Patent Application
20240058813
The present invention generally relates to the delivery of fluids to flow-through compartments, and particularly to the providing of pressure equalization between the inlet and outlet sides of the compartments. A device implementing such delivery and pressure equalization may be utilized, for example, for performing chemical reactions in the compartments.
Devices such as automated chemistry instruments often require that volumes of liquid, typically ranging from several microliters to several milliliters, be reliably and reproducibly delivered to one or more chemical reaction compartments. One way to address this requirement is to utilize syringes or pumps that rely on positive displacement to meter the volumes of liquid. Positive displacement-based metering can be highly accurate and reproducible. However, as the number of different liquids increases, and in applications involving multiplexed delivery to more than one reaction compartment, multiple metering pumps and/or complex plumbing is needed. Another way is to rely on a pressure-time-volume relationship. For example, a bottle containing a liquid to be delivered may be provided, along with a delivery tube (dip tube) having an inlet end that extends below the surface of the liquid in the bottle and an on/off valve positioned to control fluid flow through the delivery tube. To establish a flow of liquid from the bottle into and through the delivery tube, the headspace in the bottle is pressurized with a gas that is regulated to a constant pressure, and the valve is then opened. In this technique, the volume of liquid that is delivered out from the outlet end of the delivery tube is a function of the size (length, internal diameter) of the delivery tube, the pressure drop across the length of the delivery tube (between the inlet and outlet ends), and the time during which the valve is left open.
In many automated chemistry instruments, the chemistry is performed on a solid phase material contained in a chemical reaction compartment. The solid phase material may be provided as a packed bed of beads composed of, for example, porous silica, controlled pore glass (CPG), or polymer resin. For instruments that have a limited number of reaction compartments, metering pumps may be able to effectively control the delivery of liquid into the bed of solid phase material, or individually calibrated valves may be able to do so via the pressure-time-volume relationship. However, for multiplexed deliveries to multiple reaction compartments, it can be very difficult to deliver the liquid to the solid phase material in the reaction compartments in a controlled and reproducible manner. One known method is to deliver the liquid into the reaction compartment, typically above the solid phase bed, and then rely on a fluid pressure differential to move the liquid into and through the solid phase bed. This step can be very difficult to control, and often results in an under-delivery in which insufficient liquid is delivered to the solid phase material causing the reaction compartment to overflow when multiple deliveries are made, or an over-delivery in which the liquid passes through the solid phase bed too easily and leaves the solid phase bed insufficiently wetted with the liquid.
Therefore, there is an ongoing need for further developments in devices, systems, and methods for delivering fluids to flow-through compartments such as those utilized for performing chemical reactions.
To address the foregoing needs, in whole or in part, and/or other needs that may have been observed by persons skilled in the art, the present disclosure provides methods, processes, systems, apparatus, instruments, and/or devices, as described by way of example in implementations set forth below.
According to an aspect of the present disclosure, a fluid delivery device is configured to create a pressure differential across a compartment in which a liquid resides. The pressure differential causes the liquid to flow through the compartment. The pressure differential may be actively created, and maintained for a period of time, by applying positive pressure on an inlet side of the compartment and/or negative pressure (i.e., vacuum) on an outlet side of the compartment. Once the activity maintaining the pressure differential is stopped, the fluid delivery device is configured to rapidly eliminate the pressure differential, i.e. equilibrate the pressure across the compartment, with the use of a pressure equilibration channel that is separate from the compartment. The compartment may contain a packed bed of solid phase elements such as beads. In such case, the pressure differential causes the liquid to flow through the packed bed. The liquid may include chemical reagents or precursors that participate in chemical reactions on or at the solid phase particles, one example being chemical synthesis. A more specific example is the synthesis of bio-chemicals such as polynucleotides.
According to another aspect of the present disclosure, a fluid delivery device includes: a plate comprising a plate opening; a top wall, wherein the top wall and the plate cooperatively enclose a top chamber; a bottom wall, wherein the bottom wall and the plate cooperatively enclose a bottom chamber; a drain port communicating with the bottom chamber; and a pressure equilibration channel comprising a top channel opening communicating with the top chamber and a bottom channel opening communicating with the bottom chamber, wherein: the plate is configured to hold a compartment in the plate opening, such that a compartment inlet of the compartment communicates with the top chamber and a compartment outlet of the compartment communicates with the bottom chamber; and the fluid delivery device defines: a liquid flow path running through the solid phase material and out from the compartment outlet, through the bottom chamber, and into the drain port; and a gas flow path running between the top chamber and the bottom chamber via the pressure equilibration channel.
According to another aspect of the present disclosure, a fluid delivery device includes: a plate comprising a top plate surface, an opposing bottom plate surface, and a plate opening extending from the top plate surface to the bottom plate surface; a top wall, wherein the top wall and the top plate surface cooperatively enclose a top chamber; a bottom wall, wherein the bottom wall and the bottom plate surface cooperatively enclose a bottom chamber; a compartment positioned in the plate opening, the compartment comprising a compartment inlet communicating with the top chamber, a compartment outlet communicating with the bottom chamber, and a solid phase material positioned between the compartment inlet and the compartment outlet; a drain port communicating with the bottom chamber; and a pressure equilibration channel comprising a top channel opening communicating with the top chamber and a bottom channel opening communicating with the bottom chamber, wherein the fluid delivery device defines: a liquid flow path running through the solid phase material and out from the compartment outlet, through the bottom chamber, and into the drain port; and a gas flow path running between the top chamber and the bottom chamber via the pressure equilibration channel.
