Patent Grant
10761104
The present invention generally relates to transferring liquids from one location to one or more other locations, such as from one surface to another surface or chamber. The liquids, or materials carried by the liquids, may be processed at the location(s) to which they are transferred.
Many methods involving the processing of liquids or materials carried by liquids benefit from the use of liquid handling systems configured to enable high-throughput processing and utilize a high degree of automation. Such processing may involve the measurement or assaying of a large number of chemical or biological samples in parallel, or the synthesis of chemical or biological products from a large number of precursor materials. Liquid handling systems have been developed that utilize a motorized pipettor capable of dispensing liquids into and aspirating liquids from the individual wells of multi-well plates loaded onto such systems. Such systems may also utilize a robot to load and unload multi-well plates.
There is an ongoing need, however, to develop systems and methods capable of transferring small quantities of liquids, including liquids carrying materials of interest, from one location to another. There is also an ongoing need to develop systems and methods capable of transferring liquids to and from liquid-supporting devices of different formats, such as flat slides and multi-well plates. There is also an ongoing need to develop systems and methods capable of providing a source of a large number of different liquids or materials, enabling specific liquids or materials to be selected from that source, and thereafter transferring the selected liquids or materials to specific destination sites situated remotely from the source. For certain applications entailing synthesis, it would be desirable to provide a large array of precursor materials at a source location, and then transfer selected precursor materials to a different location for further processing instead of carrying out the synthesis at the same (source) location.
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 one embodiment, a liquid transfer system includes: a source station configured for supporting a source array, the source array comprising a surface and a plurality of materials arranged on the surface according to a predetermined organization of clusters, wherein each cluster comprises one or more features, each feature comprises one or more of the plurality of materials, and each cluster is spaced from adjacent clusters by an area unoccupied by materials or occupied by inert materials; a destination station configured for supporting a destination site positioned remotely from the source station; a transfer device comprising a transfer element configured for supporting liquid; and a controller configured for: loading liquid to the transfer element; moving the transfer device to a selected cluster of the source array; operating the transfer device to simultaneously transfer the materials located at the features of the selected cluster from the surface to the transfer element, wherein the materials are carried in the liquid supported by the transfer element; moving the transfer device to the destination site; and transferring the materials from the transfer element to the destination site.
According to another embodiment, a method for transferring liquids includes: providing a source array comprising a surface and a plurality of materials arranged on the surface according to a predetermined organization of clusters, wherein each cluster comprises one or more features, each feature comprises one or more of the plurality of materials, and each cluster is spaced from adjacent clusters by an area unoccupied by materials or occupied by inert materials; loading liquid to the transfer element; selecting a cluster of the source array; moving a transfer device to the selected cluster, the transfer device comprising a transfer element configured for supporting liquid; operating the transfer device to simultaneously transfer the materials located at the features of the selected cluster from the surface to the transfer element, wherein the materials are carried in the liquid supported by the transfer element; moving the transfer device to a destination site positioned remotely from the source array; and transferring the materials from the transfer element to the destination site.
According to another embodiment, a method for processing (bio)chemical compounds includes: providing a plurality of (bio)chemical compounds, wherein one or more of the (bio)chemical compounds are different in composition from the other (bio)chemical compounds; creating a source array comprising a plurality of features by positioning a plurality of (bio)chemical compounds on a first support structure, wherein one or more of the (bio)chemical compounds are different in composition from the other (bio)chemical compounds, and the plurality of (bio)chemical compounds is positioned such that: each feature comprises one or more of the (bio)chemical compounds; and the plurality of features is arranged on the first support structure according to a predetermined organization of positions; selecting one or more features; and transferring the (bio)chemical compounds of the one or more selected features to a second support structure, by: moving a transfer element to the one or more selected features; transferring the (bio)chemical compounds of the one or more selected features to the transfer element; moving the transfer element to the second support structure; and transferring the (bio)chemical compounds from the transfer element to the second support structure.
According to another embodiment, a method for processing (bio)chemical compounds includes: providing a plurality of (bio)chemical compounds, the plurality of (bio)chemical compounds comprising different compositional species; creating a source array comprising a plurality of features by positioning a plurality of (bio)chemical compounds on a first support structure, wherein one or more of the (bio)chemical compounds are different in composition from the other (bio)chemical compounds, and the plurality of (bio)chemical compounds is positioned such that: each feature comprises one or more of the (bio)chemical compounds; and the plurality of features is arranged on the first support structure according to a predetermined organization of known positions; selecting one or more features for use in synthesizing one or more (bio)chemical products; contacting the one or more selected features with one or more reagents, under conditions effective for synthesizing the one or more (bio)chemical products from interaction between the (bio)chemical compounds and the one or more regents, wherein the one or more (bio)chemical products are synthesized at one or more respective positions on the first support structure; and transferring the one or more synthesized (bio)chemical products to a second support structure by: moving a transfer element to the one or more positions on the first support structure at which the one or more synthesized (bio)chemical products are located; transferring the one or more synthesized (bio)chemical products to the transfer element; moving the transfer element to the second support structure; and transferring the one or more synthesized (bio)chemical products from the transfer element to the second support structure.
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.
As used herein, the term “support structure” refers to a structure having at least one surface capable of retaining materials and/or liquids in a stable (and if desired, ordered) manner. The support structure may be composed of various types of glass, plastic, glass coated with a polymer, polymer coated with a glass, other multiple material/layered configurations, or silicon for this purpose. The surface of the support structure utilized to support a material or liquid may be a flat, planar surface (e.g., an upper or lower surface). For example, the support structure may be provided in the form of a thin plate or a chip (e.g., a “biochip.”). One non-limiting example of a support structure is a glass slide. The surface of the support structure may be treated (e.g., functionalized or coated) if desired or needed for a specific purpose such as, for example, enabling attachment or binding (e.g., by adsorption, ionic interaction, covalent bonding, etc.) of materials to the surface, imparting or enhancing the hydrophobicity of the surface, facilitating in situ synthesis of molecules on the surface, etc. In a typical yet non-limiting embodiment, the dimensions of the support structure are on the order of millimeters (mm). As one example, the support structure may have dimensions of 25 mm×76 mm×1 mm. The surface of the support structure is typically rectangular but may have another polygonal shape or a round shape such as a disk shape.
Alternatively, the surface of the support structure utilized to support a material or liquid may be a surface defining a chamber (e.g., a container, receptacle, well, etc.). In some embodiments, a support structure of this type includes a one-dimensional or two-dimensional array of chambers. For example, the support structure may be a multi-well plate, also known as a microtiter plate or microplate.
As used herein, the term “fluid” is used in a general sense to refer to any substance that is flowable through a conduit. Thus, the term “fluid” may generally refer to either a liquid or a gas, unless specified otherwise or the context dictates otherwise.
As used herein, the term “liquid” generally refers to a flowable substance capable of being formed into or existing as a droplet. A liquid may be part of a mixture that also includes a material. In such case, the liquid may be characterized as including or containing the material, or the material may be characterized as being in, or carried in or by, the liquid. The material may be “carried” in the liquid by any mechanism. As examples, the liquid-material mixture may be a solution, a suspension, a colloid, or an emulsion. Solid particles and/or gas bubbles may be present in the liquid. Thus, when a material is “carried in the liquid supported by the transfer element,” it is contemplated that in some embodiments the material is itself a solution before contacting the liquid, and is carried in the liquid upon contacting the liquid that is loaded on the transfer element. In some other embodiments, the material may be a dry material and is dissolved by the liquid from the transfer element and thereby carried in the liquid.
As used herein, the term “conduit” 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 tube or a channel.
In some embodiments, a conduit may have a small bore. A small-bore tube may be referred to herein as a capillary tube, or capillary. A small-bore channel may be referred to herein as a “microfluidic channel” or “microchannel.” The cross-section (or flow area) of a small-bore conduit may have a cross-sectional dimension on the order of micrometers (e.g., up to about 1000 μm, or 1 mm) or lower (e.g., nanometers (nm)). For example, the cross-sectional dimension may range from 100 nm to 1000 μm (1 mm). The term “cross-sectional dimension” refers to a type of dimension that is appropriately descriptive for the shape of the cross-section of the conduit—for example, diameter in the case of a circular cross-section, major axis in the case of an elliptical cross-section, or a maximum width or height between two opposing sides in the case of a polygonal cross-section. Additionally, the cross-section of the conduit may have an irregular shape, either deliberately or as a result of the limitations of fabrication techniques. The cross-sectional dimension of an irregularly shaped cross-section may be taken to be the dimension characteristic of a regularly shaped cross-section that the irregularly shaped cross-section most closely approximates (e.g., diameter of a circle, major axis of an ellipse, width or height of a polygon, etc.). Flow rates through a small-bore conduit may be on the order of microliters per minute (μL/min) or nanoliters per minute (nL/min).
A tube or capillary may be formed by any known technique. The tube or capillary may be formed from a variety of materials such as, for example, fused silica, glasses, polymers, and metals.
A microfluidic channel may be formed in a solid body of material. The material may be of the type utilized in various fields of microfabrication such as microfluidics, microelectronics, micro-electromechanical systems (MEMS), and the like. The composition of the material may be one that is utilized in these fields as a semiconductor, electrical insulator or dielectric, vacuum seal, structural layer, or sacrificial layer. The material may thus be composed of, for example, a metalloid (e.g., silicon or germanium), a metalloid alloy (e.g., silicon-germanium), a carbide such as silicon carbide, an inorganic oxide or ceramic (e.g., silicon oxide, titanium oxide, or aluminum oxide), an inorganic nitride or oxynitride (e.g., silicon nitride or silicon oxynitride), various glasses, or various polymers such as polycarbonates (PC), polydimethylsiloxane (PDMS), etc. The solid body of material may initially be provided in the form of, for example, a substrate, a layer disposed on an underlying substrate, a microfluidic chip, a die singulated from a larger wafer of the material, etc.
