Modular sample preparation device and method

Abstract

The present technology relates to customizable sample preparation devices (e.g., liquid sample preparation devices, such as purification, clarification, or separation devices). In particular, the present technology relates to customizable devices formed from modular segments that are modulated to address one or more of the following issues: optimization of different sample and elution volumes, incorporation of various connection mechanisms to liquid handlers, incorporation of various liquid dispensing flow conditions, and meeting a wide range of applications by selecting specific resins appropriate for sample preparation. Some embodiments are directed to affinity capture devices employing polymethacrylate resin-based, such as Protein A affinity capture devices. Other resins and other materials for processing liquid samples are described herein.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application 62 / 970,935, filed on February 6, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to sample preparation apparatus (e.g., liquid sample preparation apparatus, such as purification, sample cleansing, separation, etc.). More specifically, this disclosure relates to customizable apparatus formed from modular segments. These modular segments are tuned to address one or more of the following problems: optimizing different sample and elution volumes, integrating various connection mechanisms into liquid processors and / or separation instruments, incorporating various liquid distribution flow conditions, and meeting a wide range of applications by selecting specific resins suitable for sample preparation. In particular, the apparatus and methods disclosed herein are applicable to both manual and automated platforms, while providing high recovery rates, rapid and simple operation, and integration into liquid chromatography-based characterization and quantification. Background Technology

[0004] Affinity capture is one of the most powerful techniques for facilitating protein purification, performing biotherapeutic drug analysis, and conducting preclinical diagnostics. However, several issues continue to plague assay development, such as cumbersome sample preparation steps, insufficient target selectivity and recovery, poor reproducibility, and unoptimized compatibility with upstream sample delivery and downstream processing. For example, delays can arise not only from offline sample preparation steps but also from optimizing processing steps to conform to the shape factor of disposable laboratory equipment and integration with processing hardware.

[0005] Researchers analyzing both macromolecules and small molecule development candidates (e.g., biotherapeutic drugs and endogenous proteins) require separation and purification devices capable of rapid, simple, and high-recovery operations. From low-throughput assays to high-throughput development, the processing and optimization of hundreds of thousands of samples may be necessary. The same challenges exist for other sample preparation methods (e.g., sample preparation using different types of resins, such as phospholipid removal, ion exchange, reversed-phase, etc.). The need to seamlessly integrate these disposable tools into existing LC-based characterization and quantification assays remains unmet. Furthermore, the lack of choice in liquid / sample delivery to the device and in sample type (e.g., sample volume, concentration, and elution requirements) further slows down researchers' efforts. Summary of the Invention

[0006] Effective characterization of biotherapeutic drugs is central to process development and optimization. Understanding glycosylation, deacylation, isomerization, and aggregate formation is crucial for optimizing yield and purity. Current analytical workflows are incompatible with bioreactor conditions and require optimized sample purification and pretreatment. Development often shifts from low-throughput trials to high-throughput development. Each of these stages is slowed or delayed due to laboratory equipment optimization steps.

[0007] For example, researchers must purify monoclonal antibody-based therapeutics from cell cultures before downstream analysis. This necessitates generating thousands of samples to optimize process development conditions, all of which require purification. Due to variations in titers, sample volumes, and sample loading devices, disposable laboratory equipment of various form factors may be desirable to eliminate the need for continuous optimization.

[0008] This technology addresses these problems by providing customizable purification or liquid sample processing devices. Specifically, it provides modular components for processing devices consisting of two or more distinct segments that can be integrated to meet the needs of researchers. In one embodiment, the technology provides three modular components. In some embodiments, the technology provides more than three modular components. While combinations of pipette tips containing sample preparation media and 96-well plates have previously been described in the art as multi-part devices suitable for purification, these prior art devices are not modular. That is, these devices do not offer the option to modulate or customize the purification type or form factor by selecting appropriate modulating segments or portions of the device. The modular approach provided by this technology allows each liquid preparation device to be customized for selected sample loading, sample purification, and downstream analysis. Generally, in some embodiments, this technology is based on a pipette tip device consisting of at least three modular components: (1) a reservoir, (2) a body containing the selected resin, and (3) a tip for generating the desired droplet volume. Each of these three components can be customized, modulated, or selected to perform well in terms of sample type and / or desired sample processing and / or non-disposable liquid handling laboratory equipment (e.g., upstream liquid handling units, downstream analytical instruments). Furthermore, due to the modular approach, appropriate combinations of three or more modular components can be selected to meet specific needs determined by the sample type and desired purification / processing.

[0009] In one aspect, the present technology relates to a method for forming a liquid sample processing apparatus. The method includes at least three steps. In a first step, a single tip portion is selected from a group of at least two different modular tip segments, wherein each of the at least two different modular tip segments has an identical mating interface portion disposed at an inlet end. In a second step, a single reservoir portion is selected from a group of at least two different modular reservoir segments, wherein each of the at least two different modular reservoir segments has an identical body interface portion disposed at an outlet end. Finally, in a third step, the selected individual reservoir portion and the selected single tip portion are fluidly connected to a modular body portion. The modular body portion has a first end and a second end, the first end being adapted to mate with the identical mating body interface portion of the selected single reservoir portion, and the second end being adapted to mate with the identical mating interface portion of the selected single tip portion.

[0010] In one aspect, this technology relates to a method of providing a custom-designed liquid sample processing apparatus. The method includes receiving a design specification for the custom-designed liquid sample processing apparatus. The design specification indicates a liquid manipulator interface type and at least one or more of the following characteristics: sample volume, sample container type, desired droplet shape; desired outlet flow connector; separation culture medium type; filter assembly; and washing volume. The method also includes selecting a modular reservoir portion from a batch of reservoir portions of various configurations that is configured to meet at least one indication (e.g., characteristic or liquid manipulator interface type) of the design specification. The method further includes selecting a modular body portion from a batch of body portions of various configurations that is configured to mate with the selected reservoir portion and meet at least one indication (e.g., characteristic) of the design specification, and selecting a modular tip portion from a batch of tip portions of various configurations that is configured to mate with the selected body portion and meet at least one indication of the design specification. The method also includes securing the modular reservoir portion to the modular body portion and securing the modular body portion to the modular tip portion to create a fluid path extending through the secured modular reservoir portion, modular body portion, and modular tip portion.

