Abstract:
An interconnecting device for connecting a plurality of first fluid-bearing conduits to a corresponding plurality of second fluid-bearing conduits thereby providing fluid communication between the first fluid-bearing conduits and the second fluid-bearing conduits. The device includes a manifold and one or two ferrule plates that are held by compressive axial forces.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional application of U.S. patent application Ser. No. 11/350,541 originally filed Jan. 24, 2003 now U.S. Pat. No. 7,311,882 entitled “CAPILLARY INTERCONNECT DEVICE” from which benefit of priority is claimed. 
    
    
     STATEMENT OF GOVERNMENT INTEREST 
     This invention was made with Government support under government contract DE-AC04-94AL85000 awarded by the U.S. Department of Energy to Sandia Corporation. The Government has certain rights in the invention, including a paid-up license and the right, in limited circumstances, to require the owner of any patent issuing in this invention to license others on reasonable terms. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates generally to microfluidic systems and more particularly to structures which facilitate the introduction of fluids into devices having microfluidic channels. 
     BACKGROUND OF THE INVENTION 
     Microfluidic devices or substrates typically consist of two or more microchannels or capillaries that can range in size from about 5-100 μm wide and 5-100 μm deep etched or molded in a substrate that can be silicon, plastic, quartz, glass, or plastic. Microfluidic substrates may be fabricated using photolithographic techniques similar to those used in the semiconductor industry, and the resulting devices can be used to perform a variety of sophisticated chemical and biological analytical techniques. Microfluidic analytical technology has a number of advantages, including the ability to use very small sample sizes, typically on the order of nanoliters. The substrates may be produced at a relatively low cost, and can be formatted to perform numerous specific analytical operations, including mixing, dispensing, valving, reactions, and detections. 
     Another recently developed class of sample-receiving microfluidic substrates includes substrates having a capillary interface that allows compounds to be brought onto the test substrate from an external source, and which can be advantageously used in a number of assay formats for high-throughput screening applications. These assay formats include fluorogenic assays, fluorescence polarization assays, non-fluorogenic mobility shift assays, dose response assays, and calcium flux cell-based assays. 
     Other applications for microfluidic devices include diagnostics involving biomolecules and other analytical techniques such as micro total analysis systems. Such devices, often referred to in the art as “microchips,” also may be fabricated from plastic, with the channels being etched, machined or injection molded into individual substrates. Multiple substrates may be suitably arranged and laminated to construct a microchip of desired function and geometry. In all cases, the channels used to carry out the analyses typically are of capillary scale dimension. 
     To fully exploit the technological advances offered by the use of microfluidic devices and to maintain the degree of sensitivity for analytical techniques when processing small volumes, e.g., microliters or less, connectors which introduce and/or withdraw fluids, i.e., liquids and gases, from the device, as well as interconnect microfluidic devices, are crucial components in the use and performance of the microfluidic device. For example, chromatographic applications require an injection port that can introduce a sample into a flow stream. The varied uses of these microfluidic devices require connectors that are both versatile and resilient. The physical stresses placed on these connectors can be demanding. Not only must the connectors be inert to reactive substances that are injected into the microchannels, such as organic solvents, but also they must remain leak free when exposed to pressures that can reach as high as 10,000 psi. Moreover, these connectors must be able to act as an interface for connecting microscale devices such as injectors and fluid reservoirs to microscale capillary tubes. However, because of the extremely small tolerances involved, this has been difficult to achieve. Typically, capillary tubes have outer diameters on the order of 150 to 365 μm and nominal internal diameters of from 50 to 75 μm or less with tolerances as small as a few microns, yet these capillary tubes must be accurately aligned. 
     A common technique used in the past involves bonding a length of tubing to a port on the microfluidic device with epoxy or other suitable adhesive. Adhesive bonding is unsuitable for many chemical analysis applications because the solvents used attack the adhesive which can lead to channel clogging, detachment of the tubing, and/or contamination of the sample and/or reagents in or delivered to the device. Furthermore, adhesive bonding results in a permanent attachment of the tubing to the microfluidic device which makes it difficult to change components, i.e., either the microfluidic device or the tubing, if necessary. Thus assembly, repair and maintenance of such devices become labor and time intensive, a particularly undesirable feature when the microfluidic device is used for high throughput screening of samples such as in drug discovery. 
     To avoid problems associated with adhesive bonding, other techniques have been proposed, e.g., press fitting the tubing into a port on the microfluidic device. However, such a connection typically is unsuitable for high-pressure applications such as HPLC. Additionally, pressing the tubing into a port creates high stress loads on the microfluidic device which could lead to fractures of the channels and/or device. 
     Other methods involved introducing liquids into an open port on the microfluidic device with the use of an external delivery system such as a pipette. However, this technique also is undesirable due to the possibility of leaks and spills which may lead to contamination. In addition, the fluid is delivered discretely rather than continuously. Moreover, the use of open pipetting techniques does not permit the use of elevated pressure for fluid delivery such as delivered by a pump, thereby further restricting the applicability of the microfluidic device. 
     Microfluidic devices generally comprise an array of micron-sized wells or reservoirs and interconnecting channels disposed on a substrate. The wells are connected to distribution means for dispensing fluids to and collecting fluids from the array. Connection to the wells is typically by means of a micropipette end. While this serves for benign addition of fluids, this means of fluid addition cannot be used for those applications where the access ports are exposed to a pressure differential or where it is desired to connect capillary tubes to fluid wells. 