According to another aspect of the present disclosure, a fluid delivery system includes: a fluid delivery device according to any of the aspects or embodiments disclosed herein; and a pressure regulating device communicating with at least one of the top chamber or the bottom chamber, and configured to create a pressure differential between the top chamber and the bottom chamber.
According to another aspect of the present disclosure, a method for delivering fluids includes: providing a fluid delivery device according to any of the aspects or embodiments disclosed herein; dispensing a liquid into the compartment; operating a pressure regulating device to create a pressure differential between the top chamber and the bottom chamber; continuing to operate the pressure regulating device for a pulse period effective for flowing the liquid along the liquid flow path such that the liquid wets the solid phase material; after the pulse period, ceasing to operate the pressure regulating device; and after the ceasing, eliminating the pressure differential by allowing a gas to flow through the pressure equilibration channel, wherein the liquid ceases to flow through the solid phase material.
According to another embodiment, a non-transitory computer-readable medium includes instructions stored thereon, that when executed on a processor, control or perform one or more of the steps of any of the methods disclosed herein.
According to another embodiment, a fluid delivery system includes the non-transitory computer-readable storage medium.
Other devices, apparatus, systems, methods, features and advantages of the invention will be or will become apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be included within this description, be within the scope of the invention, and be protected by the accompanying claims.
The invention can be better understood by referring to the following figures. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. In the figures, like reference numerals designate corresponding parts throughout the different views.
The illustrations in all of the drawing figures are considered to be schematic, unless specifically indicated otherwise.
In this disclosure, all “aspects,” “examples,” and “embodiments” described are considered to be non-limiting and non-exclusive. Accordingly, the fact that a specific “aspect,” “example,” or “embodiment” is explicitly described herein does not exclude other “aspects,” “examples,” and “embodiments” from the scope of the present disclosure even if not explicitly described. In this disclosure, the terms “aspect,” “example,” and “embodiment” are used interchangeably, i.e., are considered to have interchangeable meanings.
In this disclosure, the term “substantially,” “approximately,” or “about,” when modifying a specified numerical value, may be taken to encompass a range of values that include +/−10% of such numerical value.
In this disclosure, the term “fluid” refers to a liquid or a gas, or both a liquid and a gas, as dictated by the context in which the term is used.
In this disclosure, the term “liquid” encompasses a single liquid-phase composition or a mixture or blend of two or more liquid-phase compositions. Examples of a liquid include, but are not limited to, a solution, a suspension, a colloid, or an emulsion. A liquid may contain or carry solid particles (e.g., inorganic particulates, whole biological cells or lysed cell components, etc.) and/or gas or vapor bubbles.
In this disclosure, the term (fluid) “conduit” or (fluid) “line” generally refers to any type of structure enclosing an interior space that defines a repeatable path for fluid to flow from one point (e.g., an inlet of the conduit) to another point (e.g., an outlet of the conduit). A conduit generally includes one or more walls defining a pipe, tube, capillary, channel, or the like. The inner bore or lumen of a conduit may have any shape such as, for example, circular, elliptical, or polygonal. A conduit may be formed by any known technique. A conduit may be formed from a variety of materials such as, for example, fused silica, glasses, ceramics, polymers, and metals. In some embodiments, the material forming the conduit is optically transparent for a purpose such as performing an optics-based measurement or sample analysis, detecting or identifying a substance flowing through the conduit, enabling a user to observe flows and/or internal components in the conduit, etc. Alternatively, the conduit may include an optically transparent window for such purposes.
In this disclosure, the term “(bio)chemical compound” encompasses (non-biological) chemical compounds and biological compounds. Likewise, the term “(bio)chemical reaction” encompasses (non-biological) chemical reactions and biological reactions.
A chemical compound may be, for example, a small molecule or a high molecular-weight molecule (e.g., a polymer, carbohydrate, etc.).
A biological compound may be, for example, a biopolymer. Examples include, but are not limited to, nucleic acids (or polynucleotides). The term “nucleic acid” may refer to a biopolymer of any length, e.g., greater than about 2 bases, greater than about 10 bases, greater than about 100 bases, greater than about 500 bases, greater than 1000 bases, up to about 10,000 or more bases composed of nucleotides, e.g., deoxyribonucleotides or ribonucleotides, which may be produced enzymatically or synthetically, and which can hybridize with naturally occurring nucleic acids in a sequence specific manner analogous to that of two naturally occurring nucleic acids, e.g., can participate in Watson-Crick base pairing interactions. In addition to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), the term “nucleic acid” (or “polynucleotide”) may encompass peptide nucleic acid (PNA), locked nucleic acid (LNA), and unstructured nucleic acid (UNA). Additional examples include oligonucleotides (or “oligos”). The term “oligonucleotide” may refer to a biopolymer of nucleotides that may be, for example, 10 to 300 or greater nucleotides in length. Oligonucleotides may be synthetic or may be made enzymatically. Oligonucleotides may contain ribonucleotide monomers (i.e., may be oligoribonucleotides) and/or deoxyribonucleotide monomers (i.e., may be oligodeoxyribonucleotides). Oligonucleotides may include modified nucleobases.
