Patent Application
20050252772
This invention relates to flow devices.
Many systems make use of flow devices, including micro-flow devices, which include a conduit through which there is electroosmotic and/or pressure-driven flow of a liquid. Such systems include, for example, chromatography systems, including high-performance liquid chromatography (HPLC) systems, electrokinetic (also known as electroosmotic) pumping systems, chemical processing systems, and electrophoric separation systems. Reference may be made for example to U.S. Pat. Nos. 6,074,725, 6,156,273, 6,176,962 and 6,287,440, and International Publication Nos. WO 99/16162 and WO 02/101474, the entire disclosures of which are incorporated herein by reference for all purposes.
It is often desirable, for example in order to increase the surface-to-volume ratio of the conduit and/or to provide different surface chemistry, to fill the conduit with a fluid-permeable packing material. In the known methods, the packing material is placed in the conduit (i) in the form of loose particles or (ii) as a liquid polymeric composition which is cured in the conduit. These methods suffer from various disadvantages, for example the need to prevent the packing materials from falling out of the channel and/or falling into adjacent channels or other components; shrinkage of the polymeric compositions when they cure; and the difficulty of changing the surface chemistry of a packing material after it has been placed in the channel.
We have discovered, in accordance with the present invention, a wide variety of novel flow devices which make use of solid porous materials as liquid flow media. The invention is particularly useful when pre-shaped porous materials are used to provide conduits in flow devices, but the invention is not limited to pre-shaped porous materials. The term “pre-shaped” is used to denote a member having a shape before it is enclosed by the barrier member, as distinct from a member which is shaped within the conduit. The porous materials are often laminar, but can be of any shape. The term “laminar” is used in this specification to include, but is not limited to, planar. Thus, a laminar member can for example be a planar member of constant thickness, a planar member of regularly or irregularly varying thickness, a curved member of constant thickness, or a curved member of regularly or irregularly varying thickness. The periphery of a laminar member can be of any shape, and a laminar member can comprise one or more windows of any shape, i.e. areas within the periphery in which there is no material.
In a first aspect, this invention provides a novel flow device comprising a conduit which comprises
In a second aspect, this invention provides a method of causing pressure-driven and/or electroosmotic flow through a device according to the first aspect of the invention, the method comprising
In a third aspect, this invention provides a method of preparing a flow device comprising a conduit, preferably a novel conduit according to the first aspect of the invention, which comprises
The Figures in the accompanying drawings, which are diagrammatic and not to scale, illustrate the invention. In the Figures, a component appearing in more than one Figure is identified by the same reference numeral in each Figure.
In the Summary of the Invention above and in the Detailed Description of the Invention, the Examples, and the claims below, and in the accompanying drawings, reference is made to particular features of the invention. It is to be understood that the disclosure of the invention in this specification includes all appropriate combinations of such particular features. For example, where a particular feature is disclosed in the context of a particular aspect or embodiment of the invention, or a particular Figure, or a particular claim, that feature can also be used, to the extent appropriate, in combination with and/or in the context of other particular aspects and embodiments of the invention, and in the invention generally.
The term “comprises”, and grammatical equivalents thereof, are used herein to mean that other components, ingredients, steps etc. are optionally present in addition to the component(s), ingredient(s), step(s) specifically listed after the term “comprises”. The term “at least” followed by a number is used herein to denote the start of a range beginning with that number (which may be a range having an upper limit or no upper limit, depending on the variable being defined). For example “at least 1” means 1 or more than 1, and “at least 80%” means 80% or more than 80%. The term “at most” followed by a number is used herein to denote the end of a range ending with that number (which may be a range having 1 or 0 as its lower limit, or a range having no lower limit, depending upon the variable being defined). For example, “at most 4” means 4 or less than 4, and “at most 40%” means 40% or less than 40%. When, in this specification, a range is given as “(a first number) to (a second number)” or “(a first number)-(a second number)”, this means a range whose lower limit is the first number and whose upper limit is the second number. Where reference is made herein to “first” and “second” components, e.g. first and second conduits, this is generally done for identification purposes; unless the context requires otherwise, the first and second components can be the same or different.