[0011] The aforementioned aspects and features of this technology include numerous advantages. For example, this technology is characterized by a novel processing apparatus consisting of two or more modular components (e.g., 2, 3, 4, 5, etc.). Each of these modules is tuned to process or deliver optimal results for different sample and elution volumes, incorporates various adapter mechanisms, and enables a wide range of applications through the selection of specific resins. Compared to existing or conventional apparatuses, the apparatus and methods described herein are applicable to both manual and automated platforms, while providing high recoveries, rapid and simple operation, and seamless integration into liquid chromatography-based characterization and quantification. Therefore, increased speed and efficiency can be achieved during assay development. Furthermore, it is now easy to optimize and tune for sample types and desired laboratory equipment. Another advantage is the ability to employ continuous manufacturing techniques for biotherapeutic drugs, as this technology can be used to perform sideline analytical tests. Attached Figure Description

[0012] The present technology will be more fully understood through the following detailed description taken in conjunction with the accompanying drawings, in which:

[0013] Figure 1A A front view of an embodiment of the preparation apparatus according to the present technology in an assembled state is shown.

[0014] Figure 1B It shows Figure 1A A cross-sectional view of the preparation apparatus.

[0015] Figure 1C It shows Figure 1A An exploded view of the preparation apparatus (e.g., in an aligned but unassembled state, having a reservoir segment, a body segment, and a tip segment).

[0016] Figure 1D It shows Figure 1C A cross-sectional view of the device.

[0017] Figure 1E A front view of another embodiment of the preparation apparatus according to the present technology is shown.

[0018] Figure 1F It shows Figure 1E A cross-sectional view of the embodiment shown.

[0019] Figure 1G A front view of another embodiment of the preparation apparatus according to the present technology is shown.

[0020] Figure 1H It shows Figure 1G A cross-sectional view of the preparation apparatus.

[0021] Figure 1IA front view of yet another embodiment of the preparation apparatus according to the present technology is shown.

[0022] Figure 1J It shows Figure 1I A cross-sectional view of the preparation apparatus.

[0023] Figure 1K A front view of another embodiment of the preparation apparatus according to the present technology is shown.

[0024] Figure 1L It shows Figure 1K A cross-sectional view of the preparation apparatus.

[0025] Figures 2A to 2H Each shows a cross-sectional view of one embodiment of a modular storage segment according to the present technology.

[0026] Figure 3A A cross-sectional view is shown of multiple modular storage segments that are detachably connected together to form a strip.

[0027] Figure 3B It shows Figure 3A The top view of the strip shown shows that each individual reservoir segment is detachably connected to at least one other individual reservoir.

[0028] Figures 4A to 4C Cross-sectional views of different embodiments of the modular tip segment according to the present technology are shown.

[0029] Figure 5A An embodiment of a droplet outlet based on a modular tip segment according to the present technology is shown.

[0030] Figure 5B Another embodiment of a droplet outlet based on the modular tip segment of this technology is shown.

[0031] Figures 6A to 6E Cross-sectional views of different embodiments of the modular body segment according to this technology are shown.

[0032] Figure 7A This illustrates a possible combination of modular elements for forming a custom fabrication apparatus according to one embodiment of the present technology.

[0033] Figure 7B This illustrates another possible combination of modular elements for forming a custom fabrication apparatus according to another embodiment of the present technology.

[0034] Figure 7C This illustrates yet another possible combination of modular elements for forming a custom fabrication apparatus according to another embodiment of the present technology.

[0035] Figure 8A An embodiment of a custom preparation apparatus with a permanent connection according to the present technology is shown.

[0036] Figure 8B and Figure 8C Another embodiment of a component of a customized preparation apparatus connected according to this technology is shown. Figure 8B It is a perspective view and Figure 8C Provide a sectional view.

[0037] Figure 8D and Figure 8E Another embodiment of a component of a customized preparation apparatus connected according to this technology is shown. Figure 8D It is a perspective view and Figure 8E Provide a sectional view.

[0038] Figure 8F and Figure 8G Another embodiment of a component of a customized preparation apparatus connected according to this technology is shown. Figure 8F It is a perspective view and Figure 8G It is a sectional view.

[0039] Figure 9A An embodiment of a clamp for connecting and sealing the main body portion between the reservoir segment and the tip segment is shown.

[0040] Figure 9B Another embodiment of the clamp for connecting and sealing the main body portion between the reservoir segment and the tip segment is shown.

[0041] Figure 9C A cross-sectional view shows one embodiment with weldable or weldable connections between modular segments.

[0042] Figure 10A A strip configuration comprising multiple interconnected individual preparation devices according to the present technology is shown.

[0043] Figure 10B A front view of a strip configuration of a device comprising 12 connections according to the present technology is shown.

[0044] Figure 10C It shows Figure 10B A cross-sectional view of the stripes.

[0045] Figure 10D A front view of another embodiment of a strip configuration including 12 connections is shown.

[0046] Figure 10E It shows Figure 10D A cross-sectional view of the stripes.

[0047] Figure 10FA 96-well plate form is shown for use with multiple separate preparation devices according to this technique.

[0048] Figure 10G A direct connection between a preparative apparatus made according to the present technology and a liquid chromatography system is shown.

[0049] Figures 11A to 11D A cross-sectional view of a two-part preparation apparatus according to the present technology is shown.

[0050] Figure 12 This is a cross-sectional view showing one embodiment of the sample preparation apparatus of this technology having a deformable storage section.

[0051] Figure 13A yes Figure 12 A perspective view of the deformable storage section.

[0052] Figure 13B yes Figure 13A A cross-sectional view of the deformable storage section.

[0053] Figure 13C This is a perspective view of another embodiment of the deformable storage unit.

[0054] Figure 13D yes Figure 13C A cross-sectional view of the deformable storage section.

[0055] Figure 13E This is a perspective view of another embodiment of the deformable storage unit.

[0056] Figure 13F yes Figure 13E A cross-sectional view of the deformable storage section. Detailed Implementation

[0057] This technology's modular sample preparation device comprises a pipette tip-based apparatus that offers flexibility and simplicity for rapidly addressing sample preparation needs. The device includes at least two (or more, e.g., three, four, etc.) customizable modular components. Each of these modules is modulated during manufacturing to optimize for different sample and elution volumes, incorporate various adapter mechanisms, and enable a wide range of applications through the selection of specific resins. Compared to existing technologies, this modular device is suitable for both manual and automated platforms, while providing high recoveries, rapid and simple operation, and seamless integration into liquid chromatography-based characterization and quantification.

[0058] Biotherapeutic researchers often purify monoclonal antibody-based therapeutics from cell cultures prior to downstream analysis. This necessitates the generation of thousands of samples, all requiring purification, to optimize process development conditions. Due to variations in titer, sample volume, and sample load, having a range of devices customizable to specific process flows is advantageous for meeting diverse requirements. Previous systems using pipette tips and 96-well plates including prepared culture media have been described as having multiple components. While these existing devices include multiple components, they are not modular in assembly. Furthermore, these existing devices do not allow for customization for different sample loads, sample purification, and / or downstream analyses.