The channel may be formed in a solid body of material by any technique, now known or later developed in a field of fabrication, which is suitable for the material's composition and the size and aspect ratio (e.g., length:diameter) of the channel. As non-limiting examples, the channel may be formed by an etching technique such as focused ion beam (FIB) etching, deep reactive ion etching (DRIE), soft lithography, or a micromachining technique such as mechanical drilling, laser drilling or ultrasonic milling. Depending on the length and characteristic dimension of the channel to be formed, the etching or micromachining may be done in a manner analogous to forming a vertical or three-dimensional “via” partially into or entirely through the thickness of the material (e.g., a “through-wafer” or “through-substrate” via). Alternatively, an initially open channel or trench may be formed on the surface of a substrate, which is then bonded to another substrate to complete the channel. The other substrate may present a flat surface, or may also include an initially open channel that is aligned with the open channel of the first substrate as part of the bonding process.
Depending on its composition, the material defining the conduit may be inherently chemically inert relative to the fluid flowing through the conduit. Alternatively, the conduit (or at least the inside surface of the conduit) may be deactivated as part of the fabrication process, such as by applying a suitable coating or surface treatment/functionalization so as to render the conduit chemically inert and/or of low absorptivity to the material. Moreover, the inside surface of the conduit may be treated or functionalized so as to impart or enhance a property such as, for example, hydrophobicity, hydrophilicity, lipophobicity, lipophilicity, low absorptivity, etc., as needed or desirable for a particular application. Alternatively or additionally, the outside of the conduit may also be treated or functionalized similarly. Coatings and surface treatments/functionalizations for all such purposes are readily appreciated by persons skilled in the art.
In some embodiments, the material forming the conduit is optically transparent for a purpose such as performing an optics-based measurement, performing a sample analysis, detecting or identifying a substance flowing through the channel, enabling a user to observe flows and/or internal components, etc.
As used herein, the term “(bio)chemical compound” encompasses chemical compounds and biological compounds. A chemical compound may, for example, be a small molecule or a high molecular-weight molecule (e.g., a polymer). A biological compound may be, for example, a biopolymer.
As used herein, the term “oligonucleotide” denotes 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. Oligonucleotides may be synthesized as part of or in preparation for methods disclosed herein, or may be pre-synthesized and provided as a starting material for methods disclosed herein. For convenience, oligonucleotides are also referred to herein by the short-hand term “oligos.” Oligos utilized to assemble synthons may be referred to herein as “synthon precursor oligos” to distinguish them from other types of oligos that may be utilized or present in the methods and systems, such as the probes of a capture array and adaptor oligos (AOs).
The terms “nucleic acid” and “polynucleotide” are used interchangeably herein to describe a polymer 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, and may be produced enzymatically or synthetically (e.g., PNA as described in U.S. Pat. No. 5,948,902 and the references cited therein) 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 terms “nucleic acid” and “polynucleotide” may encompass peptide nucleic acid (PNA), locked nucleic acid (LNA), and unstructured nucleic acid (UNA). Nucleic acids or polynucleotides may be synthesized using methods and systems disclosed herein.
As used herein, the term “gene” refers to a segment (e.g., 102-106 base pairs (bp)) of DNA that encodes function. Genes may be synthesized using methods and systems disclosed herein.
As used herein, the term “synthon” refers to a synthetic nucleic acid that has been assembled in vitro from several shorter nucleic acids (e.g., oligos) in a defined sequence or order. A synthon may include, for example, a chain assembled from of 3 to 50 oligos. Synthons may be utilized as building blocks to form larger constructs such as, for example, genes. Synthons may be assembled (synthesized) using methods and systems disclosed herein. A synthon so assembled may be of any sequence and, in certain cases, may encode a sequence of amino acids, i.e., may be a coding sequence. In other embodiments, the synthon may be a regulatory sequence such as a promoter or enhancer. In particular cases, the synthon may encode a regulatory RNA. In certain cases a synthon may have a biological or structural function.
As used herein, the term “releasing” in the context of releasing an oligo from the surface of a support structure refers to breaking or overcoming a bond or cleavage site of the oligo such that all or part of the oligo is freed (or unbound, liberated, detached, untethered, de-anchored, etc.) from the surface. Typically, releasing an oligo entails “cleaving” the oligo such as by chemical cleaving, enzymatic cleaving, and photocleaving techniques, as appropriate for the particular embodiment.
The present invention generally relates to transferring (physically transporting) liquids from one or more locations (e.g., a source location or site) to one or more other locations (e.g., a destination location or site), such as from one surface to another surface or chamber. For example, a liquid may be transferred from one glass slide to another glass slide, or from a glass slide to a multi-well plate. In embodiments described herein, liquids are transferred in small amounts and may be in the form of droplets. Transfer elements (examples of which are described below) capable of supporting liquids in small amounts or as droplets may be utilized to transfer the liquids. The liquids to be transferred may be the subject of further processing after being transferred from one location to another. Alternatively, the liquids to be transferred may contain materials of interest for further processing, in which case the liquids may function solely or predominantly as vehicles or media for the transfer of the materials of interest.
The transfer of liquids may be useful in a wide range of applications. One example is transferring one or more liquids from a source location to a destination location so that the liquid(s) may be processed at the destination location. Another example is processing one or more liquids at the source location, and then transferring the processed liquids (or the products of the process) to the destination location for further processing, transport, etc. Examples of processing include, but are not limited to, reacting, diluting, buffering, thermal treatment, incubating, mixing, lysing, cleaving, denaturing, labeling (e.g., with a dye, fluorophore, etc.), distilling, fractionating, filtering, purifying, etc. In some embodiments, reaction may entail or result in synthesis or assembly. For example, one or more (bio)chemical compounds may be transferred from a source location to a chamber, at which the (bio)chemical compounds are contacted with one or more reagents to yield a product. The reagents may be dissolved or suspended in solvents or co-solvents, and added to the chamber before or after the (bio)chemical compounds are transferred to the chamber. In the present context, the term “reagent” encompasses reactants, catalysts, and enzymes. In another example of synthesis, oligonucleotides may be transferred from a source location to a chamber, at which the oligonucleotides are contacted with one or more reagents to assemble a larger nucleotide-based construct (e.g., a synthon).
In typical yet non-limiting embodiments, the size of each feature 108 may be on the order of micrometers (μm). As one example, the size of each feature 108 may be in a range from 3.0 μm to 200 μm. In the present context, the “size” of a feature 108 generally refers to the characteristic dimension of the area on the feature 108 spans on the support structure surface. The “characteristic dimension” is the dimension appropriately descriptive of the shape that the feature 108 has or most closely approximates, such as diameter for a circular feature 108 or edge-to-opposing edge length for a polygonal feature 108. In a typical yet non-limiting embodiment, the clusters 116, or at least those clusters 116 occupying the same subarray 112 (or at least those clusters 116 occupying the same row or column in the same subarray 112), are uniformly spaced from each other. The spacing between adjacent clusters 116 in each subarray 112 (or in a common row or column thereof) may range from, for example, 100 to 500 μm. The spacing between adjacent clusters 116 may be set as needed to avoid cross-contamination between adjacent clusters 116.
Depending on the embodiment, the features 108 of a given cluster 116 may include the same materials (materials having the same composition) or different materials (materials having different compositions). Moreover, a single feature 108 may include multiple materials having the same composition or different compositions. In either case, different clusters 116 may include different materials.
In the non-limiting example illustrated in
As noted above, each feature 108 may be associated with a unique feature address on the source array 100. Likewise, each cluster 116 may be associated with a unique cluster address on the source array 100. Thus, all materials occupying a given feature 108 may be associated with the address of that particular feature 108 and/or the cluster 116 containing that particular feature 108. Moreover, the identity of the materials located at a given feature 108 may be known (predefined or predetermined) at the time the feature 108 is created on the source array 100. Accordingly, at the time the source array 100 is created, the source array 100 may constitute a fully addressable collection of features 108 each containing a known material or combination of materials. The feature addresses may be defined by any suitable addressing scheme, such as spatial coordinates. The spatial coordinates of a feature 108 may be dimensional values measurable relative to a reference point in a Cartesian frame of reference, for example (x=3500 μm, y=4500 μm), being the distances in the x-direction and y-direction from an origin (x=0, y=0). Alternatively, the spatial coordinates of a feature 108 may be a row number and column number. Alternatively, if the features 108 are grouped into clusters 116, a feature address may include a number assigned to a particular feature 108 in a particular cluster 116, followed by a number assigned to that particular cluster 116 (or by a row number and column number, or other spatial coordinates, assigned to that particular cluster 116). For example, in a seven-feature cluster 116, the features 108 may be addressed as numbers 1 through 7. Feature addresses and cluster addresses may likewise include the address assigned to the subarray 112 of which they are a part, as well as the address (e.g., identification number) of the source array 100 of which they are a part. Thus, for example, a feature address may be expressed in formats such as the following: <source array #> <subarray #> <feature row #> <feature column #>; or <source array #> <subarray #> <cluster #> <feature #>; etc. Feature addresses and cluster addresses may be displayed to and utilized by a user in the form of an alphabetic, numeric, or alphanumeric combination of characters according to any suitable addressing nomenclature. Feature addresses and cluster addresses may be assigned digital values that are stored and utilized by a system controller (e.g., a computing device) for various purposes such as mapping and displaying the collection of features 108, tracking the locations of materials associated with the features 108, controlling the movement of a material transfer device (examples of which are described below) including the end points of travel and the paths taken between end points, etc.