PFM Shapes
The PFM can be straight, or regularly or irregularly curved, the curve being a smooth curve and/or a succession of straight sections at an angle to each other, in two or three dimensions. When the PFM is obtained by division of a sheet of porous material, it is easy to prepare PFMs of different shapes, for example straight strips of constant or varying width, (e.g. with flared end sections), strips which are part of a circle, strips which bend through an angle of at least 360°, for example so that the fluid path includes two or more sections which are substantially parallel to each other and are substantially the same distance (measured directly, not along the liquid flow path to) from the inlet, e.g. strips in the form of a smooth or angular spiral or zigzag, so that a long conduit becomes more compact. When the sheet of porous material is flexible, a strip divided from it can be bent so that it is no longer flat. The cross-section of the PFM (i.e. a section at right angles to the local axis of the PFM) can be of any shape. When the PFM is obtained by division of a sheet of porous material, the cross-section will generally be rectangular (including square), but may be more complex if the sheet is not of constant thickness. One or both end sections of the PFM can have a cross-section different from the intermediate portion of the PFM. The end sections can be the same or different. The porous material can extend out from the barrier member, for example by a distance of 1 to 3 mm, be flush with the end of the barrier member, or terminate within the barrier member.
PFM Materials
The PFM can comprise any solid porous material that will provide a conduit having desired physical and electrical properties. The PFM can consist of the porous material, or can also include one or more auxiliary components having substantially no effect on the fluid flow through the porous material. For example, an auxiliary component can surround, or be surrounded by, or form a layer adjacent to, the porous material, and can provide desired strengthening, electrical or protective properties. Thus, in one embodiment of the invention, the PFM is a tube of circular, rectangular (including square) or other cross-section, e.g. a conventional capillary tube, into which the porous material has been placed. In this embodiment, because the tube is surrounded and supported by the barrier material, there is no need to use the specialized fittings currently needed to support the ends of such tubes. In addition, the tube can be such that, if it was used without the barrier material, it would be too delicate, for example would not be sufficiently strong to withstand the internal pressure in the tube.
The PFM can comprise a single layer of porous material or two or more layers of porous material. When there are two or more layers, the layers can be the same or different, and can be arranged so that the liquid flows through them simultaneously or sequentially, and/or, if the layers are different, so that different components of the liquid follow different paths. The layers can be in contact with each other or separated from each other by an auxiliary member which may be permeable or impermeable to the liquid or permeable to one or more components of the liquid and impermeable to one or more other components of the liquid.
Many porous materials are readily available as self-supporting sheets of uniform thickness, preferably 20-600 microns, particularly 50-250 microns, e.g. about 100 microns. PFMs can be divided, e.g. by machining, die-cutting or kiss-cutting, from such sheets. Available materials include, for example, porous sheets which are based on polymers (but which may also contain other ingredients, for example fillers), or inorganic materials, for example silica, alumina and other ceramics.
Factors to be considered in the choice of porous material include surface chemistry, surface charge, pore size, pore topology, and formation factor, in conjunction with the system in which the conduit is to be employed. Porous materials suitable for use in this invention include materials in which the average pore size is less than 10 micron or less than 1 micron, for example materials in which all the pores have a size less than 10 or less than 1 micron.
When the pore geometry of the sheet is isotropic, a PFM can be divided from the sheet without regard to the intended direction of liquid flow. When the pore geometry is anisotropic, a PFM divided from the sheet must be used in a conduit such that at least a component of the liquid flow is in the direction of the pores. In some ultra-filtration membranes, the pore size distribution is highly asymmetric in the direction normal to the membrane. A PFM divided from such a membrane can be used in a separation device as described in paragraph (H2) of The first aspect of the invention. Depending on the type of device, it may be preferable to use a material having a low surface charge density, preferably less than 1013, for example about 1012, charges/cm2, or a material having a high surface charge density, preferably greater than 1014, for example greater than 5×1014, charges/cm2. For example, hydrophilic polyvinylidene fluoride (PVDF), polyether sulfone and polyvinyl alcohol, are suitable for bridges; polyamides, nitrocellulose, and sulfonated polytetrafluoroethylene (PTFE) membranes are suitable in ion-exchange elements; and modified PVDF, modified polyamides, modified polyetherether ketones, silica, and alumina are suitable for electrokinetic pumps. Hydrophobic materials, e.g. polypropylene and other polyolefins, and PTFE, are suitable for vents.