[0059] In one embodiment, the technology relates to a device based on a pipette tip, comprising three customizable modular components: a reservoir portion, a body portion, and a tip portion. For example, Figure 1A and Figure 1B An embodiment of the device according to the present technology is shown. Figure 1A A front view of the device 100 is shown, while Figure 1B A cross-sectional view of the device 100 is provided. The device 100, which can be used for sample preparation, includes a reservoir portion 105, a body portion 110, and a tip portion 115. When assembled and as can be seen in the cross-section, the body portion 110 is sandwiched between the reservoir portion 105 and the tip portion 115. Figure 1B In the illustrated embodiment, the end or outlet portion 107 of the reservoir portion 105 connects to the tip 111 of the fluid receiving end of the body portion 110, and the inlet portion 118 of the tip portion 115 receives the bottom end 113 of the body portion 110. The body portion includes two retaining structures 109a and 109b, such as, for example, glass frit or support membrane filters, to hold the resin or other culture medium used for processing liquid samples. The outlet portion 120 of the tip portion 115 is customized to generate a desired droplet volume and / or shape exiting the device 100.

[0060] See Figure 1C and Figure 1D The device 100 is formed by three modular components. Each of these components can be customized for a specific sample or processing step. The customized modular components are then assembled to create the device 100. Figure 1C and Figure 1D The device 100 is shown in an unassembled state. That is, Figure 1C The device 100' is shown in an exploded view, in which each modular component (i.e., reservoir portion 105, body portion 110, and tip portion 115) is aligned but not assembled (and therefore not fluidly connected to process liquid samples). Figure 1D The unassembled device 100' is shown in cross-section.

[0061] Each modular component in the modular design (i.e., reservoir portion 105, body portion 110, and tip portion 115) is customizable. That is, in one embodiment, multiple different types of reservoir portions can be manufactured (e.g., three different types, four different types, five different types, etc.). The user can then select the appropriate reservoir type for a specific sample type and / or sample preparation or processing conditions to meet their specific needs. For example, in an embodiment where three different reservoir types are manufactured, the user selects the type best suited to their sample processing needs, and because each reservoir portion is modular, a customized device can be assembled using the selected reservoir portion type along with the selected body portion type and the selected tip portion type.

[0062] although Figures 1A to 1D One embodiment of the preparation apparatus 100 is shown, wherein the connection between the modular components is achieved by receiving each end of the body portion 110 within the corresponding ends of the reservoir portion 105 and the tip portion 115, but other types of connections are also possible. For example, in Figure 1E and Figure 1F In the illustrated embodiment, the outlet portion 107 is fitted within the main body portion 110, rather than the reservoir portion, where the outlet portion 107 accommodates one end of the main body portion 110. Similar to... Figures 1A to 1D In the illustrated embodiment, the inlet portion 118 of the tip portion 115 is received within the corresponding end of the body portion 110. Figure 1G and Figure 1H In the illustrated embodiment, the main body 110 houses both the outlet portion 107 of the reservoir portion 105 and the inlet portion 118 of the tip portion 115 within the main body 110. And... Figure 1I and Figure 1J In the illustrated embodiment, the outlet portion 107 of the reservoir accommodates an end of the main body portion 110 therein, and the main body portion 110 accommodates the inlet portion 118 of the tip portion 115 within the main body portion 110. Figure 1K and Figure 1L In another possible embodiment shown, the body portion 110 is enclosed within the reservoir portion 105 and the tip portion 115. That is, the reservoir portion 105 and the tip portion 115 each extend around the body portion such that the ends of each of the reservoir portion 105 and the tip portion 115 are in direct contact, as... Figure 1K and Figure 1L As shown.

[0063] Memory type

[0064] See Figures 2A to 2HThis diagram illustrates eight possible reservoir section configurations that can be used in embodiments of this technology. Generally, the reservoir section intersects with a handheld pipette (for a manual platform) or an automated pipette / liquid manipulator (for an automated platform). In some embodiments, the interface may be designed to intersect with a pipette capable of bidirectional (or simply unidirectional) manipulation of liquids for sample loading and washing. For each volume and brand of pipette or automated liquid manipulator, the reservoir is specifically designed to intersect with the liquid manipulator (i.e., a manual pipette or automated liquid processor). Thus, the top end 103 of the reservoir section may be shaped or configured to intersect with a specific liquid manipulator—and therefore may vary between different possible reservoir types. On the other hand, the bottom or outlet end 107 is standardized so that it can connect to or intersect with any type of modular body section when assembling the custom device 100. In other embodiments, the reservoir may include a top end with a universal connection that can connect to or intersect with multiple types of liquid processors or pipettes. The volume of the reservoir section may also be customized to suit a specific liquid handling device. For example, the volume or size of the reservoir section can be customized to work with the most common liquid handling devices, such as Gilson and Eppendorf single-channel and multi-channel pipettes in the 200-µL to 300-µL range. Furthermore, the type of reservoir section can be customized to work with positive pressure or vacuum manifolds. In one embodiment, the individual reservoir section works with both large-volume pipettes (e.g., P100 to P300) and small-volume pipettes (e.g., P1 to P20) to achieve final sample elution for end-to-end sample preparation using a single tip. End cap 103 may be adapted or configured to work with one or more of the following types of liquid processors: for manual platforms (Gilson, Pipetteman; Waters Corporation, vacuum manifold or positive pressure manifold; Eppendorf, Research Plus; TTE Laboratories, EON S; Drummond Scientific, Pipet-Aid; SCILOGEX Levo pipette); for automated platforms (Hamilton, MPE2 (positive pressure) or STAR / STARlet 8-channel tip; Tecan, Freedom Evo Fixed Tip, Freedom Evo LiHa (disposable, liquid arm), Freedom Evo LiHa (disposable, air arm), Fluent FCA (air arm), or Fluent FCA (liquid arm); Andrew Alliance, PipettePlus; Apricot, Even 96 (positive pressure).

[0065] In addition to the specific geometry for interface connection with different liquid processors (e.g., different configurations of end 103), the reservoir portion may have different lengths and / or different volumes to provide a suitably customized reservoir portion 105 for the desired sample processing. Figure 2A A cross-sectional view of a storage portion according to one embodiment of the present technology is shown. Figure 2A The implementation scheme shown has a small working volume and short length. Figure 2B The illustrated embodiment has a medium length and its diameter is also greater than [a certain value]. Figure 2A The diameter shown. Therefore, the working volume of this embodiment is larger than... Figure 2A The working volume is shown in the implementation plan. Figure 2C The third embodiment (or third reservoir section type) is shown in cross-section. The inner diameter of this reservoir section is smaller than... Figure 2B The diameter shown is [diameter], but it has a longer length. Generally, for automated platforms, the reservoir volume ranges from about 5 mL to 6 mL to about 4 μL to 5 μL; while for manual platforms, the large reservoir volume can be more than 10 times that of 5 mL to 6 mL (e.g., 60 mL to 65 mL). Manual platforms can have any reservoir volume, typically between 65 mL and 4 μL. Therefore, the range of length, width, and inner diameter can vary depending on the application.

