contact surface 658, from... Figure 6D From this angle, the contact surface is the bottom surface of the heated mold 664. The heat generated by the heated mold 664 is transferred from the contact surface 658 to the top outer surface 606 of the intermediate structured substrate 648. For a given force applied by the heated mold 664, the size (surface area) of the contact surface 658 determines the magnitude of the pressure applied by the heated mold 664 to the top outer surface 606. The shape (or geometry) of the contact surface 658 can conform to the shape (or geometry) of the top outer surface 606 in a complementary manner. For example, in this embodiment, the top outer surface 606 is completely flat (planar) without any other geometric features; in this case, the contact surface 658 can also be completely flat. However, in other embodiments, one or more areas of the top outer surface 606 may not be completely flat. For example, all or part of the top outer surface 606 may be curved or arc-shaped, or include additional edges or corners (e.g., steps, shoulders, etc.). In the latter case, the contact surface 658 of the heated mold 664 can be complementaryly shaped to conform to the non-planar shape of the top outer surface 606.

[0109] During the application of heat and force / pressure, the heated mold 664 (particularly the contact surface 658) can come into direct or indirect contact with the top outer surface 606 of the intermediate structured substrate 648. For example, it can be observed that the thermoplastic material used for the substrate body 646 tends to adhere to the heated mold 664 during the fixing process. Figure 6DAs shown, this problem can be solved by placing a sheet 662 between the heated mold 664 and the substrate body 646. The sheet 662 is made of a thermally conductive, non-stick material that effectively transfers heat and force from the heated mold 664 to the top outer surface 606 while preventing thermoplastic material from adhering to the heated mold 664 (contact surface 658). Examples of suitable materials for use as the sheet 662 include, but are not limited to, PTFE, PI, polydimethylsiloxane (PDMS), ceramics, etc. In this embodiment, the sheet 662 is first placed on the top outer surface 606, and then the heated mold 664 is pressed onto the sheet 662. In other words, the heated mold 664 applies heat and force / pressure to the top outer surface 606 through the sheet 662. In one embodiment, the sheet 662 is a temporary component of the fixing process. That is, after the heated mold 664 is removed, the sheet 662 is also removed and is not retained on the top outer surface 606 as part of the final product.

[0110] Alternatively or additionally, the capillary 104 may be coated with a thermally conductive non-stick material, such as the materials mentioned above, in which case a separate non-stick sheet 662 may not be necessary.

[0111] Figure 7 This is a top view of an example of a capillary array assembly 700 (or a portion thereof) according to another embodiment of the present disclosure. Typically, the capillary array assembly 700 is configured as described above. Figures 5A to 5D The capillary array assembly 100 shown is identical. Figure 7 In the illustrated embodiment, the capillary array assembly 700 is configured to serve as a detection cell. For this purpose, the capillary array assembly 700 includes an optical detection region (or window portion) 703 located between two embedded regions 705 and 707. In the optical detection region 703, the capillary 104 is exposed and exposed to the environment outside the capillary array assembly 700. In other words, as described above... Figure 3B The optical detection region 703 is at least partially defined by the capillary window 374. Within the optical detection region 703, at least at the top of the illustrated capillary array assembly 700, all or most of the capillary window 374 is not obscured by the substrate 502, thereby enhancing light transmission with the optical detection system of the associated capillary CE instrument (e.g., see above regarding...). Figure 1 (as described above). On the other hand, in adjacent embedding regions 705 and 707, the capillary 104 can be fixed by (at least partially) embedding with the substrate 502, in a manner as described above. Figures 6A to 6D As described.

[0112] The subject matter of this disclosure, such as the fixture 108 and manufacturing method described herein, offers one or more advantages. The manufacturing method is highly repeatable, easily automated, and cost-effective compared to known methods. The fixture 108 provides an embedded capillary 104, which can be highly miniaturized. The fixture 108 provides a sealed interface between each capillary 104 and the surrounding substrate material, thereby allowing efficient heat transfer and preventing fluid migration into the interface. The fixture 108 eliminates the need for adhesives (glue), thus avoiding the disadvantages associated with adhesives, such as those mentioned in the background section above. These disadvantages may include: material compatibility with adhesives (e.g., adhesiveness of the material), additional space requirements (e.g., limiting the packing density of the capillary 104), unwanted fluorescence, operator dependence on adhesive use during the manufacturing / assembly of the fixture 108, high dependence on the surface quality / cleanliness of the adhesive contact surfaces, and unwanted movement of the capillary 104 during adhesive curing (e.g., due to capillary forces, surface adhesion, adhesive expansion or swelling, etc.). The use of an adhesive-free / glue-free process enhances the design flexibility of the clamp 108, as it eliminates the need for any specific areas, features, or surfaces designed for bonding. Therefore, the subject matter of this disclosure allows for greater variability in the configuration of the clamp 108, including a wider range of features and materials. Non-adhesive materials such as PTFE, PP, PI, fluoropolymers (e.g., perfluoroalkoxyalkanes (PFA)) can be used. Furthermore, in a given embodiment, coatings may be required on one or more surfaces of the clamp 108, such as PTFE coatings, diamond-like carbon (DLC) coatings, antistatic coatings, etc. The subject matter of this disclosure allows for the addition of a greater variety of coatings because compatibility with adhesives / glues is not required.