In use, the fluid pressure in the top chamber 14 and the bottom chamber 18 is initially the same (e.g., around or greater than atmospheric pressure) because the pressure has been equilibrated through the dry reaction compartment(s) 26. Liquid-phase biochemical reagents, or “coupling” reagents (e.g., oligonucleotide precursors), are dispensed into the reaction compartment(s) 26. The solid phase material serves as a substrate on which oligonucleotides can be formed. The coupling reagents are formulated to react with each other in a manner that results in strands of oligonucleotides growing from the solid phase material. For this purpose, the coupling reagents need to flow into the solid phase material and wet the surfaces of the solid phase material sufficiently for the synthesis of the oligonucleotides to occur with an efficient yield. To initiate and drive the liquid flow into the solid phase material, a pressure differential is applied between the top chamber 14 and the bottom chamber 18, and thus between the compartment inlet(s) 30 and the compartment outlet(s) 34. The pressure differential is created by either increasing the pressure in the top chamber 14 or decreasing the pressure in the bottom chamber 18 to thereby cause the liquid to flow through the reaction compartment(s) 26. The pressure in the top chamber 14 may be increased by opening a valve (not shown) and flowing a gas into the top chamber 14. Alternatively, the pressure in the bottom chamber 18 may be decreased by opening the drain valve 42 shown in
The coupling reagents can be quite expensive. Hence, it is desirable to utilize only as much of the coupling reagents as is required to obtain an acceptable yield of oligonucleotides, and to prevent the over-deliveries and under-deliveries noted above in the Background section. These considerations create the need for very precise control over the flow of the coupling reagents through the reaction compartment 26, and the need to continuously or iteratively (by multiple delivery and draining steps) flow fresh coupling reagents into the solid phase material for varying lengths of time. The conventional configuration illustrated in
Thus, after the pressure differential has been created (whether by increasing the pressure in the top chamber 14 or decreasing the pressure in the bottom chamber 18) to start the drain of liquid through the reaction compartment(s) 26, the pressure differential persists after the valve (e.g., the drain valve 42) is closed and after the liquid starts to flow. In other words, the pressure differential required to initiate the liquid flow will not be equilibrated by the volume of liquid moving onto the solid phase bed(s). This situation leaves a reservoir of excess pressure that will likely cause the reaction compartment(s) 26 to completely drain themselves to relieve the pressure differential. Once the reaction compartment(s) 26 are dry enough that gas can pass through them, only then can the pressures in the top chamber 14 and bottom chamber 18 be equilibrated. If a suitable pressure differential were to be applied that actually would be equilibrated by the volume of liquid moving onto the solid phase bed(s) and no further, it would not be enough pressure to reliably initiate the flow of the liquid.
The top wall 204, the bottom wall 208 (and optionally the plate 212) may be attached together by any means. In an embodiment, the manner of attachment is sufficient to render the top chamber 228 and the bottom chamber 232 substantially fluid leak-free. In the present context, “substantially” fluid leak-free means that the top chamber 228 and the bottom chamber 232 are capable of maintaining a pressure differential at least for a period of time required by the methods described herein. The fluid tightness may be enhanced by providing appropriate sealing elements at the interfaces of the top wall 204, the bottom wall 208 (and optionally the plate 212), such as elastomeric gaskets, as appreciated by persons skilled in the art. Generally, no limitation is placed on the material composition of the top wall 204, the bottom wall 208, and the plate 212. Various metals or plastics may be utilized, depending on cost and ease of manufacture.
In the context of the present disclosure, the terms “top” and “bottom” (or “upper” and “lower”) are relative to each other and relative to a horizontal plane and a vertical direction. The horizontal plane corresponds to (or is parallel with) any surface on which the fluid delivery device 200 rests or is supported (e.g., tabletop, benchtop, desktop, floor, ground, etc.). The vertical direction is orthogonal to the horizontal plane. The dimension of a structure along the vertical direction may be referred to as the elevation, height, or thickness of that structure. The “top” (or “upper”) part of a structure is located at a higher elevation than the “bottom” part of that structure relative to the vertical direction, and the “bottom” (or “lower”) part is located at a lower elevation than the “top” part relative to the vertical direction. Similarly, for a given structure and related or counterpart structure, the “top” structure is located at a higher elevation than the “bottom” structure relative to the vertical direction, and the “bottom” structure is located at a lower elevation than the “top” structure relative to the vertical direction.
The fluid delivery device 200 further includes a compartment (or column) 236 positioned in the plate opening 224. The compartment 236 includes a compartment inlet 240 communicating with the top chamber 228, a compartment outlet 244 communicating with the bottom chamber 232, and a body having a height (or length) oriented in the vertical direction between the compartment inlet 240 and the compartment outlet 244. As such, the compartment 236 has a fluid flow-through configuration in which, in normal use, a liquid is dispensed through the compartment inlet 240 and thereafter may flow through the compartment 236 and exit the compartment outlet 244. Moreover, a gas may flow through the compartment 236 (if not blocked by a liquid) in either direction (up or down) depending on the pressure differential across the length of the compartment (i.e., between the top chamber 228 and the bottom chamber 232, and thus between the compartment inlet 240 and the compartment outlet 244). In other examples, more than one compartment 236 may be provided, as described below.