[0066] The internal geometry of the storage section 105 can also be varied to accommodate the required volume for a desired shape factor. For example, Figures 2D to 2H Several exemplary embodiments of the storage section 105 are shown. Figure 2D In the illustrated embodiment, the reservoir portion 105 has a large internal volume, with end 103 leading to a small connection port for the liquid processor. Figure 2D The implementation scheme shown is the opposite. Figure 2E The reservoir section 105 has a much narrower internal volume for accommodating fluid entering from the end 103. Figure 2F and Figure 2G The reservoir sections 105 shown each have similar lengths, but their fluid volume retention capacities differ not only due to the diameter of the reservoir section but also due to the wall thickness of the reservoir section. Figure 2F In the illustrated embodiment, the wall height of the storage section is... Figure 2G The wall thickness shown in the implementation scheme is much greater. Figure 2G The inner diameter of the storage section 105 is also larger than Figure 2F The inner diameter of the implementation scheme can be easily compared at the end 103. Figure 2HAnother possible embodiment of the reservoir portion 105 is shown. In this embodiment, the inner wall forming the fluid volume retention capacity of the reservoir portion 105 is curved to form a unique internal shape.

[0067] The reservoir section can be further configured or adapted to meet different form factor requirements. For example, some platforms or laboratory fixtures are better suited to orifice plates or strip configurations. To provide additional form factor options, the reservoir section can be made into a strip structure, with each individual reservoir section detachably connected to adjacent reservoir sections. For example, Figure 3A A cross-sectional view of one embodiment is shown, in which eight reservoir sections are detachably connected at the top 103 to form a strip. Figure 3B yes Figure 3A The illustrated embodiment is shown as a top view and depicts a top surface with eight separate (non-fluidly connected) reservoir portions (105a to 105h) physically connected at a connection interface 102 at a top tip 103. In some embodiments, the connection interface 102 is removable (e.g., perforated or otherwise destructible). In other embodiments, the connection interface 102 need not be removable. In some embodiments (not shown), the strip may comprise any number of reservoir portions, such as 6, 8, 12, 24, 48, etc. Other form factors are also possible, such as a grid of removable reservoir portions (e.g., 4 rows of 12, totaling 48 reservoir portions arranged in a grid, or 6 rows of 8, or even 96 reservoir portions arranged in a grid).

[0068] Tip type

[0069] See Figures 4A to 4CThis diagram illustrates three possible tip portion type configurations for embodiments that can be used in this technology. Generally, the tip portion intersects with a collection unit or analyzer / detector (e.g., an eluent plate or UV detector). Therefore, the outflow from the tip portion (i.e., droplet shape, volume, etc.) is selected based on downstream requirements (i.e., collection type or analyzer / detector type). Generally, the tip portion type can be modified or customized relative to the tip diameter, tip length, and droplet volume or shape. The tip outlet can be designed specifically to release a droplet of the desired volume. Generally, it is desirable to have a tip portion with a dead volume of 10 μL or less (i.e., 5 μL or less, 4 μL or less, 3 μL or less, etc.). Some embodiments feature a removable guard or pre-filter at the droplet end of the tip. The pre-filter serves as a coarse filter in food and / or environmental applications or in other samples where debris may clog downstream frit or detectors. In some embodiments, multiple filters can be used in a single tip portion, or additional filter assemblies can replace clogged filter assemblies.

[0070] The outlet portion 120 of the tip portion 115 can be customized in a variety of different ways to address the outflow. For example, Figures 4A to 4C Three different types of tip sections are shown, each of which can be used as a modular part to obtain a customized device 100. Figure 4A A cross-sectional view of the tip portion according to one embodiment of the present technology is shown. Figure 4A The pointed end has a relatively wide inner diameter and a medium-length tip. Therefore, Figure 4A The tip can handle a remaining volume of approximately 5 μL to 20 μL or more. Figure 4B A cross-sectional view according to another embodiment of the present technology is shown. Figure 4B In the pointed portion shown, the inner diameter is the same as... Figure 4A Compared to the reduction. Therefore, Figure 4B The remaining volume capacity at the tip is less than Figure 4A The remaining volume capacity at the tip. Figure 4C A third possible implementation of the modular tip section type is shown. Figure 4C In the embodiments shown, the length is increased compared to the length shown in the previous two embodiments. Figure 4C The inner diameter of the tip is between Figure 4A and 4B Between the inner diameters shown. That is, Figure 4C The inner diameter of the tip is not Figure 4A Large, but greater than Figure 4C The inner diameter of the tip. By customizing the length and inner diameter dimensions, the remaining volume of the tip can be appropriately matched to downstream collection or analysis devices.

[0071] In addition to customizing the remaining volume of fluid within a specific tip type, the droplet shape and size can be further customized by modifying the droplet outlet. Figure 5A and Figure 5B Two possible droplet outlet structures are shown. Figure 5A The droplet outlet shown has a countersunk hole within the outlet end 125. Conversely, Figure 5B The droplet outlet shown has a countersunk hole within the outlet end 125'. Unbound by theory, the shape of the droplet outlet opening influences the droplet size and shape of the droplet flowing from the tip. Therefore, by modifying, customizing, or selecting the outlet shape, a desired droplet shape suitable for the target application can be generated.

[0072] In the components of the customized device according to the invention, the end 130 opposite to the outlet end 125 of the tip portion is fluidly connected to the main body portion 110 (see...). Figures 4A to 4C Generally, the end portion 130 is designed to connect / interact with a portion of the body portion 110. In embodiments, the end portion 130 of the tip portion 115 is standardized to interact and fluidly connect with multiple different types of body portions 110.