In some cases, available porous sheet materials are immediately usable in the present invention. In other cases, better results can be obtained by further treatment of the available materials, either in sheet form or as PFMs which have been divided from them. One useful treatment is to derivativize the material to modify its surface, e.g. to enhance or add surface charge or to change its chemistry. Such treatments are well-known to those skilled in the art, but are very difficult to apply to packing materials that are already in place in a conduit. Reference may be made, for example, to Macromolecules 31, 1277-1284 (1998), Jimbo et al, J. Membrane Sci 179, 1-27 (2000), Takata et al and J. Membrane Sci 139, 101-107 (2000), Belfer et al.
The preferred values of zeta potential and average pore size differ from one type and device to another. The Table below (in which the Debye length is denoted by the abbreviation X) gives further information.
PFM Dimensions
The terms length (L), width (w) and thickness (t) are used to denote the dimensions of the flowthrough section of the PFM (which may be the whole of the PFM), i.e. the part of the PFM which is enclosed by the barrier member. Thus, if end sections of the PFM extend beyond the barrier member into a junction or reservoir, those end sections are not considered in determining L, w and t. For PFMs whose cross-section at right angles to the axis of fluid flow is a rectangle, w and t denote the dimensions of the longer and shorter sides of the rectangle, respectively. In many cases, PFMs having a rectangular cross-section are preferred. For PFMs having non-rectangular cross-sections, w and t refer to the longer and shorter sides of the rectangle of minimal area which can be drawn around the non-rectangular cross-sections. For PFMs whose cross-section varies, w and t refer to the effective average value, taking into account the lengths of the PFM having particular values of w and t. Thus, for a PFM of constant thickness and varying width, the effective average value of w is the inverse of the average of the inverse of w along the length of the PFM.
When the PFM is composed of a single layer of porous material, its thickness, (or average thickness, if the thickness varies) may be for example 20 to 600 microns, preferably 50 to 250 microns, e.g. 75 to 150 microns. When the PFM is composed of a number of components, each component preferably has such a thickness. Thus, a PFM comprising two or more layers of porous material stacked on top of each other may have a thickness of, for example, 200 to 2000 microns. The term equivalent diameter, d, is used in defining the cross-section of the PFM (or the average value of the equivalent diameter if the cross-section varies). d is the diameter of a circle having the same area as the cross-section of the PFM. Thus, for rectangular cross-sections d={square root}4 wt/π.
In many embodiments of the invention, L is substantially greater than either of w and t. L is for example at least 3 times or at least 5 times, e.g. 3 to 100 times or 5 to 30 times the equivalent diameter, d. In many embodiments of the invention, especially those in which the PFM has a rectangular cross-section, w and t are such that the value of the ratio w/t is at least 3, at least 10 or at least 20, for example 3 to 200, 5 to 100, or 8 to 75. The width w may be for example 0.2-2 mm.
Barrier Members
The conduits of the invention are constructed so that, in use, a liquid follows a desired flow path through the flowthrough section of the PFM. Thus, each PFM must be enclosed along its boundaries, but not at its inlet(s) and outlet(s), by a barrier member which is not permeable to the liquid. The barrier member can be monolithic or composed of two or more barrier components or layers secured together. A preferred method of providing the barrier comprises laminating a PFM, generally a laminar PFM, between barrier components, generally laminar, barrier components. One or more of the barrier components can be pre-shaped in two or three dimensions to conform to the PFM, making allowance when necessary for deformation of the barrier components during the lamination. For example, windows and/or channels can be formed in the barrier components. The barrier components can be such that they can be secured to each other and to the PFM by lamination using heat and pressure. Suitable polymeric films, with bonding temperatures from 80 to 350° C. are well-known. Alternatively or additionally, lamination can be affected with the aid of adhesives. In another embodiment, the barrier member is provided by a liquid barrier composition which is placed around the PFM and then solidified. Examples of such compositions include potting compositions which cure at room temperature or with the aid of heat or ultraviolet, ultrasonic or other radiation, and which may contain fillers, e.g. reinforcing fibers, e.g. compositions based on epoxies, polyphenylene oxides, acrylic resins and silicones. In another embodiment, the barrier member is prepared by wrapping a flexible barrier film or tape around the PFM, and optionally treating, e.g. heating, the wrapping. Alternatively or additionally, mechanical means can be used to secure the barrier member around the PFM.