Generally, the compartment 236 may be configured as any type of fluid conduit, depending on its application. In some embodiments, the compartment 236 is configured to implement one or more chemical reactions, i.e., the compartment 236 is a chemical reaction compartment. In such cases, the liquid dispensed into the compartment 236 may be a combination of two or more chemical reagents or precursors that are dispensed simultaneously or separately. As one non-exclusive example, the compartment 236 may be utilized to synthesize polynucleotides such as oligonucleotides as described above. In this case, the liquid dispensed into the compartment 236 may be a mixture of two or more coupling reagents having compositions appropriate for the synthesis being implemented. Examples of coupling reagents include, but are not limited to, various phosphoramidites and tetrazole-based activators. To enable or promote the synthesis, the compartment 236 may include a solid phase material that serves as a substrate (or support) for the synthesis of the polynucleotides, as appreciated by persons skilled in the art. Examples of the composition of the solid phase material include, but are not limited to, silica, glass, and various polymer resins (e.g., polystyrene). The solid phase material may be provided as a plurality of solid phase support elements (particles, grains, beads, pellets, etc.) packed together as a solid phase bed. As noted above in the Background section, the solid phase support elements may be beads such as, for example, porous silica, controlled pore glass, or polymer resin. Accordingly, the fluid flow path through the solid phase bed consists of a large number of flow path sections running through the interstices between adjacent solid phase support elements, which maximizes the total surface area available for contact with the dispensed liquid reagents. The shape of the beads is typically spherical, but alternatively may be spheroidal, ellipsoidal or polygonal, or one of the foregoing shapes but somewhat irregular (i.e., not perfect shapes), or highly irregular (e.g., formed by crushing). The characteristic dimension of the beads may be, for example, in a range from 10 μm to 1000 μm, or 50 μm to 100 μm. In the present context, the “characteristic” dimension is an indication of size appropriate for a given or approximate shape, for example, diameter in the case of a sphere, major axis in the case of an ellipsoid, length in the case of a polygon, etc. The pore sizes of the beads may be, for example, in a range from 10 nm to 500 nm, or from 10 nm to 300 nm, or from 10 nm to 200 nm. More generally, the pore size should be pore size should be large enough for the growing polymer chains to be synthesized and small enough to provide enough surface area to synthesize sufficient product. Generally, no limitation is placed on the degree of polydispersity of either the characteristic dimension or the pore sized of the beads.
As an alternative to a packing of solid phase support elements, the solid phase support may be a porous “monolithic support,” which typically has a polymeric or silica based composition, as appreciated by persons skilled in the art. The size of the pores (or interstices) of the monolithic support generally may be in the range specified above regarding bead pores. As a further alternative, the solid phase support may be an “embedded” support, in which porous particles (e.g., controlled pore glass particles) are embedded into a rigid polymer network (e.g., polyethylene or polyethylene based) to form a frit positioned in the compartment 236.
Depending on the application, the outer surfaces of the beads may be functionalized, modified, treated, or coated for a specific purpose. Depending on the application, the chemical reaction performed in the compartment 236 is not limited to the synthesis of biomolecules but may instead involve the synthesis of non-biological polymers or small molecules. Moreover, the chemical reaction performed is not limited to synthesis but instead may involve other types of reactions with (bio)chemical compounds (e.g., de-protecting, cleaving, hybridizing, denaturing, dissociating, conjugating, chelating, complexing, forming of chemical adducts, ionizing, deprotonating, charge exchanging, buffering, pH adjusting, diluting, solvating, emulsifying, labeling, etc.). Furthermore, the solid phase material may be configured for a function other than (bio)chemical reaction. As one non-exclusive example, the solid phase material may be configured as an appropriate sorbent so that the compartment 236 may be utilized to retain synthesized materials, such as for purification.
The fluid delivery device 200 further includes a drain port 248 communicating with the bottom chamber 232. The drain port 248 is typically, but not necessarily, located at a bottom section or surface of the bottom wall 208 to facilitate the collection of excess liquid exiting the compartment outlet 244. For this purpose, the drain port 248 may be placed in fluid communication with a drain line (not shown) that leads to any suitable destination (not shown) for the liquid exiting the bottom chamber 232 via the drain port 248, such as fluid receptacle (container). In some examples, at least a portion of the bottom section or surface of the bottom wall 208 is inclined downwardly toward the drain ports 248 (not specifically shown), which may enhance the draining and collection of liquids exiting the compartments 236. The drain port 248 may also be utilized for fluid pressure regulation in the interior of the fluid delivery device 200 (i.e., in the top chamber 228 and bottom chamber 232). In this case, the fluid delivery device 200 may include a drain valve 252 communicating with the drain port 248. As part of pressurizing the interior of the fluid delivery device 200 in a controlled manner, the drain valve 252 is closed (switched into a closed state). To subsequently create a pressure differential between the top chamber 228 and the bottom chamber 232, the drain valve 252 is opened (switched into an open state), thereby releasing (reducing) the pressure in the bottom chamber 232 relative to the top chamber 228 due to the exiting liquid and gas. Optionally, a vacuum (negative pressure) may be applied at the drain port 248 or another port communicating with the bottom chamber 232. The drain valve 252 may be configured for flow on/off control (i.e., the drain valve 252 is switchable into either the open or closed state, and not into a partially open/closed state). Alternatively, the drain valve 252 may be configured for both on/off flow control and variable flow rate control (i.e., adjustable to intermediate states between the fully open and fully closed states). Variable flow rate control may be useful for adjusting the pressure differential applied.