The addressing scheme enables the source array 100 to be organized according to any desired set of criteria. Particularly when the source array 100 contains a collection of a large number of different features 108 (and thus a large number of different materials), the addressing scheme enables the source array 100 to be organized or sorted into smaller, less complex sub-collections, with the sub-collections being defined according to any desired set of criteria. For example, source array 100 may serve as a collection of source materials that may be utilized to synthesize any number of different products. A specific product to be synthesized may be selected. Synthesis of the selected product may require a certain material or combination of materials to be utilized as precursors. For any material or materials selected for use in synthesis (or other process), the addressing scheme enables the location(s) of the material(s) in the source array 100 to be communicated to a transfer device. The transfer device may then be programmed or commanded to move to the address(es) of the selected material(s) and transfer the material(s) from the source array 100 to a destination site at which the synthesis or other process is to be carried out, as described further below.
In the illustrated embodiment, the clusters 116 (
In a typical yet non-limiting embodiment, the subarrays 112 of the source array 100 may be arranged so as to have a substantially uniform pitch. The “pitch” of the subarrays 112 denotes the distance between any two corresponding points of two adjacent subarrays 112, for example, the center-to-center distance (distance from the center of one subarray 112 to the center of an adjacent subarray 112), an edge-to-edge distance (e.g., distance from a point on an edge of one subarray 112 to the corresponding point on the corresponding edge of an adjacent subarray 112), or the like. With the pattern or arrangement of clusters 116 (
Similarly, the chambers 212 of the destination array 200 may be arranged so as to have a uniform pitch, as is the case of commercially available multi-well plates. The pitch of the chambers 212 denotes the distance between any two corresponding points of two adjacent chambers 212. The pitch of the chambers 212 is referred to herein as the “chamber pitch” or “well pitch” WP, an example of which is depicted in
In some embodiments, the source array 100 is configured such that its format (or configuration) matches or substantially matches the format of the destination array 200. In the present context, term “format” or “configuration” refers to the subarray pitch SP and the area or footprint spanned by each subarray 112 on the surface of the support structure 104. The area of a subarray 112 may be the area of a circle or polygon that encloses all clusters 116 (
The number of rows and/or columns of subarrays 112 may or may not be equal to the number of rows and/or columns of chambers 212. For many embodiments, the physical footprint of the source array 100 may be significantly smaller than the physical footprint of the destination array 200. In such cases, and further with the subarray pitch SP matching the chamber pitch WP, the number of rows and columns of subarrays 112 may be significantly less than the number of rows and columns of chambers 212. For example, the source array 100 may be a standard-sized glass slide or biochip of typically small dimensions while the destination array 200 may be a standard-sized multi-well plate of comparatively much larger dimensions. At the same time, however, even if the overall footprint and number of rows and columns of the source array 100 are significantly smaller than those of the destination array 200, the number of clusters 116 containing materials may be significantly larger than the number of chambers 212 provided by the destination array 200. Thus, depending on the method being implemented, that method may require the transfer device to make multiple trips between the source array 100 and the destination array 200, and may require the use of multiple destination arrays 200 simultaneously and/or sequentially. Alternatively, depending on the method being implemented, that method may require the transfer device to make multiple trips between the source array 100 and the destination array 200 such that materials from multiple source clusters 116 are transferred to the same chamber 212.
Like the features 108 and clusters 116, each chamber 212 (or other type of destination site of the destination array 200) may be associated with a unique address. The source addresses (or cluster addresses) of the clusters 116 (and/or individual features 108) and the destination addresses (or chamber addresses) of the chambers 212 may be utilized to define the transfer paths along which the transfer device is to move between the source array 100 and the destination array 200, and track the positions of materials. Additionally, the source addresses may be utilized to map the positions of the specific materials or sets of materials on the source array 100 on a cluster-by-cluster basis (or further, on a feature-by-feature basis), and the destination addresses may be utilized to map the positions of the specific materials or sets of materials on the destination array 200 on a destination site-by-site basis (e.g., chamber-by-chamber basis, or spot-by-spot basis).
Depending on the embodiment, the system 300 may include other components as needed for proper operation, which are not specifically shown but understood by persons skilled in the art in fields such as, for example, high-throughput liquid handling and sample assaying. Examples of such other components may include, but are not limited to, a reservoir station containing one or more reservoirs (e.g., bottles) for supplying various liquids (e.g., material transfer media, buffer solutions, etc.); a reagent station containing one or more reservoirs for supplying various reagents utilized in reactions; a liquid handling system (e.g., pumps, valves, tubing, capillaries, etc.) for flowing various liquids to various stations such as those noted above or to a waste station, and dispensing (metering) or aspirating liquid in precise volumes as needed at such stations; array storage stations for holding source arrays 100 and/or destination arrays 200; an array handling system, such as may include one or more devices for gripping/manipulating and transporting source arrays 100 and/or destination arrays 200 and thereby enabling automated loading and unloading of source arrays 100 and/or destination arrays 200 at the source station 334 and/or destination station 336 (e.g., a robotic gripper element or other end effector supported by a multi-axis stage, a conveyance device for supporting and moving one or more source arrays 100 and/or destination arrays 200, etc.); positional sensors (e.g., optical encoders, relay switches, etc.) for detecting the positions of source arrays 100 and/or destination arrays 200 and/or their presence at particular positions; liquid sensors for detecting the presence of liquids and/or measuring liquid volumes in chambers 212 (
The source station 334 may include any suitable support or holding structure (e.g., platform, stage, etc.) for securely mounting one or more source arrays 100 in a fixed position during use such that the clusters 116 or features 108 (
The transfer device 338 may include a transfer element head 352 and an automated three-axis (X-Y-Z) staging device or robot 354 that supports and actuates movement of the transfer element head 352 in three dimensions. Generally, the staging device 354 may have a design similar to automated instruments utilized in fields such as, for example, high-throughput liquid handling and sample assaying. For example, the staging device 354 may be a Cartesian coordinate robot that includes three (X, Y, and Z) motorized linear stages. Each stage may include a carriage coupled to a motor (e.g., a precision, bi-directional stepper motor) via a mechanical linkage (e.g., a screw), whereby the carriage is driven by the motor along a linear guide in either direction along the axis (X, Y, or Z) of that stage. For example, the X-stage may be supported by a fixed base, the Y-stage may be supported by the carriage of the X-stage, and the Z-stage may be supported by the carriage of the Y-stage, thereby enabling horizontal translation of the transfer element head 352 in two dimensions. Further, the transfer element head 352 may be supported by the carriage of the Z-stage to enable vertical translation (lowering and raising) of the transfer element head 352. In some embodiments, the transfer device 338 is configured to provide a positioning accuracy in the X-Y plane that is lower than the dimensions of the individual features 108 (
The transfer element head 352 may include one or more transfer elements 356 mounted thereto. For example, the transfer element head 352 may include a 1D or 2D array of transfer elements 356 mounted thereto. As noted above, in some embodiments the pitch (center-to-center spacing) of the transfer elements 356 may be matched (be equal or substantially equal) to the subarray pitch SP and the chamber pitch WP (
As examples, the transfer elements 356 may be contact transfer elements (involving direct contact with an array surface) or non-contact transfer elements, which are available in various configurations as appreciated by persons skilled in the art. Examples of contact transfer elements include, but are not limited to, solid pins, split pins, micro-spotting pins (“ink stamps”), tweezers, and capillary tubes. Contact transfer elements may be dipped into the solution provided by the solution station 340, whereby small amounts of the solution are retained on the surfaces of the transfer element tips of solid pins (or retained in the openings of small rings, through which the solid pins are subsequently pushed when depositing the solution), or in internal gaps or channels of the other types of contact transfer elements. To facilitate light-impact, non-damaging, and accurate contact with array surfaces, contact transfer elements may be supported (e.g., by gravity) in the transfer element head 352 so as to be free to translate in the vertical direction (z-axis) in response to making contact with a surface. Examples of non-contact transfer elements include, but are not limited to, capillaries coupled to precision stepper motor-controlled syringes, and ink-jet printing-type dispensers such as capillaries squeezed by piezoelectric-driven elements or nozzles coupled to solenoid valves and syringes. Non-contact transfer elements may not utilize the solution station 340, but instead may be coupled via tubing to one or more liquid (transfer medium) reservoirs positioned remotely from the transfer element head 352.
In an embodiment, the liquid used for the transfer of the material is chosen such that the material, when put into contact with the transfer liquid, will go into solution. Further, if used with a transfer element 356 that transports the liquid/material solution on the outside of a transfer pin, i.e., not within a capillary, the liquid should not appreciably evaporate during the transfer process. To this end, the environmental humidity may be controlled around the whole transfer system 300 and/or the transfer liquid may be selected such that its evaporation is controlled or slowed to an acceptable amount. Further, the transfer liquid should not damage the material, negatively modify the transfer element 356, or interfere with the post-transfer use of the transfer element 356. In an embodiment, the transfer liquid may include one or more additives effective for suppressing evaporation. Examples of additives that may be used with an aqueous solution (i.e., water) include, but are not limited to, glycerol, polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), various salt solutions, sugar alcohols, and other compounds that retard evaporation when added to water.