The barrier components and the way in which they are secured around the PFM should be such that the PFM is not penetrated by the barrier material or otherwise physically or chemically damaged. If need be, a protective layer can be placed between the PFM and the barrier component(s).
The conduits of the invention preferably have physical properties such that they can be conveniently handled and used, including the ability to withstand the fluid pressure within the conduit, which can vary widely between different types of system. Such physical properties may be provided by the barrier member alone. Alternatively or additionally, the device can include one or more support members, e.g. of metal or glass, to provide desired physical properties. Generally the conduits of the invention are rigid, i.e. do not bend or flex in use. However, the conduit can be flexible.
Additional Components
The devices of the invention can include a wide variety of additional components, for example junctions and capillaries through which, in use, liquids enter or leave an inlet, outlet or an intermediate point of the PFM; reservoirs for liquids; electrodes; electrode leads; pumps, and optical and/or electrical components for monitoring the system. Such additional components can be incorporated into the device at the same time as the barrier member is placed around the PFM, for example by placing them between layers which are secured together as part of a lamination process. Alternatively, or additionally, they can be added after the barrier member has been placed around the PFM, for example by creating vias in the barrier member(s) and/or support member(s), inserting the additional component and sealing the via around the additional component. The fluidic junctions in the devices of the invention preferably have a low dead volume.
Devices and Systems
The conduits of the invention can form a part of, or be used in association with, a wide variety of flow devices, including, for example, devices for chromatographic separation, devices for chemical processing, analytical devices, pumps, injectors, flow controllers, separation elements, bridges, reactors, mixers, and detection elements, including the devices disclosed in copending commonly assigned U.S. patent application Ser. Nos. 10/137,215, 10/155,474, 10/273,723 and 10/322,083, and International Patent Applications PCT/US 02/19121 (published as International Publication Number WO 02/101474) and PCT/US 03/13315, the disclosures of which are incorporated herein by reference.
Multilayer Devices
Many devices of the invention contain two or more, for example, at least 3 or at least 4, e.g. 3-6, laminar PFMs, each PFM forming part of a layer in a multilayer device. Each PFM-containing layer can contain one or more PFMs. The PFMs in different layers can be placed so that the major surfaces of adjacent PFMs completely overlap, partially overlap, or do not overlap. Adjacent PFM-containing layers can be separated from each other by a barrier layer, or can contact each other directly. When adjacent PFM-containing layers contact each other directly, and the PFMs overlap, the PFMs will contact each other. The liquid flows in the PFMs can be in the same direction or in different directions, including opposite directions. Different PFMs can be in fluid communication with each other through direct contact and/or because both communicate with the same fluidic junction. A multilayer device can contain two or more fluid systems which operate independently of each other, or fluid systems whose operation is dependent on the behavior of each other.
The mixing devices, the multilayer devices with two or more overlapping PFMs, and the filtration devices described below are particular examples of the multilayer devices of the invention.
Mixing Devices
One embodiment of the invention is a mixing device having characteristic (F) set out in the first aspect of the invention. Such mixing devices optionally can have one or more of the following characteristics:—
The mixing device can be used for example, to mix two aqueous liquids, two organic liquids, or an aqueous liquid and an organic liquid. The liquids can be of different viscosities, may contain dissolved chemicals, including biochemicals, and may be dispersions of particulate materials or emulsions. The liquids can be miscible or immiscible, for example in order to produce an emulsion or as part of a chemical extraction, or can undergo a chemical reaction together. The solid porous material of the PFMs should be selected so that they are not damaged by, and do not damage, the liquids being mixed or the products of the mixing. The liquid flow can be one or both of pressure-driven flow and electroosmotic flow. The flowrates through the PFMs can be the same or different and can be constant or can vary.