[0113] It should be understood that this document uses terms such as “connected” and “connected to” (e.g., the first component is “connected” to or “connected to” the second component) to indicate a structural, functional, mechanical, electrical, signaling, optical, magnetic, electromagnetic, ionic, or fluid relationship between two or more components or elements. Therefore, the stated connection between a component and a second component does not preclude the possibility of other components existing between the first and second components, and / or other components operatively associated with or engaged with the first and second components.

[0114] It should be understood that modifications can be made to various aspects or details of the invention without departing from its scope. Furthermore, the foregoing description is for illustrative purposes only and not for limiting purposes—the invention is defined by the claims.

Claims

1. A method for manufacturing a capillary array assembly, the method comprising the following steps: A substrate is provided, the substrate being made of a thermoplastic material, the substrate including a substrate length, a substrate width, a substrate height, a top outer surface, and a plurality of grooves. The plurality of grooves extend along at least a portion of the length of the substrate, extend from the top outer surface along the height of the substrate into the substrate, and are spaced apart from each other along the width of the substrate; Multiple capillaries are inserted into the grooves respectively; and The capillary is fixed to the substrate by the following steps: Apply heat and force to the substrate for a fixed time, the fixed time being sufficient to displace a portion of the substrate to cover the capillary; and After the fixed time, the heat and force are removed to stop the displacement; After fixing, the displaced portion of the substrate hardens and at least partially covers the capillary, such that the substrate at least partially embeds the capillary.

2. The method according to claim 1, wherein, The step of providing the substrate includes: forming the groove.

3. The method according to claim 1, wherein, The substrate has a configuration according to at least one of the following: The substrate is a single piece; The substrate is a non-laminated material.

4. The method according to claim 1, wherein, The fixing step is performed according to at least one of the following: The fixing step is performed without adding any additional material to the substrate; The fixing step is performed without adding any additional material to the capillary; The fixing process is performed without the use of adhesives.

5. The method according to claim 1, wherein, Each capillary includes an outermost capillary surface, and after the fixing step, the substrate directly contacts the outermost capillary surface.

6. The method according to claim 5, wherein, For each capillary, the outermost capillary surface is defined by one of the following: The exposed outer surface of the capillary; An outer protective layer that coaxially surrounds at least one segment of the capillary; An outer protective layer, which coaxially surrounds at least a segment of the capillary and extends at least partially to the outside of the substrate; An additional outer layer, which coaxially surrounds at least a segment of the capillary, wherein the additional outer layer comprises a conductive or thermally conductive material; An additional outer layer coaxially surrounds at least a segment of the capillary and extends at least partially to the outside of the substrate, wherein the additional outer layer comprises a conductive or thermally conductive material. An additional outer layer, which coaxially surrounds at least a segment of the capillary, wherein the additional outer layer comprises a thermally conductive non-stick material.

7. The method according to claim 1, wherein, Each groove has a bottom groove surface, each groove has an initial groove height defined between the bottom groove surface and the top outer surface prior to the fixing step, and the initial groove height is greater than the outer diameter of the capillary.

8. The method according to claim 7, wherein, The initial groove height is in the range of 125% to 200% of the outer diameter of the capillary.

9. The method according to claim 1, wherein, The substrate includes a plurality of groove partitions defining the groove, the step of applying heat and force includes applying heat and force to at least a portion of the groove partitions, and the displaced portion of the substrate that at least partially covers the capillary includes at least a portion of the groove partitions.

10. The method according to claim 1, wherein, The step of applying heat and force includes: applying a heated mold to the top outer surface.

11. The method according to claim 10, wherein, The top outer surface includes a non-flat shape, and the heated mold includes a contact surface whose shape conforms to the non-flat shape.

12. The method of claim 10, comprising: Prior to the pressing step, a sheet is placed between the heated mold and the top outer surface, wherein the sheet is made of a thermally conductive non-stick material sufficient to transfer heat and force from the heated mold to the top outer surface.

13. The method of claim 12, comprising: After the pressure application step, the sheet is removed.

14. The method according to claim 1, wherein, The outer diameter of each capillary ranges from 50µm to 400µm, and the inner diameter of each capillary ranges from 0.5µm to 200µm.

15. The method according to claim 1, wherein, After the fixing step, the capillaries are spaced apart from each other along the width of the substrate by a capillary spacing, and the capillary spacing is selected from the group consisting of: The outer diameter of the capillary is 30 μm, wherein the outer diameter is in the range of 50 μm to 400 μm; The outer diameter of the capillary is 30 μm or greater, wherein the outer diameter of the capillary is in the range of 50 μm to 400 μm; and Within the range of 100μm to 600μm.

16. The method according to claim 1, wherein, The fixing step forms a plurality of slots extending along at least a portion of the length of the substrate, and the capillaries are exposed to the top outer surface through the slots respectively.

17. The method according to claim 1, wherein: Each capillary has a lower half and an upper half, which define the cross-section of the capillary in a cross-section defined by the width of the substrate and the height of the substrate. After the fixing step, the lower half of the capillary is completely embedded in the substrate; and After the fixing step, the upper half of the capillary is at least partially embedded in the substrate.

18. The method according to claim 1, wherein: Each of the plurality of capillaries includes a capillary window; The plurality of capillaries, except at the capillary windows, are each covered by an outer protective layer; and Multiple capillary windows are positioned in the substrate with their alignment with each other and are exposed to the external environment of the substrate.

19. The method according to claim 1, wherein, After the fixing step, the displaced portion completely covers the capillary along at least a portion of the length of the substrate, such that the substrate completely embeds the capillary.

20. A capillary array assembly manufactured according to the method of claim 1.

Images