In an embodiment, prior to the movement of the transfer element head 352 (and thus the transfer elements 356), the physical locations of the various destinations for the transfer element(s) 356 are ascertained/calibrated, most especially the exact positions of the clusters 116 (
In some embodiments such as when the source array 100 is, for example, an array of oligonucleotides on a glass slide, the individual features 108 may have a hydrophobicity that is different from the background area surrounding each feature 108. This may enable a method to visualize the features 108 and thereby the clusters 116 of features 108 by using a humid gas stream blown over the array such that there is a differential condensation rate between the features 108 and their background. The difference in condensation rate may clearly delineate the locations of the features 108 and thereby the clusters 116, enabling visualization of the array features 108 and the calibration of the transfer system 300 to the array features 108. As an example,
The motion of the transfer element head 352 (and thus the transfer elements 356) may be controlled by the system controller 344 in accordance with user input enabled by the user input devices 346 or a pre-programmed itinerary as may be dictated by a software program (e.g., a set of instructions executed by the system controller 344). The transfer elements 356 may be moved according to precise, predefined velocity profiles, and along predefined transfer paths between the source array(s) 100 and the destination array(s) 200 respectively loaded in operative positions at the source station 334 and the destination station 336. At the source station 334, the transfer elements 356 may be lowered toward a source array 100 such that the tips of the transfer elements 356, or liquids present at the tips of the transfer elements 356, contact the material or materials occupying the targeted clusters 116 (or specific targeted features 108 of the clusters 116) respectively aligned with the transfer elements 356, whereby the material or materials are drawn into the respective liquid volumes.
The transfer elements 356 may then be moved to the destination station 336. At the destination station 336, the transfer elements 356 may be lowered toward a destination array 200 so as to deposit the material or materials borne on the transfer element tips into targeted chambers 212 or destination sites of the destination array 200.
After the selected material or materials have been transferred to a selected chamber 212, the material or materials may be processed at the chamber 212 as prescribed by the particular method being implemented. A given process may require the material(s) to be contacted (e.g., mixed, interacted) with one or more liquids, which may be or carry reagents. Such liquids may be added to the chamber 212 before or after the material(s) have been transferred to the chamber 212. In some embodiments, such liquids may be added by operating liquid handling components of the system 300.
As described elsewhere herein, in some embodiments the tip of a transfer element 356 may be sized so as to be capable of addressing an individual cluster 116 and extracting materials from all or some of the features 108 of the cluster 116 simultaneously. The transfer element 356 may then transfer all of the materials carried by that transfer element 356 simultaneously into a single targeted chamber 212. The ability to simultaneously transfer materials from multiple features 108 of the same cluster 116 is useful, for example, in an embodiment where the cluster 116 contains a combination of different materials utilized in carrying out a particular reaction or assembly/synthesis process. In such case, a particular combination of different materials needed to carry out a desired reaction or assembly/synthesis process may be selected simply by selecting a cluster 116 of the source array 100 containing the particular combination, and the transfer element 356 is required to make only a single trip from the source array 100 to the destination array 200.
To prevent material or liquid carryover from a preceding transfer process, between each transfer process iteration the transfer element head 352 may be moved to the wash station 342 at which the transfer elements 356 may be dipped into a wash/rinse solution. The wash/rinse process may be assisted by vacuum and/or liquid or gas jets. After washing/rinsing, the transfer element head 352 may be returned to the source array 100 (or moved to a different source array 100) to extract additional materials.
The system controller (e.g., computing device) 344 may schematically represent one or more modules (or units, or components) configured for controlling, monitoring and/or timing various functional aspects of the system 300 such as, for example, tracking the locations of specific materials or sets of materials, tracking and controlling the movement of the transfer element head 352 at and between the various stations, controlling liquid handling operations, controlling materials processing operations carried out at the source array 100 and/or destination array 200, etc. One or more modules may be, or be embodied in, for example, a computer workstation or desktop computer, or a mobile computing device such as a laptop computer, portable computer, tablet computer, handheld computer, personal digital assistant (PDA), smartphone, etc. The system controller 344 may also be configured for providing and controlling a user interface that provides screen displays of objects or data with which a user may interact, such as maps of source arrays 100 and destination arrays 200, fields for inputting data and control parameters of the system 300, etc. The system controller 344 may include one or more reading devices on or in which a non-transitory (tangible) computer-readable (machine-readable) medium may be loaded that includes instructions for performing all or part of any of the methods disclosed herein. For all such purposes, the system controller 344 may be in signal communication with the drivers of the transfer device 338 and various sensors and other components of the system 300 via wired or wireless communication links (as partially represented in
In the example illustrated in
After the selected materials have been transferred to the respective transfer element tips, the transfer element head 352 may then be raised along the vertical Z-axis and driven to move along the X-Y plane to a position over the destination array 200 at which the transfer elements 356 are respectively aligned with the selected chambers 212.
Depending on the method being carried out, the liquid/material transfer process described above may be repeated as many times as needed to transfer additional liquids/materials to the same group of chambers 212 or to additional groups of chambers 212. The row/column ratio of the array of transfer elements 356 mounted to the transfer element head 352 may be proportionally matched to the row/column ratio of the subarrays 112 of the source array 100 (and to the row/column ratio of the chambers 212 of the destination array 200) to facilitate the simultaneous use of multiple transfer elements 356 and the ability to address each subarray 112 and/or chamber 212 at least once during the same method if desired. For example, if a source array 100 has 1536 subarrays 112 arranged in thirty-two rows and forty-eight columns (thus having a row/column ratio of 2:3), a transfer element array with four rows and six columns (thus also having a 2:3 row/column ratio) may be utilized by having the transfer element head 352 make eight trips to the source array 100 in order to address each subarray 112 once. The collection of materials may be carefully constructed on and mapped to the source array 100 to facilitate the use of a multi-transfer element array. Additionally, the system controller 344 may execute a materials tracking module and a transfer device control module in a coordinated manner.
Depending on the number of materials or sets of materials to be transferred, additional destination arrays 200 may be needed. Two or more destination arrays 200 may be loaded adjacent to the each other at the destination station 336 (
In other embodiments, a single transfer element 356 may be mounted to the transfer element head 352. As the transfer element head 352 can move the transfer element 356 from any cluster of the source array 100 to any chamber 212 of the destination array 300, use of a single transfer element 356 may be desirable for imparting greater flexibility to method development, although at the expense of lower processing throughput and increased consumption of time.
An alternative embodiment to the transfer element head 352 being the sole moving component in the system may be implemented. The most stringent alignment and accuracy needed for the transfer system is between the transfer elements 356 and the features 108 and clusters 116 of the source array 100. The high accuracy is not needed for movement of the transfer elements 356 to the other locations (destination array 200, solution station 340, wash station 342, etc.) unless the destination array 200 requires high accuracy. For example, if the destination array 200 is a well plate, the required accuracy may be as large as 0.5 millimeters. This provides the opportunity to configure the system as follows: place the source array 100 on a short travel, very accurate X-Y stage system; place the transfer elements 356 on a Z-travel stage mounted on a fixed base; and place all other low-accuracy-requirement stations, including the destination array 200, on a large travel X-Y stage. In one example of operating a transfer system with this configuration, the transfer element head 352 is only moved up and down to and away from the source array 100 below it. The source array is moved short distances to accurately align its features 108 and clusters 116 to the transfer elements 356. The low-accuracy stations are placed on a plane that is between the plane of the source array 100 and the maximum Z-travel height of the transfer elements 356. When it is necessary for the transfer elements 356 to be placed at the destination array 200 or one of the low accuracy stations, the large-travel X-Y stage is activated such that they are placed as needed below the transfer elements 356. In this manner, the low accuracy stations and destination array 200 are brought to the transfer elements 356 rather than vice versa as in previously described embodiments. This has an advantage of using a small high accuracy stage rather than a large high accuracy stage.
Although the capillaries 556 may be configured to pick up materials without the capillary tips physically contacting the materials or support, in other embodiments the capillaries 556 may be configured to allow the capillary tips to contact the materials or support. The use of capillaries 556 that contact the materials may relax the degree of accuracy required in positioning of the capillaries 556 relative to the target materials on the source array 100. As another example, the capillaries 556 depicted in
For simplicity,
The upstream controllable pressure source 602 may schematically represent a source of a suitably inert gas (e.g., air, helium, nitrogen, argon, etc.), a valve or other type of flow controller, a conduit communicating with the end of the capillary channel 606 opposite to the capillary tip 614, etc. The controllable pressure source 602 is configured to provide positive pressure (relative to, e.g., ambient air pressure) to the capillary channel 606 on command. The controllable pressure source 602 is utilized to extrude the transfer liquid 610 from the capillary 656. The controllable pressure source 602 may also be utilized to extrude a liquid utilized for cleaning and rinsing the capillary channel 606.
Referring to
It will be understood that, as in other embodiments disclosed herein, multiple capillaries 656 may be provided as an array of transfer elements carried by a single transfer element head (e.g., the transfer element head 352 described above and illustrated in
The transfer liquid flow system 702 further includes a transfer liquid reservoir and flow source 772 communicating with the transfer liquid input channel 730, which may be via a valve 744 (e.g., an open/close valve), as indicated by respective arrows in
In some embodiments, the valve 774 may be integrated with the fluidic chip 756. For example, the valve 744 may be configured as a flexible diaphragm that selectively closes off (i.e., by creating a pinch in) the transfer liquid input channel 730 in response to an appropriately routed input of control fluid.
Thus, the metered active capillary system 700 is differentiated from the non-metered active capillary system 600 described above and illustrated in
Referring to
Alternatively, the valve 774 may remain closed and the control fluid reservoir and pressure source 766 may be utilized to extrude the transfer liquid 710 containing the materials 708 out from the capillary channel opening 718. This alternative method is only capable of extruding the maximum amount of transfer liquid 710 that activation of the flexible diaphragm 766 can provide. By comparison, opening the valve 744 and activating the transfer liquid reservoir and flow source 772 to extrude the transfer liquid 710 may provide any desired amount of transfer liquid 710, and is generally limited only by the amount of transfer liquid 710 present in the transfer liquid reservoir and flow source 772.