[0073] Main type

[0074] See Figures 6A to 6E This illustrates five possible body portion types configurations that can be used in embodiments of this technology. Generally, the body contains resin or other sample processing materials. In embodiments, the resin or other sample processing materials are sandwiched within a shell between two glass frits (e.g., sieves, meshes, membranes, etc.) containing the resin. The shape of the body portion can be customized to accommodate a range of resin volumes and patterns. For example, many different patterns can be selected for use with this technology, including but not limited to solid-phase extraction, affinity capture, and sample purification using anti-human IgG, streptavidin, biotinylated targets, nanobodies, nucleic acid ligands, and particles with custom ligands attached to their surfaces. Therefore, a variety of types of resins are available that can be used in conjunction with this technology. Possible resin types include, but are not limited to, phospholipid-removing resins (e.g., hydrophobic-lipophilic balanced Ostro). TM resin and Resins (both available from Waters Corporation, Milford, MA), ion exchange resins, and reverse-phase resins (desalted, silica, C18, C8, C4, alumina, etc.) Available resins include: US Silica, Berkeley Springs, WV; mixed-mode resins; size exclusion resins; affinity resins (protein A, protein G, streptavidin, biotin, avidin, Ni-, silica-IMAC, lectins, borates, anti-human Fc, anti-insulin, anti-idiotype); phosphopeptide resins (e.g., ZrO2, titanium); hydrophobic interaction resins; HILIC resins; aminopropyl resins; cyanopropyl resins; immobilized enzyme resins (e.g., trypsin, sialidase, glucuronidase); fluoropolymers; metal resins (e.g., Ca, Fe, Ni, Ga); and dispersible SPE materials (e.g., QuEchERS). The total amount of resin can be selected / customized for a specific application. In some embodiments, the resin volume ranges from about 1 μL to 1 mL. In embodiments for mixed-mode separation, multiple resin beds may be stacked back-to-back, with or without glass flotation within a single body portion 110 between them. Alternatively, multiple main body parts (either permanently connected together or removably stacked back to back) can be used together within a single device to provide a mixed pattern or custom resin combination for sample processing.

[0075] Figures 6A to 6E Cross-sectional views of various possible body section types are provided. While five different implementation types are shown, other body section type configurations are also possible. Generally, body section type configurations can be customized to accommodate various resin volumes, bed lengths, and bed aspect ratios. Furthermore, it is possible to accommodate different resins, and even to house multiple resin beds or different types of resins within a single bed section. Figure 6A A bed section type is shown, in which a short bed length of resin is contained between two glass blocks 109a and 109b. Figure 6A In the illustrated embodiment, the resin bed volume does not fill the entire internal volume of the main body portion 110; an empty flow channel or space exists above the glass flotation 109a. The top end 111 and bottom end 113 intersect with other modular components of the device 100. Specifically, the top end 111 of the main body portion 110 is configured to intersect with the outlet end 107 of the reservoir portion 105; while the bottom end 113 is configured to intersect with the inlet portion 118 of the tip portion 115.

[0076] Figure 6B The main body type shown is similar to Figure 6A The difference in the illustrated embodiment is that almost the entire (if not the entire) internal flow path volume of the main body is filled with a resin bed and its retaining mechanism. That is, not as... Figure 6A As shown, there is an empty flow channel or space above the glass frit 109a. Figure 6BIn one embodiment, the top glass element 109a is positioned close to and directly adjacent to the top end 111 of the body portion 110. Therefore, Figure 6B The main body of it has more Figure 6A The embodiment shown has a longer bed length. The bed width can also be customized / modified to accommodate different types of resins or different processing modes. Figure 6C In the implementation scheme shown, with Figure 6A and Figure 6B Compared to the embodiment shown, the width of the bed is increased. Furthermore, the bottom end of the resin bed is tapered, resulting in glass frits 109a and 109b used to fix the bed having different diameters.

[0077] Figure 6D The body section type shown has been customized to provide a longer bed length. A longer bed length may be suitable if a longer interaction with the resin type is required, or if it is a mixed-mode operation in which two or more (e.g., multiple) different beds of different resin types are filled along the length of the body section 110. Although Figure 6D The illustrated embodiment includes only the top glass flotation 109a and the bottom glass flotation 109b, but in some embodiments (not shown) that include multiple bed layers, additional glass flotation separating each bed layer may also be used. Figure 6D The implementation schemes shown are similar. Figure 6E The main body type shown has a relatively long bed length. Figure 6E The illustrated embodiment also features a large bed width, thereby increasing the resin volume and providing a higher density. Figure 6D The illustrated implementation has a larger bed aspect ratio.

[0078] Glass frits 109a and 109b are used to confine the resin bed within a specific area of ​​the body portion 110. For example, the glass frit helps to hold the resin in place within the body portion and inhibits the migration of resin or other sample processing materials from the body portion 110. The type of glass frit used (e.g., material, shape, thickness, pore size, pore shape, pore volume, etc.) is selected to optimize its use with the resin type. For example, when using 50-micron monodisperse spherical particles as the resin type, a glass frit with an average pore size of 40 microns and a thickness of about 0.75 mm can be used to ensure the resin culture medium is at maximum solvent flow rate. Possible glass frit materials include, but are not limited to, polyethylene, polypropylene, PEEK, and Teflon. The glass frit material can be tailored to be hydrophilic or hydrophobic depending on the application. In some embodiments, glass frits 109a and 109b may be similar or identical to each other in one or more of the material type, size, shape, and pore characteristics. For example, as... Figure 6A As shown in the embodiments, glass frits 109a and 109b are identical in size and shape. However, in other embodiments, the glass frits need not be identical or even similar. For example, as... Figure 6C and Figure 6E As shown in the embodiments, glass flotation 109a has a different dimension than glass flotation 109b. In some embodiments, glass flotation 109a or 109b may be formed from multiple stacked glass flotations. In some embodiments, more than two glass flotations may be present in a single body portion 110. For example, more than two glass flotations may be used to separate different resin bed types; more than two glass flotations may be used to fix a resin bed; more than two glass flotations may be used as filters; and / or more than two glass flotations may be used as flow restrictors. And in some embodiments, only a single glass flotation may be used. By slowing down the solvent flow (i.e., using one or more glass flotations as flow restrictors), in some cases, the liquid sample is allowed to interact with the resin for a longer period of time, allowing for more efficient sample processing.

[0079] Some embodiments of the modular body portion 110 may include a removable lip, cap, or flap. For example, for transporting or storing the modular body portion 110, a detachable cap covers the top 111 and bottom 113 of the body portion 110. The cap or other covering protects the integrity of the resin before use. In some embodiments, the removable cap, cover, or flap is used in conjunction with a fully assembled detachable device according to the present technology (e.g., a device made of two or more modular components, such as three, joined together). The cap, cover, or flap may be secured to the top and / or bottom of the assembled device.

[0080] coating

[0081] The modular segments (i.e., reservoir portion 105, body portion 110, and tip portion 115) can be further modified / customized by adding coatings. Coatings can provide additional benefits / advantages during sample processing. These advantages include minimizing nonspecific binding (e.g., inhibiting protein adsorption), additional separation capacity, and wettability operation (e.g., hydrophilic / hydrophobic portions). Because each device consists of two or more modular components (e.g., 2, 3, 4, etc.), the same or different coatings can be applied to each modular component / segment. Specialized coatings can also be added to specific components (e.g., frit or filter) housed within the modular segments.