In one example, a vacuum pump (not shown) also may be positioned in the drain line to enhance the application and control of the pressure differential.
The fluid delivery device 200 further includes one or more pressure equilibration channels 256. The pressure equilibration channel 256 is a flow restricted channel that fluidly connects the top chamber 228 and the bottom chamber 232. Accordingly, the pressure equilibration channel 256 includes a top channel opening 260 communicating with the top chamber 228, a bottom channel opening 264 communicating with the bottom chamber 232, and body defining a lumen (inside bore) of a predetermined size (length and inside diameter) extending between the top channel opening 260 and the bottom channel opening 264. The pressure equilibration channel 256 may be positioned at the plate 212 and at some distance from the compartment 236. The pressure equilibration channel 256 may include a bore extending through a section of the plate 212, or a tube extending from and/or through a bore or opening of the plate 212, or a tube extending from the top wall 204 to the bottom wall 208 but positioned outside of the plate 212. Accordingly, the lumen may be defined by a bore, a tube, or a combination of both.
The pressure equilibration channel 256 is a passive device that has no moving parts and does not require any type of active control. The lumen of the pressure equilibration channel 256 is typically open, or unobstructed, in the sense that no additional components or features need to be provided in the lumen (for example, in comparison to the compartment 236 that may include a solid phase material as described above). The pressure equilibration channel 256 is flow restricted in the sense that it provides limited gas conductance in comparison to the drain port 248. That is, the pressure equilibration channel 256 is sized to provide a greater flow restriction (or flow resistance) to gas flow than the drain port 248. As one non-exclusive example, the inside diameter of the pressure equilibration channel 256 may be in a range from 1/32 inch (about 0.8 mm) to ⅛ inch (about 3.2 mm), while the inside diameter of the drain port 248 may be in a range from ¼ inch (6.35 mm) to ½ inch (12.7 mm). The flow restriction of the pressure equilibration channel 256 may be increased by decreasing its inside diameter and/or increasing its length.
The pressure equilibration channel 256 provides a pathway for gas conductance between the top chamber 228 and the bottom chamber 232. Gas will flow through the pressure equilibration channel 256 in the presence of a pressure differential between the top chamber 228 and the bottom chamber 232, and thus between the top channel opening 260 and the bottom channel opening 264 (across the length of the pressure equilibration channel 256). Typically, a pressure differential is applied such that the pressure in the top chamber 228 is higher than the pressure in the bottom chamber 232, in which case gas will flow downward through the pressure equilibration channel 256 from the top chamber 228 to the bottom chamber 232. Even after such pressure differential is no longer actively applied, the gas will continue to flow downward through the pressure equilibration channel 256 until the pressures in the top chamber 228 and the bottom chamber 232 are equilibrated (equalized).
The pressure equilibration channel 256 is advantageous in that it may allow a greater pressure differential to be applied, and enable the pressures to subsequently be equilibrated more rapidly (enable the pressure differential to be eliminated), than the conventional situation in which the pressure equilibration channel 256 is not provided. The flow restriction presented by the pressure equilibration channel 256 is set such that the fluid flow (e.g., volumetric flow rate) through the drain port 248 (and open drain valve 252) is greater than the fluid flow through the pressure equilibration channel 256. This configuration allows for the desired higher pressure differential between the top chamber 228 and the bottom chamber 232 that is needed to reliably initiate the liquid flow through the compartment 236 (and the solid phase material therein). When the drain valve 252 is thereafter closed (or the pressure differential is otherwise no longer actively applied), the pressures in the top chamber 228 and the bottom chamber 232 rapidly equilibrate via the pressure equilibration channel 256, and consequently the liquid flow through the compartment 236 stops. Hence, unlike a conventional fluid delivery device such as described above in conjunction with
Moreover, a larger pressure differential may be applied without draining the compartment 26 completely, which is particularly useful when draining multiple compartments 236. Due to the variability among multiple compartments 236, some compartments 236 may require a larger pressure differential to initiate the liquid flow. By applying a short-lived and large pressure differential, liquid may be delivered to multiple compartments 236 more reliably.
Another advantage of the pressure equilibration channel 256 is that it may dramatically decrease the effect of gas pressure leaks in the bottom chamber 232. Such leaks may occur in the bottom chamber 232 itself or in any valves (e.g., the drain valve 252) communicating with the bottom chamber 232. Without the pressure equilibration channel 256, such leaks will result in a pressure differential that can be relieved only by equilibration through the compartment 236, which in turn will result in either an unintentional delivery or an over-delivery of any liquid present in the column. On the other hand, the pressure equilibration channel 256 compensates for any such leaks by equilibration through the pressure equilibration channel 256, thereby preventing the development of a pressure differential due to the leaks and thus preventing an unintentional delivery or over-delivery of liquid. Moreover, the pressure equilibration channel 256 reduces the risk of backflow through the compartment 236 in the event of an upward directed pressure differential, such as if the top chamber 228 is opened while the bottom chamber 232 is (still) pressurized. Furthermore, because the pressure equilibration channel 256 is a passive device, it does not require any electronics or control system for its operation. Hence, the pressure equilibration channel 256 does not appreciably contribute to the complexity and cost of the fluid delivery device 200, and avoids any problems or challenges that may occur if components associated with electronics or a control system were to be installed in the same enclosed space where liquid reagents are added and chemical reactions are carried out.