It will be understood that, as in other embodiments disclosed herein, multiple capillary tips 714 (with corresponding groups of transfer liquid chambers 750, control fluid chambers 764, flexible diaphragms 776, etc.) may be provided as an array of transfer elements carried by a single transfer element head (e.g., the transfer element head 352 described above and illustrated in
Each control fluid channel includes a control fluid input channel 862 communicating with a control fluid chamber. From the perspective of
In the present embodiment, the fluid flow selector 882 is configured as a switch that can be actuated to move between a first operating position at which transfer liquid is supplied to the transfer liquid input channels 830 and a second operating position at which control fluid is supplied to the control fluid input channels 862. In one specific yet non-limiting embodiment, the fluid flow selector 882 may be configured as a small-scale rotary multi-port valve. In this case, the fluid flow selector 882 may include a stator and an adjacent rotor. The stator may include a plurality of ports, and the rotor may include a plurality of internal flow paths (e.g., channels, grooves, etc., between the sides of the rotor and stator that face other). Each flow path of the rotor has a length, and is positioned relative to the ports of the stator, such that at any operating position of the fluid flow selector 882, the flow path fluidly couples two of the ports (whereby one of the ports serves as an inlet port and the other port serves as an outlet port). Rotation of the rotor may be driven by any suitable mechanism. Generally, the operation of the fluid flow selector 882 may be similar to that of larger-scale rotary multi-port valves utilized in applications requiring the switching of fluid flow paths, such as chromatography.
In the present embodiment, one of the ports (a transfer liquid supply port) of the stator is coupled to the transfer liquid source, and another port (a control fluid supply port) is coupled to the control fluid source. When rotated to the first operating position, the fluid flow selector 882 couples (via one of the flow paths) the transfer liquid supply port to multiple outlet ports, each communicating with one of the transfer liquid input channels 830. At the first operating position, the control fluid supply port is blocked, i.e., the control fluid supply channel 884 and control fluid input channels 862 are decoupled from the control fluid source. When rotated to the second operating position, the fluid flow selector 882 couples (via one of the flow paths) the control fluid supply port to an outlet port communicating with the control fluid input channels 862. At the second operating position, the transfer liquid supply port is blocked, i.e., the transfer liquid input channels 830 are individually decoupled from the transfer liquid source and there is no communication between the individual transfer liquid input channels 830.
Generally, the multi-channel, metered active capillary system 800 may be operated in a manner similar to the metered active capillary device or system 700 described above and illustrated in
According to further embodiments of the present disclosure, the materials transferred from the source array 100 to the destination array 200 are oligos or larger compounds containing multiple oligos (e.g., synthons). Thus, the source array 100 may be an organized collection of a potentially very large number of oligos, which populate features 108 and clusters 116 as described herein. The source array 100 containing oligos may be created (i.e., features 108 containing oligos may be created) by in situ synthesis, i.e., the oligos may be synthesized directly on the source array 100. Alternatively, the source array 100 may be created by ex situ synthesis followed by hybridization to the source array 100. That is, the oligos first may be synthesized on a separate support structure (e.g., a separate glass slide) that is located off-site from the source array 100. The oligos may then be released from the off-site support structure and hybridized to capture probes attached to the source array 100. The capture probes may be arranged on the source array 100 according to the predetermined organization of feature addresses. Depending on the stage of a method utilizing an oligo source array, the oligos located at the features 108 may be bound to or unbound (released) from the features 108.
As in the case of other (bio)chemical compounds, the oligos may be processed in accordance with any desired method. In particular, different combinations of oligos may be selected for assembly into different types of synthons. For example, the source array 100 may be organized or mapped into multiple sets (groups or sub-collections) of oligos. Each oligo set may include all of the oligos required to assemble a particular type of synthon. Depending on how the source array 100 is created, assembly may be performed at the source array 100 after which the assembled synthons are transferred to the destination array 200, or precursor oligos may be transferred to the destination array 200 after which assembly is performed at the destination array 200. In either case, potentially thousands to millions of synthons and thus thousands to millions of genes or other nucleic acid sequences may be synthesized from an oligo collection provided on a single source array 100. According to an aspect of the present disclosure, complex oligo collections are able to be sorted into sub-collections, and oligos are able to be selectively extracted from the sub-collections for subsequent processing such as assembly into synthons.
Each feature 108 of the source array 100 may contain a large number of oligos. Depending on the embodiment, each feature 108 of a given cluster 116 may contain the same type of oligos, or the features 108 of the cluster 116 may contain different types of oligos. Oligos of the same type contain the same sequence of nucleotides (nucleotide monomers), whereas oligos that are “different” contain different sequences of nucleotides. A given cluster 116 may contain the same combination of oligos as another cluster 116, or different clusters 116 may contain different combinations of oligos. For convenience in the present disclosure, oligos having different sequences may be considered as being an example of materials having different compositions.
An example of a method for processing oligos will now be described. In this example, a source array 100 is created by synthesizing oligos on the surface of the source array 100, such that each oligo is attached to the surface through a cleavable linker. The oligos are synthesized so as to create an array of addressable features 108 on the surface. Each feature 108 of the array contains the same type of oligo on that particular feature 108, while different features 108 of the array may contain different oligos. The oligos are synthesized in such a way that the features 108 are grouped into separate clusters 116. Each cluster 116, or set of clusters 116, contains all of the oligos needed to assemble a particular synthon (having a particular sequence of oligos). Direct synthesis may be performed, for example, by drop deposition from pulse jets or by pin deposition of nucleotide units, or by photolithographic techniques. Protected oligos are then de-protected and released (e.g., cleaved) from the support structure surface, either stepwise or simultaneously, by any suitable technique. In some cases, washing of the source array 100 may be performed to remove de-protection salts and side products without removing the oligos. Any suitable wet-cleaving, dry-cleaving (e.g., using a gas-phase cleaving agent), or photocleaving mechanism may be utilized, such as those described in U.S. Patent Application Publication Nos. US 2015/0361423 and US 2015/0361422, both titled HIGH THROUGHPUT GENE ASSEMBLY IN DROPLETS, the contents of both of which are incorporated by reference herein. Before or after releasing oligos of the source array 100, one or more clusters 116 needed to assemble one or more desired synthons are selected. The transfer device 338 may then be utilized in the manner described above to transfer the oligos located at the selected cluster(s) 116 to one or more chambers 212 (or other type of destination sites) of a destination array 200.
At the chamber(s) 212, the oligos are contacted with one or more appropriate reagents (added to the chamber(s) 212 before or after transferring the oligos), whereby one or more types of synthons are assembled in a desired order of oligos at one or more chambers 212. Examples of reagents include, but are not limited to, polymerase, ligase, endonuclease, exonuclease, other enzymes or coenzymes, adenosine triphosphate (ATP), other nucleotide triphosphates (NTPs) or deoxy-NTPs (dNTPs), other nucleotide derivatives, nucleotides, and buffer. Also, any particular reaction conditions (e.g., temperature program, time) required to assemble the synthons are implemented at the chambers 212, as appreciated by persons skilled in the art. For example, the destination array 200 may be loaded into an incubation chamber if needed. More generally, various techniques may be utilized to assemble synthons from the oligos of respective oligo sets, as appreciated by persons skilled in the art. Examples include, but are not limited to, polymerase chain assembly (PCA) and ordered ligation, as further described in above-referenced U.S. Patent Application Publication Nos. US 2015/0361423 and US 2015/0361422.
Another example of a method for processing oligos will now be described. In this example, a source array 100 is provided or created initially as a capture array. The capture array contains a plurality of capture probes (nucleotide sequences) attached to the surface according to the predetermined organization of feature addresses. The capture probes are located such that each feature 1008 (
In this example, the source array 100 is created (or completed) by drawing the oligos initially provided on the separate support structure into a solution, and then bringing the solution containing the oligo mixture into contact with the capture array. This initiates the hybridization process, whereby oligos having capture sequences complementary to specific capture probes are hybridized to (captured by) those capture probes. Consequently, oligos having the same capture sequences are co-located at the same feature 1008 of the capture array. Oligos co-located at the same feature 1008 may, however, have different assembly payloads.
In this example, a given feature 1008 has all of the different oligos (oligos with different assembly payloads) needed to assemble a particular synthon. To increase the number of oligos available for assembly, a plurality of features 1008 may be grouped into a cluster 116 (
One or more clusters 116 needed to assemble one or more desired synthons are selected. The transfer device 338 (
In some embodiments, synthon precursor oligos utilized in methods and systems disclosed herein may be described as follows. A first oligo set includes oligos of formula A-X, where A is a capture sequence (terminal indexer sequence) that is common to all of the oligos in the first oligo set, and X is an assembly sequence that is different among the oligos in the first oligo set (e.g., X1, X2, X3, and so on); a second oligo set includes oligos of formula B-Y, where the capture sequence B is common to all of the oligos in the second oligo set and is different to A, and the assembly sequence Y is different among the oligos in the second oligo set (e.g., Y1, Y2, Y3, and so on); and so on. The X oligos may be assembled into a first synthon that includes a first synthon sequence in a defined order (e.g., X1-X2-X3- . . . ), the Y oligos may be assembled into a second synthon that includes a second synthon sequence in a defined order (e.g., Y1-Y2-Y3- . . . ), and so on.