Preferably, the PFMs and the dimensions of the device are selected so that the pressure drop over at least one, and preferably all, of the flowthrough sections is greater than, for example at least 2 times, preferably 5 to 15 times, for example about 10 times, the pressure drop between the mixing stage and the outlet
The mixing device can be used to mix three or more liquids simultaneously, by using a corresponding number of conduits having overlapping transfer sections. The mixing device can contain two or more mixing stages, for example a first mixing stage in which two different liquids are mixed, and a second mixing stage in which the product of the first mixing stage is mixed with a third liquid. In this way, for example, successive stages of a chemical synthesis can be carried out in the different mixing stages.
FIGS. 23 to 27 depict mixing devices of the invention.
Multilayer Devices
One embodiment of the invention is a multilayer device having the characteristic (G) as set out in the first aspect of the invention. Such a multilayer device optionally can have one or more of the following characteristics:—
One embodiment of the invention is a filtration device having characteristic (G1) or (G2) as set out in the first aspect of the invention. When a liquid containing relatively small molecules or particles of one type and relatively large molecules or particles of another type is passed through a layered PFM as defined in (G1) or a PFM having an asymmetric pore size distribution as defined in (G2), some of the smaller molecules or particles migrate to one surface of the PFM, and a product containing only the smaller molecules or particles can be recovered from that surface, while a product containing the larger particles and a smaller proportion of the smaller molecules can be recovered from the opposite surface. A liquid can be passed through the device to assist in recovery of the smaller molecules or particles.
Devices with Two PFMs Having Different Zeta Potentials
One embodiment of the invention is a device containing two PFMs having different zeta potentials, in particular a device having characteristic (I) as set out in the first aspect of the invention. Such devices can optionally have one or more of the following characteristics
When two PFMs are butted together at a fluidic junction, the area of contact between them is limited to the smaller of the two PFM cross-sections (or a somewhat larger, but still small, area if the ends of the PFMs are shaped to fit each other]. Consequently, there may be substantial resistance to the movement of liquid out of an outlet of the junction. In addition, there is a danger that, during preparation of the device, the junction between the PFM will be partially blocked by liquid barrier material. In one embodiment of the invention, these problems are ameliorated through the use of at least one auxiliary porous member which contacts the sides of the PFMs and bridges the butt joint between them. The auxiliary porous member is preferably made of a porous material having a pore size greater than the pore size of either of the PFMs; preferably a pore size which is at least 2 times, particularly at least 5 times, for example 5 to 20 times, the pore size of the PFM having the larger pore size.
Preparation of the Devices
The devices of the invention can be prepared by either of, or a combination of, the methods included in the definition above of the third aspect of the invention Before the barrier is placed around the PFM, a wide variety of additional components, e.g. capillary tubes, electrodes, electrode leads, optical and/or electrical monitoring components, preformed junctions and preformed reservoirs, can be assembled in contact with and/or separated from, the PFM, and thus incorporated into the device, at the same time as the barrier is placed around the flowthrough section of the PFM. In many cases, lamination of a plurality of barrier layers is the preferred method. The additional components can be placed between two barrier layers and/or between a barrier layer and a PFM. Especially when the device comprises two or more PFMs, the device can be prepared in two or more successive steps, the steps being the same or different.
Wetting Procedures
When the devices of the invention are in use, they are filled with a liquid. When the flow of liquid is solely pressure-driven, any appropriate liquid can be used. When the flow is at least partly electroosmotic flow, the liquid must be an ionic liquid. It is, therefore, desirable to design the devices so that they can be easily wetted without trapping air pockets. The device can be filled with a liquid after it has been made (and after sterilization, if needed). In some cases parts of the device can be wetted while the device is being made. After it has been wetted, a device can be sealed and stored until it is needed. Methods of wetting flow devices are well-known to those skilled in the art.
The Drawings
In
The following Examples illustrate the invention.
Three devices as illustrated in
A mixing device as shown in
This application is a continuation-in-part of our application Ser. No. 10/198,223, filed Jul. 17, 2002 (Docket No. 14138), the entire disclosure of which is incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US03/22306 | 7/16/2003 | WO | 1/12/2005 |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10198223 | Jul 2002 | US |
| Child | 10521093 | Jan 2005 | US |