As evident from the foregoing, the fluid delivery device 200 defines or establishes at least two fluid flow paths: The first is a liquid flow path that runs through the compartment 236 (and through the solid phase material therein, if provided) and out from the compartment outlet 244, through the interior space of the bottom chamber 232, and into the drain port 248 (and through the drain valve 252 if opened. The second is a gas flow path that runs between the top chamber 228 and the bottom chamber 232 via the pressure equilibration channel 256, typically in the direction from the top chamber 228 to the bottom chamber 232, but more generally in a direction dependent on which chamber is at a higher pressure than the other chamber.
In this example, the plate openings of the plate 212 are sized and positioned (arranged) such that, when the compartments 236 are positioned in the plate openings, the compartments 236 (or at least the compartment inlets 240) are spaced from each other at a desired distance such as one of the pitch values specified above.
As also illustrated, the fluid delivery device 500 may also include multiple pressure equilibration channels 256 (or 456), which have been arbitrarily located in
Accordingly, in the present example, the fluid delivery device 500 defines or establishes multiple liquid flow paths that run from the respective compartments 236, through the bottom chamber 232, and to the drain port 248, and multiple gas flow paths that run through the respective pressure equilibration channels 256. More than one drain port 248 may be provided.
In the present example, the arrangement of compartment groups is realized by the plate openings of the plate 212 likewise being divided into groups of plate openings, with each sub-chamber 610 separately communicating with a respective one of the plate opening groups.
Accordingly, in the present example, the fluid delivery device 600 defines or establishes multiple liquid flow paths that run from the respective compartments 236, through the corresponding sub-chambers 610, and to the corresponding drain ports 248, and multiple gas flow paths that run through the respective pressure equilibration channels 256 between the top chamber 228 and respective sub-chambers 610.
Similar to the fluid delivery device 600 described above and illustrated in
Alternatively or additionally, the pressurized gas source 822 may include a fluid pump 830 communicating with the drain valve 252 and the drain port 248 via a drain line 834 that leads to a liquid collection receptacle 838. Alternatively or additionally, the pressurized gas source 822 may include a gas pump (or vacuum pump) 842 that communicates with a gas outlet port 846, which communicates with the bottom chamber 232 separately from the drain port 248.
The fluid delivery system 800 may be configured for dispensing liquids into the compartments 236 manually and/or automatically (or robotically). For example, a user may open the top chamber 232 (e.g., by removing the top wall 204, see
As one example, the pipettor head 862 is lowered toward a liquid source 870 (e.g., a reservoir) to immerse the pipette tip(s) 866 in the liquid supplied by the liquid source 870. A controlled aliquot or aliquots of the liquid are then aspirated into the pipette tip(s) 866. The pipettor head 862 is then raised, moved to a position above the (opened) top chamber 228, and lowered toward the compartment(s) 236 far enough to avoid splashing or spilling during the dispensing step (e.g., the pipette tip(s) 866 may extend through the compartment inlet(s) 240, see
The fluid delivery system 800 may further include, or electrically or electromagnetically communicate by one or more wired or wireless communication links, an electronics-based system controller 874 (or controller, control unit, control module, computing device, etc.). The system controller 874 may be configured to control the operation of one or more of the active components of the fluid delivery device 200 and/or fluid delivery system 800, such as the drain valve 252, components of the pressure regulating device 818, liquid dispensing system 850 and/or other robots or automated devices, etc., as partially depicted by a few dashed lines in
A non-exclusive example of a method or process for delivering fluids will now be described. The method may be implemented with the use of a fluid delivery device according to any of the embodiments or examples disclosed herein (e.g., the fluid delivery device 200, 500, 600, or 700, illustrated in
Subsequently, at the end of the pulse period, the operation of the pressure regulating device 818 is stopped so as to no longer actively apply the pressure differential, by performing any of the pertinent techniques described herein. The pressure differential is then eliminated or relieved by allowing a gas to flow through the pressure equilibration channel(s) 256. As one example, the duration of time required to fully equilibrate the pressures in the top chamber 228 and the bottom chamber 232 may be in a range from 0.1 s to 1000 s. Consequently, removal of the actively applied pressure differential and subsequent rapid pressure equilibration causes the liquid(s) to stop flowing downward through the solid phase material(s) 368. During the performance of this method, any liquid(s) exiting the compartment(s) 236 are collected at the drain port(s) 248. If the volume of the liquid 380 permits, multiple additions of the liquid 380 may be performed by subjecting the fluid delivery device 200 to another pulse period of the same or a different duration. In this way, the solid phase material 368 can be exposed to fresh reagent without having to deliver more fluid to the compartment 236.