The above-described methods for processing oligos are useful when it is desired to capture or synthesize the oligos on an array, but then remove them from the array for further processing, rather than assembling them in droplets in situ on the surface of the array as described in above-referenced U.S. Patent Application Publication Nos. US 2015/0361423 and US 2015/0361422. For example, if the assembly process includes multiple enzymatic steps requiring different buffers and/or reagents, it may be more convenient to perform such steps at a separate assembly site (e.g., at a destination array as described herein) rather than directly on the array where the oligos were captured or synthesized.
In other applications, however, assembly on the source array 100 may be desirable. Accordingly, in another example of a method for processing oligos, a source array 100 is created from a capture array as just described. The present example differs in that after hybridization and cleaving, synthons are assembled directly on the source array 100. This may be done in a preferred embodiment, for example, by placing or creating droplets containing reagent(s) on one or more selected features 108 of the source array 100, thereby initiating the assembly process at the selected feature(s) 108. In this way, synthons are assembled directly within each selected feature 108 on the source array 100. The source array 100 is then dried, and the transfer device 338 may then be utilized to transfer the synthons to destination array 200 for further processing, storage, transport, etc.
Alternatively, in another example of a method for processing oligos, a source array 100 is created from a capture array as just described. After hybridization and cleaving, synthons are assembled directly on the source array 100. This may be done by placing or creating droplets containing reagent(s) over the whole of one or more selected clusters 116 of the source array 100, thereby initiating the assembly process at the selected cluster(s) 116. In this way, synthons are assembled directly from the features 108 within each cluster 116. The source array 100 is then dried, and the transfer device 338 may then be utilized to transfer the synthons to a destination array 200 for further processing, storage, transport, etc.
In some embodiments, methods described herein may utilize one or more aspects of methods for hybridizing an oligonucleotide mixture to an array using capture probes disclosed in above-referenced U.S. Patent Application Publication Nos. US 2015/0361423 and US 2015/0361422.
Synthons assembled according to the methods disclosed herein may be further processed for any pertinent purpose. For example, the synthons may be utilized to synthesize genes or other larger polynucleotide-based constructs. The synthons may be extracted from the chambers 212 and utilized to create an array of synthons, which may serve as an intermediate product for further processing or otherwise stored for later use.
From the present disclosure, it is evident that the disclosed systems and methods may provide one or more advantages. The addressability of the source array, which may be potentially large and complex, enables selective extraction of liquids or materials, including (bio)chemical compounds, for any pertinent purpose. In the case of processing oligos, amplification is not required. The ability to extract materials or liquids (or sets of materials or liquids) from the source array and transfer them to separate destination sites, such as may be conveniently provided by a multi-well plate of standard format or other environment separate and isolated from the source array, affords a high degree of flexibility in the further processing of the selected liquids or materials. For instance, the further processing of the selected materials or liquids is not constrained by the environment of the source array, and ensures that any further processing will have no adverse effect on (and thus need not account for) the source array. Instead, the further processing may be implemented by a wide variety of further processing steps, which may include for example multiple enzymatic steps requiring different reagents and buffers. Moreover, processing conditions may be optimized, as such processing may be carried out at destination sites separate and isolated from the source array. Moreover, thousands or millions of materials or liquids may be provided on the source array. Hence, depending on the number of destination sites provided, the systems and methods disclosed herein may enable the processing of thousands or millions of liquids or materials of the same composition or different compositions in a massively parallel operation.
The materials tracking module 1170 may be configured for tracking the locations (addresses) of specific materials (and/or sets of materials) at specific features 108, clusters 116 and subarrays 112 of a source array 100, and at specific chambers 212 of a destination array 200 (
The transfer device control module 1172 may be configured for tracking and controlling the movement of the transfer element head 352 at and between the various stations, including the paths taken from one selected address to another, and the raising and lowering of the transfer element head 352 at selected addresses and various stations. The transfer device control module 1172 may carry out an itinerary of the transfer element head 352 based on pre-programmed instructions or user input, or may calculate the itinerary based on selected materials. For such purposes, the transfer device control module 1172 may utilize data (e.g., identities and addresses of materials) provided by materials tracking module 1170. In some embodiments, the itinerary may be based on the selection of a specific reaction or synthesis to be carried out or other process to be performed on materials provided by the source array 100. For example, a user may input the identity of a desired synthon to the system controller 344. Based on the knowledge of the oligo collection contained on an available source array 100, the transfer device control module 1172 may, in cooperation with the materials tracking module 1170, select a source address or addresses in the oligo collection at which the required oligo set is located, select a destination address at which to transfer the oligo set for assembly into the desired synthon, and set appropriate parameters for movement of the transfer element head 352. The parameters (e.g., velocity and acceleration profiles, paths of travel, etc.) may be set so as to optimize the movement, for example to minimize the total amount of time required to execute the movement.
The liquid handling control module 1174 may be configured for controlling the operation of the liquid handling system and associated non-contact transfer elements 356, which may be done in coordination with the transfer device control module 1172. Alternatively or additionally, the liquid handling control module 1174 may control other liquid handling operations and systems, such as for supplying buffer solution, wash/rinse solution, and reagents.
It will be understood that
Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the following:
1. A liquid transfer system, comprising: a source station configured for supporting a source array, the source array comprising a surface and a plurality of materials arranged on the surface according to a predetermined organization of clusters, wherein each cluster comprises one or more features, each feature comprises one or more of the plurality of materials, and each cluster is spaced from adjacent clusters by an area unoccupied by materials or occupied by inert materials; a destination station configured for supporting a destination site positioned remotely from the source station; a transfer device comprising a transfer element configured for supporting liquid; and a controller configured for: loading liquid to the transfer element; moving the transfer device to a selected cluster of the source array; operating the transfer device to simultaneously transfer the materials located at the features of the selected cluster from the surface to the transfer element, wherein the materials are carried in the liquid supported by the transfer element; moving the transfer device to the destination site; and transferring the materials from the transfer element to the destination site.
2. The liquid transfer system of embodiment 1, wherein: the selected cluster of the source array is a selected first cluster at which a first set of materials is located; and the controller is configured for: after transferring the first set of materials to the destination site, moving the transfer device back to the source array and to a selected second cluster on the surface at which a second set of materials is located; operating the transfer device to transfer the second set of materials from the surface to the transfer element; moving the transfer device back to the destination site at which the first set of materials is located or to a different destination site; transferring the second set of materials from the transfer element to the destination site at which the first set of materials is located or to a different destination site; and repeating the foregoing steps zero or more times to transfer zero or more additional materials.
3. The liquid transfer system of embodiment 1, wherein: the selected cluster of the source array is a selected first cluster at which a first set of materials is located; the destination station is configured for supporting a plurality of destination sites; the transfer device comprises a plurality of transfer elements configured for supporting a plurality of liquids; and the controller is configured for: operating the transfer device to transfer the first set of materials, and one or more additional sets of materials located at one or more additional clusters, to the respective transfer elements; moving the transfer elements to the plurality of destination sites simultaneously; and transferring the first set of materials and the one or more additional sets of materials from the transfer elements to respective destination sites.
4. The liquid transfer system of any of the preceding embodiments, wherein each cluster comprises two or more features.
5. The liquid transfer system of any of the preceding embodiments, wherein the features in each cluster are arranged as a hexagonal pattern, or a concentric circular pattern, or a rectilinear pattern.
6. The liquid transfer system of any of the preceding embodiments, wherein: the plurality of clusters is organized on the surface as a one-dimensional or two-dimensional array of subarrays, such that each cluster in each subarray is spaced from another cluster in an adjacent subarray by a subarray pitch; and the transfer device comprises a one-dimensional or two-dimensional array of transfer elements configured for supporting a plurality of liquids, and each transfer element is spaced from an adjacent transfer element by a distance substantially equal to the subarray pitch.
7. The liquid transfer system of embodiment 6, wherein the subarray pitch is substantially equal to 9.0 mm, or 4.5 mm, or 2.25 mm.
8. The liquid transfer system of any of the preceding embodiments, wherein: the destination station is configured for supporting a plurality of destination sites; the controller is configured for moving the transfer device to a selected one of the destination sites; and the controller is configured for transferring the materials from the transfer element to the selected destination site.
9. The liquid transfer system of embodiment 8, wherein the destination sites have respective addresses, and the controller is configured for moving the transfer device to a selected address of the destination sites.
10. The liquid transfer system of any of the preceding embodiments, wherein the destination station is configured for supporting a plurality of destination sites having a configuration selected from the group consisting of: the plurality of destination sites is a one-dimensional or two-dimensional array of destination sites; the plurality of destination sites is a two-dimensional array of chambers, and the number of destination sites is 96, or 384, or 1536; the plurality of destination sites is a two-dimensional array of destination sites, and each destination site is spaced from an adjacent destination site by a distance substantially equal to 9.0 mm, or 4.5 mm, or 2.25 mm; the destination sites are chambers; and the destination station is configured for supporting a microtiter plate, and the destination sites are wells of the microtiter plate.
11. The liquid transfer system of any of the preceding embodiments, wherein the transfer element is selected from the group consisting of: a pin comprising a pin tip surface and configured for supporting liquid on the pin tip surface; a pin comprising a pin tip opening and an internal conduit communicating with the pin tip opening, and configured for drawing liquid through the pin tip opening and into the internal conduit; a capillary comprising a capillary channel and a capillary tip opening communicating with the capillary channel, and configured for drawing liquid into the capillary channel via the capillary tip opening; and a capillary comprising a capillary channel, a capillary tip opening communicating with the capillary channel, and a liquid inlet communicating with the capillary channel, wherein the capillary is configured for receiving liquid into the capillary channel via the liquid inlet and drawing liquid into the capillary channel via the capillary tip opening.