[0082] The coating can be polymer-based (e.g., for wettability or separation properties) or metal-based (for thermal and electrical properties). Generally, the coating thickness ranges from a single layer to about 1 micrometer or 2 micrometers. In some embodiments, the coating is applied to the entire modular segment. In other embodiments, the coating is applied to a portion (e.g., an interface or outlet / inlet end). Furthermore, a coating applied to an interface of a component can be applied to the interface of a mating part. For example, if a coating is applied to the outlet 107 of the reservoir portion 105, a similar coating can be applied to the tip 111 of the mating body portion 110.

[0083] Select modular segments to form a customized / made-to-order sample processing device.

[0084] For example in Figures 1A to 1L The device 100 shown combines selected and / or modular reservoir portions 105, selected and / or modular body portions 110, and selected and / or modular tip portions 115 to form a customized device. The selection of each modular segment type (i.e., reservoir, body, tip) is to optimize specific sample processing results. That is, a specific reservoir portion, a specific body portion, and a specific tip portion are selected to meet the needs of the sample processing and laboratory equipment used (e.g., platform type).

[0085] In one embodiment, a custom liquid sample preparation or processing apparatus is manufactured to house a specific liquid handling platform (e.g., a specific liquid manipulator) and discharge a specific droplet shape from the custom apparatus. Specifically, a method of manufacturing a liquid sample preparation apparatus includes: selecting a modular reservoir portion based on a desired liquid manipulator interface design (e.g., manual platform, Gilson, Pipetteman); selecting a modular body portion based on desired sample preparation container characteristics (e.g., resin type, resin volume, mixing mode separation, bed length, etc.); selecting a modular tip portion based on desired outlet droplet characteristics (e.g., droplet size, droplet shape, etc.); and fluidly connecting the modular reservoir portion, the modular body portion, and the modular tip portion. For example, the fluid connection can be achieved by connecting a second end of the modular reservoir portion to a first end of the modular body portion and connecting the second end of the modular body portion to an inlet of the modular tip portion to create a fluid path through the apparatus.

[0086] In addition to selecting each modular segment based on platform or delivery requirements of processed samples, modular segments can be selected and combined to build a custom device based on the sample to be processed. For example, Figures 7A to 7C Three possible combinations of different modular segments for creating a custom sample processing device according to this technology are shown. See also Figure 7AResearchers or users with large volumes of highly concentrated samples but without specific elution requirements (e.g., droplet shape and elution volume do not require a specific shape factor) can have a device tailored to their specific needs by following these steps: selecting a custom reservoir section 105a with a longer length to handle large volumes of samples; selecting a body section 110a with a larger bed width / above aspect ratio to handle highly concentrated samples; and selecting a custom tip 115a that allows fluid to flow freely from the tip.

[0087] For users or researchers with average sample volumes requiring longer residence times to meet binding and critical elution volume requirements, different sets of modular segments can be combined to form customized sample processing devices. See details... Figure 7B This shows the custom storage section 105b (compared to...). Figure 7A As shown, it has a shorter length / smaller volume); the custom body part 110b (compared to...) Figure 7A As shown, it has a narrower resin bed and a smaller aspect ratio; and a custom tip portion 115b (with a tip outlet with a countersunk hole to produce a specific droplet shape). To produce a custom device that meets the requirements of this specific sample, the reservoir 105b is fluidly connected to the body portion 110b and the body portion 110b is fluidly connected to the tip portion 115b.

[0088] Alternatively, for users or researchers with large volumes of highly diluted samples containing limited analytes (or limited or expensive resin materials), custom-made devices can be produced to suit these needs. See details... Figure 7C The storage section 105a (long-length storage section, with) is shown. Figure 7A (The same as shown); a custom body portion 110c (a compact resin bed that does not extend through the entire body portion and has an empty fluid space above, below, or both of the glass flotation within the body portion); and a custom tip portion 115c (a tip length with a controlled volume).

[0089] Other combinations of modular segments are also possible, and one combination is not limited to... Figures 2A to 2H The implementation scheme shown is for a storage device; Figures 4A to 4C and Figure 5A and Figure 5B (For the tip); and Figures 6A to 6E(For the body). Other possible customized modular section implementations are possible for each of the reservoir section (e.g., 105), the body section (e.g., 110), and the tip section (e.g., 115). To make the modular components compatible and fluidly connectable to each other, one or more of the following techniques can be used. For example, in one implementation, the modular segment may be made of a weldable material, and the selected reservoir section may be connected to the selected body section, and then welded to the selected tip section to create a fluid path through the customized device. Another possible technique is to apply standard connection terminals to the interface of the segment. That is, by customizing the reservoir section type (e.g., respectively in...) Figure 7A and Figure 7B Each of 105a and 105b shown in the diagram provides for accepting customized body part types (e.g., respectively in...). Figure 7A , Figure 7B and Figure 7C All fluid inlet ends and / or second or outlet ends that intersect with them (110a, 110b, and 110c) shown herein can be modularly assembled (e.g., easy connection between many different parts). The modular assembly method with each connection end allows for both permanent and removable connections.

[0090] Because this is a modular device, the various components are attached together in a manner that forms a tight liquid seal under pressure generated by various liquid handling devices (e.g., a liquid manipulator that inserts liquid into the device at the reservoir section). The tip portion is attached to the body portion, and the body portion is attached to the reservoir section. Permanent bonding techniques include heating, melting, gluing, radio frequency bonding, adding materials (e.g., metal, plastic) at the interface to form a seal, using adapters or ring compression, threaded connections, ultrasonic welding, and other mechanical means (e.g., clamps, retaining rings, etc.). Alternatively, to take advantage of the modularity of the device, the bonding can be temporary or removable. This allows switching the reservoir section during processing (e.g., changing the reservoir section so that it can be interchanged with different liquid manipulators or liquid handling platforms) or switching the tip portion (e.g., changing the droplet shape or other droplet characteristics), or even allowing the removal of either or both of the reservoir section and the tip portion for in-line or offline processing without modifying the remaining components. This type of switching or modification is possible because standard fittings are integrated into the body section. That is, some implementations are characterized by the main body having the same dimension at both outlets, regardless of resin or construction / type. Temporary or removable bonding techniques include threaded connections, the use of retaining clips, and engagement on shoulder features.

[0091] See Figures 8A to 8GThis paper illustrates four possible implementations of the present technology for connecting and sealing modular segments to create fluid flow paths through a customized device. Some of these methods form a permanent connection, while others are removable, thereby allowing for replacement, purification, or further customization of the device based on the present technology. Figure 8A The illustrated embodiment is a permanent connection solution. In this embodiment, the body portion 110 is inserted between and into the storage portion 105 and the tip portion 115. To form a fluid seal between the components and permanently secure the device, the components are fused together around and in the area of ​​the interface 135. In some embodiments, in addition to or instead of applying heat to form a molten band to hold the components together, an adhesive may be used to form a leak-proof interface between the components.