In some examples, the dispensed liquid(s) 380 and the solid phase material(s) 368 are configured to promote (or induce, carry out, perform, conduct, etc.) one or more (bio)chemical reactions on or at the solid phase material(s) 368, as described herein. The duration of time required to complete these types of (bio)chemical reactions is referred to herein as a reaction period. Typically, but not necessarily, these types of (bio)chemical reactions begin to occur as soon as the dispensed liquid(s) 380 begin to wet the solid phase material(s) 368. In this case, the start of the reaction period may coincide (or substantially coincide) with the start of the pulse period. Typically, but not necessarily, the duration of the reaction period is longer than the pulse period. In other words, the (bio)chemical reaction(s) may proceed after removing the actively applied pressure differential and thus after liquid flow through the compartment(s) 236 has ceased. Moreover, the (bio)chemical reaction(s) (i.e., the reaction period) may end either while pressure equilibration is still ongoing or after pressure equilibration has been completed. In all such cases, after the end of the reaction period, the top chamber 228 may be reopened, and the synthesized (bio)chemicals (or products of another type of (bio)chemical reaction) may then be subjected to further chemical reactions in order to continue or complete the synthesis of the (bio)chemical, or be subjected to further processing or analysis as called for by the application being implemented.
Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the following:
1. A fluid delivery device, comprising: a plate comprising a plate opening; a top wall, wherein the top wall and the plate cooperatively enclose a top chamber; a bottom wall, wherein the bottom wall and the plate cooperatively enclose a bottom chamber; a drain port communicating with the bottom chamber; and a pressure equilibration channel comprising a top channel opening communicating with the top chamber and a bottom channel opening communicating with the bottom chamber, wherein: the plate is configured to hold a compartment in the plate opening, such that a compartment inlet of the compartment communicates with the top chamber and a compartment outlet of the compartment communicates with the bottom chamber; and the fluid delivery device defines: a liquid flow path running through the solid phase material and out from the compartment outlet, through the bottom chamber, and into the drain port; and a gas flow path running between the top chamber and the bottom chamber via the pressure equilibration channel.
2. The fluid delivery device of embodiment 1, further comprising the compartment, positioned in the plate opening.
3. The fluid delivery device of embodiment 2, wherein the compartment comprises a solid phase material positioned between the compartment inlet and the compartment outlet.
4. The fluid delivery device of embodiment 3, wherein the compartment comprises a frit, and the solid phase material is retained on or embedded with the frit.
5. The fluid delivery device of embodiment 3 or 4, wherein the solid phase material is selected from the group consisting of: a plurality of solid phase support elements packed together as a solid phase bed; a porous monolithic support; and a porous material embedded in a frit.
6. The fluid delivery device of embodiment 3 or 4, wherein the solid phase material comprises a plurality of solid phase support elements, and the solid phase support elements have a characteristic dimension in a range from 10 μm to 1000 μm.
7. The fluid delivery device of any of embodiments 3-6, wherein the solid phase material has a pore size in a range from 10 nm to 200 nm.
8. The fluid delivery device of any of embodiments 3-7, wherein the solid phase material is composed of a material selected from the group consisting of: controlled pore glass; porous silica; and polymer resin.
9. The fluid delivery device of any of the preceding embodiments, comprising a drain valve communicating with the drain port and configured for on/off flow control, or configured for both on/off flow control and variable flow rate control.
10. The fluid delivery device of any of the preceding embodiments, comprising a gas inlet port communicating with the top chamber.
11. The fluid delivery device of embodiment 10, comprising a pressure regulating device communicating with the gas inlet port.
12. The fluid delivery device of embodiment 10 or 11, comprising a gas inlet valve communicating with the gas inlet port and configured for on/off flow control, or configured for both on/off flow control and variable flow rate control.
13. The fluid delivery device of any of the preceding embodiments, wherein the plate opening is one of a plurality of plate openings, and the plate is configured to hold a plurality of compartments in the respective plate openings, such that respective compartment inlets of the compartments communicate with the top chamber and respective compartment outlets of the compartments communicate with the bottom chamber.
14. The fluid delivery device of embodiment 13, wherein the plate openings are sized and positioned such that, when the compartments are positioned in the plate openings, the compartment inlets are spaced from each other at a distance selected from the group consisting of: a distance in a range from 2 mm to 50 mm; a distance of 9.0 mm; a distance of 4.5 mm; and a distance of 2.25 mm.
15. The fluid delivery device of embodiment 13 or 14, comprising the plurality of compartments, positioned in the respective plate openings.
16. The fluid delivery device of any of embodiments 13-15, wherein: the plurality of plate openings comprises a plurality of plate opening groups, each plate opening group comprising one or more of the plate openings; and the bottom chamber comprises a plurality of sub-chambers, each sub-chamber separately communicating with a respective one of the plate opening groups.
17. The fluid delivery device of embodiment 16, wherein: the pressure equilibration channel is one of a plurality of pressure equilibration channels comprising respective top channel openings communicating with the top chamber and bottom channel openings; and each bottom channel opening separately communicates with a respective one of the sub-chambers.
18. The fluid delivery device of embodiment 16 or 17, wherein the drain port is one of a plurality of drain ports, each drain port separately communicating with a respective one of the sub-chambers.
19. The fluid delivery device of any of the preceding embodiments, wherein the pressure equilibration channel is one of a plurality of pressure equilibration channels comprising respective top channel openings communicating with the top chamber and bottom channel openings communicating with the bottom chamber.