12. The liquid transfer system of any of embodiments 1-10, wherein the transfer element comprises a pin, and the controller is configured for operating the transfer device to transfer the materials located at the selected cluster from the surface to the pin by moving the pin with the liquids supported thereon into contact with the materials or with a liquid carrying the materials.
13. The liquid transfer system of any of embodiments 1-10, comprising a controllable pressure source, wherein the transfer element comprises a capillary communicating with the controllable pressure source, and the controller is configured for operating the transfer device to transfer the materials located at the selected cluster from the surface to the capillary by drawing a liquid carrying the materials into the capillary using capillary forces.
14. The liquid transfer system of any of embodiments 1-10, comprising a transfer liquid flow system and a control fluid flow system, wherein the transfer element comprises: a tip opening, a liquid inlet communicating with the transfer liquid flow system, and a liquid chamber communicating with the tip opening and with the liquid inlet; a control fluid chamber communicating with the control fluid flow system; and a flexible diaphragm interposed as a common boundary between the liquid chamber and the control fluid chamber, wherein: the transfer liquid flow system is configured for flowing liquid into the liquid chamber via the liquid inlet; and the control fluid flow system is configured for flowing a control fluid into the control fluid chamber to deform the flexible diaphragm such that the liquid chamber is reduced in volume.
15. The liquid transfer system of embodiment 14, wherein the transfer element comprises a flow selector configured for switching between a first operating position at which the transfer liquid flow system flows liquid into the liquid chamber, and a second operating position at which the control fluid flow system flows control fluid into the control fluid chamber.
16. The liquid transfer system of any of the preceding embodiments, wherein the transfer device comprises a one-dimensional or two-dimensional array of transfer elements configured for supporting a plurality of liquids.
17. The liquid transfer system of embodiment 16, wherein each transfer element is spaced from an adjacent transfer element by a distance substantially equal to 9.0 mm, or 4.5 mm, or 2.25 mm.
18. A method for transferring liquids, the method comprising: providing a source array comprising a surface and a plurality of materials arranged on the surface according to a predetermined organization of clusters, wherein each cluster comprises one or more features, each feature comprises one or more of the plurality of materials, and each cluster is spaced from adjacent clusters by an area unoccupied by materials or occupied by inert materials; selecting a cluster of the source array; loading liquid to a transfer element of a transfer device configured to support the liquid; moving the transfer device to the selected cluster; operating the transfer device to simultaneously transfer the materials located at the features of the selected cluster from the surface to the transfer element, wherein the materials are carried in the liquid supported by the transfer element; moving the transfer device to a destination site positioned remotely from the source array; and transferring the materials from the transfer element to the destination site.
19. The method of embodiment 18, wherein the selected cluster of the source array is a selected first cluster at which a first set of materials is located, and further comprising: after transferring the first set of materials to the destination site, moving the transfer device back to the source array and to a selected second cluster on the surface at which a second set of materials is located; operating the transfer device to transfer the second set of materials from the surface to the transfer element; moving the transfer device back to the destination site at which the first set of materials is located or to a different destination site; transferring the second set of materials from the transfer element to the destination site at which the first set of materials is located or to a different destination site; and repeating the foregoing steps zero or more times to transfer zero or more additional materials.
20. The method of embodiment 18, wherein: the selected cluster of the source array is a selected first cluster at which a first set of materials is located; the destination site is one of a plurality of destination sites; the transfer device comprises a plurality of transfer elements configured for supporting a plurality of liquids, and further comprising: operating the transfer device to transfer the first set of materials and one or more additional sets of materials located at one or more additional clusters to the respective transfer elements; moving the transfer elements to the plurality of destination sites simultaneously; and transferring the first set of materials and the one or more additional sets of materials from the transfer elements to respective destination sites.
21. The method of any of embodiments 18-20, wherein each cluster comprises two or more features.
22. The method of any of embodiments 18-21, wherein the features in each cluster are arranged as a hexagonal pattern, or a concentric circular pattern, or a rectilinear pattern.
23. The method of any of embodiments 18-22, wherein: the plurality of clusters is organized on the surface as a one-dimensional or two-dimensional array of subarrays, such that each cluster in each subarray is spaced from another cluster in an adjacent subarray by a subarray pitch; and the transfer device comprises a one-dimensional or two-dimensional array of transfer elements configured for supporting a plurality of liquids, and each transfer element is spaced from an adjacent transfer element by a distance substantially equal to the subarray pitch.
24. The method of embodiment 23, wherein the subarray pitch is substantially equal to 9.0 mm, or 4.5 mm, or 2.25 mm.
25. The method of any of embodiments 18-24, wherein the destination site is one of a plurality of destination sites, and further comprising selecting one of the destination sites, wherein: moving the transfer device to the destination site comprises moving the transfer device to a selected one of the destination sites; and transferring the materials from the transfer element to the destination site comprises transferring the material from the transfer element to the selected destination site.
26. The method of any of embodiments 25, wherein the destination sites have respective addresses, and moving the transfer device to a selected one of the destination sites comprises moving the transfer device to a selected address of the destination sites.
27. The method of any of embodiments 18-26, wherein the destination site is one of a plurality of destination sites having a configuration selected from the group consisting of: the plurality of destination sites is a one-dimensional or two-dimensional array of destination sites; the plurality of destination sites is a two-dimensional array of destination sites, and the number of destination sites is 96, or 384, or 1536; the plurality of destination sites is a two-dimensional array of destination sites, and each destination site is spaced from an adjacent destination site by a distance substantially equal to 9.0 mm, or 4.5 mm, or 2.25 mm; the destination sites are chambers; and the destination station is configured for supporting a microtiter plate, and the destination sites are wells of the microtiter plate.
28. The method of any of embodiments 18-27, wherein the transfer element is a pin, and operating the transfer device to transfer the materials located at the selected cluster from the surface to the pin comprises moving the pin into contact with the materials or with a liquid carrying the materials.
29. The method of any of embodiments 18-28, wherein the clusters of the source array are associated with different addresses, and moving the transfer device to the selected cluster programming the address associated with the selected cluster into the transfer device.
30. The method of any of embodiments 18-29, wherein the transfer device comprises a one-dimensional or two-dimensional array of transfer elements configured for supporting a plurality of liquids.
31. The method of embodiment 30, wherein each transfer element is spaced from an adjacent transfer element by a distance substantially equal to 9.0 mm, or 4.5 mm, or 2.25 mm.
32. The method of any of embodiments 18-31, comprising contacting the transferred materials with one or more reagents at the destination site.
33. The method of embodiment 32, wherein contacting the transferred materials with the one or more reagents is done under conditions effective for synthesizing a product at the destination site.
34. The method of any of embodiments 18-33, wherein the materials are (bio)chemical compounds or oligonucleotides.
35. The method of any of embodiments 18-34, wherein the liquids carrying the materials comprise an additive effective for suppressing evaporation of the liquid.
36. The method of embodiment 35, wherein additive is selected from the group consisting of: glycerol; sugar alcohols; polyethylene glycol; dimethyl sulfoxide, a salt solution; and a combination of two or more of the foregoing.
37. The method of any of embodiments 18-36, comprising, after providing the source array, ascertaining locations of the clusters on the source array.
38. The method of embodiment 37, wherein ascertaining locations comprises flowing a humid gas onto the source array.
39. A method for processing (bio)chemical compounds, the method comprising: providing a plurality of (bio)chemical compounds, wherein one or more of the (bio)chemical compounds are different in composition from the other (bio)chemical compounds; creating a source array comprising a plurality of features by positioning a plurality of (bio)chemical compounds on a first support structure, wherein one or more of the (bio)chemical compounds are different in composition from the other (bio)chemical compounds, and the plurality of (bio)chemical compounds is positioned such that: each feature comprises one or more of the (bio)chemical compounds; and the plurality of features is arranged on the first support structure according to a predetermined organization of positions; selecting one or more features; and transferring the (bio)chemical compounds of the one or more selected features to a second support structure, by: moving a transfer element to the one or more selected features; transferring the (bio)chemical compounds of the one or more selected features to the transfer element; moving the transfer element to the second support structure; and transferring the (bio)chemical compounds from the transfer element to the second support structure.
40. The method of embodiment 39, comprising contacting the transferred (bio)chemical compounds with one or more reagents at the second support structure.
41. The method of embodiment 40, wherein contacting the transferred (bio)chemical compounds with the one or more reagents is done under conditions effective for synthesizing a (bio)chemical product from interaction between the transferred (bio)chemical compounds and the one or more reagents, wherein the (bio)chemical product is synthesized at the second support structure.
42. The method of any of embodiments 39-41, wherein: positioning the plurality of (bio)chemical compounds on the first support structure is done such that the plurality of features is organized as a plurality of clusters, each cluster containing one or more of the plurality of features, and each cluster spaced from adjacent clusters by an area unoccupied by materials or occupied by inert materials; selecting the one or more features comprises selecting a cluster containing the one or more selected features; and moving the transfer element to the one or more selected features comprises moving the transfer element to the selected cluster.
43. The method of embodiment 42, wherein the features of each cluster are arranged as a hexagonal pattern, or a concentric circular pattern, or a rectilinear pattern.
44. The method of embodiment 42 or 43, wherein for each cluster, the one or more (bio)chemical compounds located at each feature contained in the cluster are different in composition from the one or more (bio)chemical compounds located at each of the other features contained in the cluster.