[0092] Figure 8A The illustrated implementation is a permanent solution. Other implementations can be removably joined (e.g., a threaded fitting at interface 135). However, it should be noted that adhesive, heat, or welded joints can be added to the removable connection to further secure and permanently hold the modular segments together.

[0093] Figure 8B and Figure 8C The illustrated embodiments can be either permanent or removable connections. This embodiment is characterized by an interference fit between the body portion 110 and the surrounding reservoir portion 105 and tip portion 115, and a restrictive outer sleeve 140 that further secures the assembly in place. In one embodiment, the outer sleeve is made of a heat-sensitive material that contracts and, in some cases, adheres to a portion of the reservoir portion 105 and tip portion 115, thereby forming a permanent bond. In other embodiments, the restrictive outer sleeve 140 is biased in a radially inward direction of contraction but is made of a material that can be easily cut or removed. The restrictive outer sleeve 140 surrounds and seals the interface between the reservoir portion 105 and the body portion 110, and the interface between the body portion 110 and the tip portion 115. In some embodiments, a mechanical clamp replaces the restrictive outer sleeve. In some embodiments, a permanent bond is formed by an interference fit. In some embodiments, a permanent bond is formed by means of a permanently fixed clamp.

[0094] Figure 8D and Figure 8E Another possible component of the customized device of this technology is shown. In this embodiment, a metal ring 145 is added to the interface 135 to secure the modular segments together.

[0095] Figure 8F and Figure 8GAnother embodiment is shown. In this embodiment, flange connections 150 are added to the inlet and outlet ends of the body portion 110, and the outlet end of the reservoir portion 105 and the inlet of the tip portion 115. The flange assembly 150 forms a flat interface that can be subsequently sealed using clamps 155 for leak-proof connection. These clamps are removable, thereby allowing switching, cleaning, or removal of any of the three modular segments 105, 110, and 115. However, in some embodiments, an adhesive may be added to permanently seal the flange 150 to its adjacent adjacent flange.

[0096] Other types of clamps or mechanical devices may also be used to secure and form a liquid-tight connection between modular components 105, 110, and 115. For example... Figure 9A and Figure 9B Two other embodiments are shown, in which clamps are added to hold the three modular components together to achieve an impermeable fluid connection. Figure 9A In the illustrated embodiment, the clamp 160 is integrated into the tip portion 115 and connected to the reservoir portion 105, thereby clamping the body portion 110 therebetween and forming a fluid-impermeable connection (e.g., clamp face upwards). Figure 9B In the illustrated embodiment, clamp 165 is integrated into reservoir portion 105 and connected to tip portion 115, thereby clamping body portion 110 and forming a fluid-impermeable connection (e.g., clamp face down).

[0097] This technology also envisions other types of connections between modular segments 105, 110, and 115. For example, the three modular segments could be designed as a mechanical connection and then permanently fixed together using welding techniques. For example, in Figure 9C In the illustrated embodiment, the bottom end 107 of the reservoir portion 105 includes a protrusion 170. The body portion 110, which mates with the reservoir portion 105, includes a receiving / mate opening 175 for the protrusion 170. During assembly, the protrusion 170 is inserted into the opening 175 and secured by friction (e.g., rotational or ultrasonic) welding. The bottom end of the body portion includes another mate opening that mates with another protrusion 180 extending from the tip portion. To secure the tip portion 115 to the device, friction welding is formed at the location of the inserted protrusion 180.

[0098] This technology can be used as a single device (such as) with a single-channel pipette. Figure 1A The device 100 shown may be, or in other forms, such as, for example, one of eight (such as...) Figure 3AThe devices shown may be in the form of 12 or more wells, or in the form of a support or grid for multi-channel applications (e.g., 48, 96, or 384 devices). Furthermore, devices according to this technology can be arranged in the form of a 96-well plate for use with 96-tip manifolds, positive pressure manifolds, or automated liquid processors. Devices can be broken into the desired number by perforation, slotting, or weakening joints from strips of 8 or 12 or more. This allows for the loading of flexible handheld pipettes into an array or onto an automated sampler. See also Figure 10A An implementation in the form of an eight-unit strip is shown. The strip does not necessarily include eight devices. That is, the strip can include any number or multiple devices (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.), and adjacent devices can be permanently or detachably connected. For example, Figure 10B and Figure 10C An embodiment comprising 12 devices connected together at a location 163 along the length of the reservoir section (i.e., not at the inlet). Figure 10D Front view and Figure 10E In the embodiment shown in the cross-sectional view, 12 devices are connected together in the form of a strip. To form connections between individual devices, the body portion 110 includes a connector 173, which may include perforated or weakened locations to allow adjacent devices to be separated from the strip. Non-linear connection arrangements are also possible. Figure 10F The example shown uses a 96-well plate. Other plate sizes are also possible, such as 384-well or 1536-well plates. Figure 10G This demonstrates yet another form. In Figure 10G In the illustrated implementation, this form is suitable for direct connection to a liquid chromatography system used in online or off-line applications.

[0099] This technology also includes embodiments characterized by the connection of two customizable parts. That is, in some embodiments, the technology is characterized by a custom-made preparation apparatus formed by two custom parts, rather than by joining and forming an impermeable liquid connection between three components. Use may include, but is not limited to, direct connection to an LC system.

[0100] Generally, the two-part implementation is characterized by an integrated reservoir / body segment, or alternatively, an integrated body / tip segment. See, for example, [link to relevant documentation]. Figures 11A to 11D Four possible two-part implementations are shown. Other two-part implementations are also within the scope of this technology. Figure 11A In the two-part device 200, a custom-designed reservoir portion 205 is connected to the integrated body / tip portion 212. For example... Figure 11AAs shown, the end 206 of the reservoir portion 205 is sealed within the top portion 216 of the integral body / tip portion 212. Figure 11B The two-part device 200 shown also includes an integral body / tip portion 212; however, in this embodiment, the end 206 of the reservoir portion is received and sealed within a portion 216 of the integral body / tip portion 212. Figure 11C and Figure 11D An embodiment including an integrated storage / body portion 204 is shown. Figure 11C In the middle, the integrated reservoir / body portion 204 has an end 214 surrounding the inlet 209 and sealing it to the tip portion 210. Figure 11D One embodiment of the device 200 is shown, wherein the tip portion 210 is positioned on the integral reservoir / body 204 such that the inlet 209 surrounds the end portion 214 to form a fluid-impermeable seal. Any and all combinations of the features and embodiments described above in conjunction with three- or more part / segment devices can be implemented or used with a custom-made two-part device 200. For example, although Figures 11A to 11D All the embodiments shown use a cylindrical reservoir or a one-piece reservoir / body section, but other shapes are also possible, such as those similar to Figure 2H The curved shape shown or Figure 2D The circular shape is shown. In some embodiments, a coating may be used. And some embodiments are characterized by the use of any of the above-described joining or sealing techniques (e.g., adhesives, melting, clamps, etc.). Additionally, the two-part device can be made in any shape factor, such as a single device, a strip of four, eight, twelve or more detachable or permanently connected devices, or a plate, hole or grid of any desired number of devices.