20. A fluid delivery system, comprising: a fluid delivery device according to any of embodiments 1-19; and a pressure regulating device communicating with at least one of the top chamber or the bottom chamber, and configured to create a pressure differential between the top chamber and the bottom chamber.
21. The fluid delivery system of embodiment 20, comprising a gas inlet port communicating with the top chamber, wherein the pressure regulating device communicates with the top chamber via the gas inlet port.
22. The fluid delivery system of embodiment 20 or 21, wherein the pressure regulating device comprises a pressurized gas source.
23. The fluid delivery system of embodiment 22, wherein the pressurized gas source comprises a pressurized gas reservoir and a gas inlet valve.
24. The fluid delivery system of embodiment 22, wherein the pressurized gas source comprises a pump.
25. The fluid delivery system of any of embodiments 20-24, wherein the pressure regulating device comprises a pump communicating with the bottom chamber.
26. The fluid delivery system of any of embodiments 20-25, comprising a liquid dispensing device configured to dispense a liquid into the compartment.
27. The fluid delivery system of any of embodiments 20-26, comprising a controller configured to control the steps of: operating the pressure regulating device to create the pressure differential; continuing to operate the pressure regulating device for a pulse period effective for flowing a liquid along the liquid flow path such that the liquid wets the solid phase material; and after the pulse period, ceasing to operate the pressure regulating device.
28. A method for delivering fluids, the method comprising: providing a fluid delivery device according to any of the aspects or embodiments disclosed herein; dispensing a liquid into the compartment; operating a pressure regulating device to create a pressure differential between the top chamber and the bottom chamber; continuing to operate the pressure regulating device for a pulse period effective for flowing the liquid along the liquid flow path such that the liquid wets the solid phase material; after the pulse period, ceasing to operate the pressure regulating device; and after the ceasing, eliminating the pressure differential by allowing a gas to flow through the pressure equilibration channel, wherein the liquid ceases to flow through the solid phase material.
29. The method of embodiment 28, wherein the operating of the pressure regulating device comprises applying a positive pressure pulse to the top chamber.
30. The method of embodiment 28 or 29, wherein the operating of the pressure regulating device comprises opening a gas inlet valve to flow a pressurized gas from a pressurized gas reservoir, through the gas inlet valve, and into the top chamber.
31. The method of any of embodiments 28-30, wherein the operating of the pressure regulating device comprises operating a pump to pump pressurized gas into the top chamber.
32. The method of embodiment 28, wherein the operating of the pressure regulating device comprises applying a negative pressure pulse to the bottom chamber.
33. The method of any of embodiments 32, wherein the operating of the pressure regulating device comprises operating a pump communicating with the bottom chamber.
34. The method of any of embodiments 28-33, wherein the pressure differential is in a range from 0.1 psi to 50 psi.
35. The method of any of embodiments 28-34, wherein the liquid comprises a plurality of (bio)chemical reagents, and the flowing of the liquid promotes a (bio)chemical reaction involving the (bio)chemical reagents on the solid phase material.
36. The method of embodiment 35, wherein the (bio)chemical reaction comprises a (bio)chemical synthesis.
37. The method of embodiment 35, wherein the (bio)chemical synthesis produces nucleotides.
38. The method of any of embodiments 35-37, wherein the (bio)chemical reaction occurs during a reaction period, and the reaction period is longer than the pulse period.
39. A non-transitory computer-readable medium, comprising instructions stored thereon, that when executed on a processor, control or perform one or more of the steps of any of embodiments 28-38.
40. A fluid delivery system, comprising the non-transitory computer-readable medium of embodiment 39.
It will be understood that one or more of the processes, sub-processes, and process steps described herein may be performed by hardware, firmware, software, or a combination of two or more of the foregoing, on one or more electronic or digitally-controlled devices. The software may reside in a software memory (not shown) in a suitable electronic processing component or system such as, for example, the controller 874 schematically depicted in
The executable instructions may be implemented as a computer program product having instructions stored therein which, when executed by a processing module of an electronic system (e.g., the controller 874 schematically depicted in
It will also be understood that the term “in signal communication” or “in electrical communication” as used herein means that two or more systems, devices, components, modules, or sub-modules are capable of communicating with each other via signals that travel over some type of signal path. The signals may be communication, power, data, or energy signals, which may communicate information, power, or energy from a first system, device, component, module, or sub-module to a second system, device, component, module, or sub-module along a signal path between the first and second system, device, component, module, or sub-module. The signal paths may include physical, electrical, magnetic, electromagnetic, electrochemical, optical, wired, or wireless connections. The signal paths may also include additional systems, devices, components, modules, or sub-modules between the first and second system, device, component, module, or sub-module.
More generally, terms such as “communicate” and “in . . . communication with” (for example, a first component “communicates with” or “is in communication with” a second component) are used herein to indicate a structural, functional, mechanical, electrical, signal, optical, magnetic, electromagnetic, ionic or fluidic relationship between two or more components or elements. As such, the fact that one component is said to communicate with a second component is not intended to exclude the possibility that additional components may be present between, and/or operatively associated or engaged with, the first and second components.
It will be understood that various aspects or details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation—the invention being defined by the claims.