45. The method of embodiment 42 or 43, wherein: the (bio)chemical compounds comprise oligonucleotides; each feature comprises one or more of the oligonucleotides; and for each cluster, the one or more oligonucleotides located at each feature contained in the cluster is different from the one or more oligonucleotides located at each of the other features contained in the cluster.
46. The method of embodiment 45, wherein transferring the (bio)chemical compounds of the one or more selected features to the second support structure comprises transferring the oligonucleotides of the selected cluster to the second support structure.
47. The method of embodiment 46, comprising contacting the transferred (bio)chemical compounds with the one or more reagents comprises contacting the transferred oligonucleotides with the one or more reagents, under conditions effective for assembling the transferred oligonucleotides into a synthon or gene.
48. The method of embodiment 46 or 47, wherein: positioning the plurality of (bio)chemical compounds on the first support structure comprises attaching the oligonucleotides to the first support structure; and transferring the (bio)chemical compounds of the one or more selected features to the second support structure comprises cleaving the oligonucleotides of the selected cluster to produce unbound oligonucleotides, followed by transferring the unbound oligonucleotides to the second support structure.
49. The method of any of embodiments 42-48, wherein for each cluster, each feature contained in the cluster has the same (bio)chemical compound or the same combination of different (bio)chemical compounds as the other features contained in the cluster.
50. The method of embodiment 42 or 43, wherein: the (bio)chemical compounds comprise oligonucleotides, the oligonucleotides comprising respective assembly payloads; and for each cluster, each feature contained in the cluster has the same assembly payload or the same combination of different assembly payloads as each of the other features contained in the cluster.
51. The method of embodiment 50, wherein transferring the (bio)chemical compounds of the one or more selected features to the second support structure comprises transferring the assembly payloads of the selected cluster to the second support structure.
52. The method of embodiment 51, comprising contacting the transferred assembly payloads with one or more reagents, under conditions effective for assembling the transferred assembly payloads into a synthon.
53. The method of embodiment 51 or 52, wherein: the oligonucleotides further comprise respective capture sequences; creating the source array comprises: providing a plurality of capture probes on the first support structure at the predetermined organization of positions, wherein one or more of the capture probes are different in composition from the other capture probes; and wherein positioning the plurality of (bio)chemical compounds on the first support structure comprises hybridizing the oligonucleotides to the plurality of capture probes, wherein the capture sequences specifically bind to complementary capture probes; and transferring the (bio)chemical compounds of the one or more selected features to the second support structure comprises cleaving the oligonucleotides of the selected cluster to produce unbound assembly payloads on each feature of the selected cluster, followed by transferring the unbound assembly payloads to the second support structure, wherein the capture probes remain attached to the first support structure.
54. The method of any of embodiments 42-53, wherein the selected cluster is a selected first cluster, and further comprising: selecting one or more additional clusters; and transferring the (bio)chemical compounds of the one or more selected additional clusters to the second support structure.
55. The method of embodiment 54, comprising contacting the transferred (bio)chemical compounds of the first cluster and the one or more selected additional clusters with one or more reagents at the second support structure, under conditions effective for synthesizing a first (bio)chemical product and one or more additional (bio)chemical products, respectively.
56. The method of embodiment 55, wherein at least one of the (bio)chemical products synthesized is different in composition from the other(bio)chemical products synthesized.
57. The method of any of embodiments 54-56, wherein transferring the (bio)chemical compounds of at least some of the selected additional clusters to the second support structure is done simultaneously using a transfer device comprising a plurality of transfer elements.
58. The method of any of embodiments 54-56, wherein transferring the (bio)chemical compounds of at least some of the selected additional clusters to the second support structure is done sequentially.
59. The method of any of embodiments 54-58, comprising creating a destination array by transferring the (bio)chemical compounds of at least some of the selected clusters to different positions on the second support structure.
60. The method of embodiment 59, wherein the different positions are on a planar surface of the second support structure.
61. The method of embodiment 59 or 60, wherein the second support structure comprises a plurality of chambers, and the different positions are at different chambers.
62. The method of any of embodiments 59-61, wherein: the plurality of clusters are arranged on the first support structure as a one-dimensional or two-dimensional array of subarrays, such that each cluster in each subarray is spaced from another cluster in an adjacent subarray by a subarray pitch; the selected clusters are respectively located in different subarrays; the different positions on the second support structure to which the selected clusters are transferred are spaced from another by a distance substantially equal to the subarray pitch.
63. The method of embodiment 62, wherein the subarray pitch is substantially equal to 9.0 mm, or 4.5 mm, or 2.25 mm.
64. The method of any of embodiments 39-63, wherein the second support structure comprises a plurality of chambers having a configuration selected from the group consisting of: the plurality of chambers is a one-dimensional or two-dimensional array of chambers; the plurality of chambers is a two-dimensional array of chambers, and the number of chambers is 96, or 384, or 1536; the plurality of chambers is a two-dimensional array of chambers, and each chamber is spaced from an adjacent chamber by a distance substantially equal to 9.0 mm, or 4.5 mm, or 2.25 mm; and the second support structure is a microtiter plate, and the plurality of chambers are wells of the microtiter plate.
65. The method of any of embodiments 39-64, wherein: the positions at which the features are located on the first support structure are associated with respective source addresses such that each feature is positioned at a corresponding one of the source addresses; and transferring the (bio)chemical compounds of the one or more selected features to the second support structure comprises controlling movement of the transfer element based on the source address or addresses of the one or more selected features.
66. The method of embodiment 65, wherein: a plurality of destination positions are defined at the second support structure, and further comprising selecting one or more of the destination positions to which to transfer the (bio)chemical compounds; and controlling movement of the transfer element is further based on the one or more destination positions selected.
67. The method of any of embodiments 39-66, wherein: transferring the (bio)chemical compounds of the one or more selected features to the transfer element comprises moving the transfer element into contact with the (bio)chemical compounds of the one or more selected features, wherein the (bio)chemical compounds are drawn into a solution residing on the transfer element; and transferring the (bio)chemical compounds from the transfer element to the second support structure comprises dipping the transfer element into solution disposed at the second support structure.
68. The method of any of embodiments 39-66, wherein: transferring the (bio)chemical compounds of the one or more selected features to the transfer element comprises extruding an amount of solution from the transfer element such that the (bio)chemical compounds are drawn into the extruded solution, and aspirating the extruded solution with the (bio)chemical compounds back into the transfer element; and transferring the (bio)chemical compounds from the transfer element to the second support structure comprises dispensing the extruded solution with the (bio)chemical compounds from the transfer element to the second support structure.
69. A method for processing (bio)chemical compounds, the method comprising: providing a plurality of (bio)chemical compounds, the plurality of (bio)chemical compounds comprising different compositional species; creating a source array comprising a plurality of features by positioning a plurality of (bio)chemical compounds on a first support structure, wherein one or more of the (bio)chemical compounds are different in composition from the other (bio)chemical compounds, and the plurality of (bio)chemical compounds is positioned such that: each feature comprises one or more of the (bio)chemical compounds; and the plurality of features is arranged on the first support structure according to a predetermined organization of known positions; selecting one or more features for use in synthesizing one or more (bio)chemical products; contacting the one or more selected features with one or more reagents, under conditions effective for synthesizing the one or more (bio)chemical products from interaction between the (bio)chemical compounds and the one or more reagents, wherein the one or more (bio)chemical products are synthesized at one or more respective positions on the first support structure; and transferring the one or more synthesized (bio)chemical products to a second support structure by: moving a transfer element to the one or more positions on the first support structure at which the one or more synthesized (bio)chemical products are located; transferring the one or more synthesized (bio)chemical products to the transfer element; moving the transfer element to the second support structure; and transferring the one or more synthesized (bio)chemical products from the transfer element to the second support structure.
70. The method of embodiment 69, wherein: positioning the plurality of (bio)chemical compounds on the first support structure is done such that the plurality of features is arranged as a plurality of clusters, each cluster containing one or more of the plurality of features, and each cluster spaced from adjacent clusters by an area unoccupied by materials or occupied by inert materials; selecting the one or more features comprises selecting one or more clusters containing one or more of the selected features; the one or more (bio)chemical products are synthesized at the one or more selected clusters on the first support structure; and moving the transfer element to the one or more selected features comprises moving the transfer element to the one or more selected clusters.
71. The method of embodiment 70, wherein: the (bio)chemical compounds comprise oligonucleotides, the oligonucleotides comprising respective assembly payloads; and for each cluster, each feature contained in the cluster has the same assembly payload or the same combination of different assembly payloads as each of the other features contained in the cluster.
72. The method of embodiment 71, wherein: the oligonucleotides comprise respective capture sequences; creating the source array comprises: providing a plurality of capture probes on the first support structure at the predetermined organization of positions, wherein one or more of the capture probes are different in composition from the other capture probes; and wherein positioning the plurality of (bio)chemical compounds on the first support structure comprises hybridizing the oligonucleotides to the plurality of capture probes, wherein the capture sequences specifically bind to complementary capture probes; further comprising, before contacting the one or more selected features with one or more reagents, cleaving the oligonucleotides of the one or more selected features to produce unbound assembly payloads, wherein the one or more (bio)chemical products are synthesized by assembling together one or more combinations of the unbound assembly payloads; and after transferring the one or more synthesized (bio)chemical products to the second support structure, the capture probes remain attached to the first support structure.
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 system controller 344 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 system controller 344 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.
This application claims the benefit of U.S. Provisional Patent Application Ser. No. 62/335,027, filed May 11, 2016, titled “SYSTEMS AND METHODS FOR TRANSFERRING LIQUIDS,” the content of which is incorporated by reference herein in its entirety.
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