[0101] Affinity capture is one of the most powerful techniques for facilitating protein purification, biotherapeutic characterization, and preclinical diagnostics. However, several challenges remain for assays relying on affinity capture technologies, such as cumbersome sample preparation steps, insufficient target selectivity and recovery, poor reproducibility, and unoptimized compatibility with downstream processing. Therefore, this technology provides a sample processing apparatus that operates in conjunction with both automated and manual platforms to offer high recovery rates, rapid and simple operation, and direct integration with downstream analytical techniques.

[0102] In one embodiment targeting protein A affinity capture, a monodisperse polymethacrylate-based resin is used. This resin provides high-resolution results when stored under wet or dry conditions. To overcome usability issues, this affinity prototype is designed to efficiently bind samples within five pipette-assisted aspirations, a significant improvement over conventional devices requiring up to 250 cycles and using automated liquid processors. Furthermore, by allowing users to select reservoir sections with large volumes (e.g., 10 μL to 300 μL), end-to-end sample preparation within a single device allows users to directly aspirate and dispense a range of volumes from a single device. This improves the user experience by providing the opportunity to further customize the user's procedure for desired transfer volumes, as well as maximum recovery and cleanliness.

[0103] As used herein, the term “about” means that the value is approximate and that minor variations will not significantly affect the practice of the disclosed embodiments. When numerical limits are used, unless the context otherwise indicates, “about” means that the value may vary by ±10% and still remain within the range of the disclosed embodiments.

[0104] Alternative options

[0105] Those skilled in the art will recognize that other implementations are possible. For example, even some implementations, such as Figures 2A to 2H The disclosed embodiment describes a reservoir section connected at the top or inlet end to a manual or automated platform, but other embodiments are also possible. One such embodiment employs a deformable reservoir section. See also Figure 12 and Figures 13A to 13F An embodiment using a deformable reservoir 305 is illustrated. The deformable reservoir 305 is filled with or holds samples and any solvents for delivery to the body portion 110 and ultimately to the tip portion 115. The deformable reservoir 305 is preferred when handling large volumes of samples (e.g., 0.5 mL to 50 mL or more) and when laboratory equipment such as pipettes and liquid processors is unavailable or impractical. The deformable reservoir can be disposable and can be replaceable. In some embodiments, samples may be pre-loaded into the deformable reservoir for transport with a cover or cap. In other embodiments, the user may load the sample into the deformable reservoir 305. Although Figure 12 and Figure 13A and Figure 13B The deformable storage portion 305 is shown as a light bulb, but other shape factors are also possible. For example, Figure 13C and Figure 13D The deformable storage section 305 shown is similar to Figure 13A and Figure 13BThe deformable reservoir section (i.e., the bulb that holds a 1 mL internal volume), however Figure 13C and Figure 13D The deformable reservoir portion also includes an opening 317 at the top. The opening 317 can be used to inject a sample into the interior of the deformable reservoir 305. In some embodiments, when in a deformable state, the opening 317 can be used to discharge gaseous material from the interior of the portion 305. Figure 13E and Figure 13F Another embodiment of the deformable reservoir portion 305 is shown. In this embodiment, the deformable reservoir portion has a cylindrical shape and has a... Figures 13A to 13D The illustrated embodiment has an internal volume approximately 10 times larger (e.g., Figures 13A to 13D The reservoir contains approximately 1 mL, while Figure 13E and Figure 13F The reservoir in the container holds a maximum of approximately 10 mL. Other implementation schemes are also possible.

[0106] Those skilled in the art will recognize, or can determine, many equivalent forms of the specific procedures described herein using only conventional experiments. Such equivalent forms are considered to be within the scope of this art and are covered by the following claims. All references, published patents, and published patent applications cited throughout this application are hereby incorporated by reference.

Claims

1. A method for producing a liquid sample preparation apparatus, the method comprising: Based on the desired liquid manipulator interface design, a modular reservoir portion is selected, the modular reservoir portion having a first end and a second end, the first end having a liquid manipulator interface portion, and the second end being opposite to the first end; A modular body portion is selected based on the desired characteristics of the sample preparation container, wherein the modular body portion comprises resin; Based on the desired exit droplet shape, a modular tip portion or a minimized inner surface area is selected, the tip portion having an inlet and an outlet, the outlet being located at the end opposite the inlet; as well as The second end of the modular storage portion is fluidly connected to the first end of the modular body portion, and the second end of the modular body portion is fluidly connected to the inlet of the modular tip portion to form a fluid path.

2. A liquid sample processing apparatus, the liquid sample processing apparatus being formed of three or more modular segments, the liquid sample processing apparatus comprising: A modular body portion having a first end and a second end, the first end having a first connection interface and the second end having a second connection interface, wherein the modular body portion comprises resin; A modular storage unit, which is fluidly connected to the first end of the modular body unit; and A modular tip portion, which is fluidly connected to the second end of the body portion, wherein the modular reservoir portion and the modular tip portion are removable from the modular body portion.

3. The liquid sample processing apparatus according to claim 2, wherein, The modular tip portion is removed, resulting in a device with two modular segments.

4. The liquid sample processing apparatus according to claim 2, wherein, The modular tip portion is removed and replaced with a different modular tip portion, or it is cleaned and reattached to the second end of the body portion to create an impermeable fluid connection.

5. The liquid sample processing apparatus according to claim 2, wherein, The size of the inlet to the modular storage section is set to allow for handover to a manual liquid handling device.

6. The liquid sample processing apparatus according to claim 2, wherein, The size of the inlet to the modular storage section is set to connect with the automated liquid handling unit.

7. The liquid sample processing apparatus according to claim 2, wherein, The size of the inlet to the modular storage section is set to connect with the vacuum manifold type liquid handling device.

8. The liquid sample processing apparatus according to claim 2, wherein, The size of the inlet to the modular storage section is set to connect with the positive pressure liquid handling unit.

9. The liquid sample processing apparatus according to claim 2, wherein, The modular storage portion includes a recess or lip sized to receive a clip, clasp, or fixture for securing the modular body portion to an outlet of the modular storage portion.

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