     Typically, in microscale devices the microchannels are terminated by ports or wells that provide access to the microchannels. Materials are added to the microchannels through these ports or wells. Access to the ports is typically by means of a micropipette end. While this serves for benign addition fluids it cannot be used for those applications where the access ports are exposed to a pressure differential or adverse environments. 
     Therefore, a need exists for an improved microfluidic connector which is useful with all types of microfluidic devices and which provides an effective, high pressure connector with low fluid dead volume seal. In general, the connector should be able to connect a first set of capillaries to a second set of capillaries. The first set can be external capillaries whereas the second set can be from a microfluidic device. 
     SUMMARY OF THE INVENTION 
     The invention is based in part on the development of an interconnecting device for connecting a plurality of first fluid-bearing conduits to a corresponding plurality of second fluid-bearing conduits thereby providing fluid communication between the first fluid-bearing conduits and the second fluid-bearing conduits. In one embodiment the connector includes: 
     a support plate; 
     a manifold that is positioned on the support plate and that defines a plurality of recess regions within the manifold and having a plurality of channels wherein each channel has a first opening at a lower end of each recess region and a second opening at a lower surface of the manifold, wherein each of the second fluid-bearing conduits is positioned within one of the channels so that the distal end of each second fluid-bearing conduit is positioned in or near the first opening; 
     a ferrule plate that is positioned on the manifold and that defines a plurality of protrusions wherein each protrusion fits into a corresponding recess region of the manifold and the ferrule plate has a plurality of passages with each passage traversing the height of the ferrule plate and through the protrusion and wherein each of the first fluid-bearing conduits is positioned within one of the passages so that the proximal end of each first fluid-bearing conduit abuts the distal end of a corresponding second fluid-bearing conduit; and 
     means for applying an axial force on the ferrule plate to cause the plurality of protrusions of the ferrule plate to contact a corresponding recess region of the manifold. 
     In another embodiment, the connector includes: 
     a support plate; 
     a lower ferrule plate that is positioned on the support plate and that defines a plurality of first protrusions; 
     a manifold that is positioned on the lower ferrule plate and that defines (i) a plurality of first recess regions within the manifold and (ii) a plurality of second recess regions within the manifold, wherein each of the first recess regions is connected to a corresponding second recess region; 
     an upper ferrule plate that is positioned on the manifold and that defines a plurality of second protrusions wherein each second protrusion fits into a corresponding second recess region and wherein the upper ferrule plate has a plurality of second passages with each second passage traversing the height of the upper ferrule plate and through the second protrusions, and wherein each first protrusion of the first ferrule plate fits into a corresponding first recess region so that each first passage of the lower ferrule plate is in communication with a corresponding second passage of the upper ferrule plate and wherein each of the first fluid-bearing conduits is positioned within one of first passages and each of the second fluid-bearing conduits is positioned within one of the second passages so that the proximal end of each first fluid-bearing conduit abuts the distal end of a corresponding second fluid-bearing conduit; and 
     means for applying an axial force on the first and second ferrule plates to cause the plurality first protrusions to contact a corresponding first recess region and to cause the plurality second protrusions to contact a corresponding second recess region. 
     The connector is particularly suited for connecting two sets of capillaries but the connector device can also accommodate ferrules and vials. In use, the connector device can be positioned on the surface of a microscale device so that the ports of the microscale device are in fluid communication with the connector. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a perspective view of a disassembled capillary interconnect device; 
         FIG. 2  is a top view of the device as assembled; 
         FIG. 3  is a cross-sectional view of the device as assembled; 
         FIG. 4  is an enlarged view of portion B of the device from  FIG. 3 . 
         FIG. 5  is a perspective view of a second disassembled capillary to microfluidic interconnect device; 
         FIG. 6  is a top view of the device as assembled; 
         FIG. 7  is a cross-sectional view of the assembled device shown positioned on a substrate; 
         FIG. 8  is an enlarged view of portion A of the device from  FIG. 7 ; 
         FIGS. 9-11  illustrate a one-piece ferrule. 
     
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The invention is directed to techniques for connecting two sets of capillaries together and for connecting capillaries and/or other fluid conduits directly to inlet and/or outlet ports of a microscale device. For convenience, one set will be referred to as the “inlet” capillaries and the other set as the “outlet” capillaries. It is not intended that the structures and dimensions of the inlet and outlet capillaries be different. Preferred capillaries have circular inner diameters that range from 5 microns to 250 microns. Capillaries are available commercially from numerous sources including, for example, PolymicroTechnologies LLC (Phoenix, Ariz.). 
     The inventive interconnecting device is particularly suited for connecting inlet capillaries to outlet capillaries that are in turn connected to a microfluidic substrate or device. The outlet capillaries, for example, may be connected to sources of chemicals, solvents and other fluids that are delivered to and used in the microfluidic device. Alternatively, some or all of the outlet capillaries may be connected to waste containers, other microfluidic devices, and/or other external bodies where fluids are sent. 
     The interconnect device is particularly suited for high pressure operations where the internal, i.e., liquid fluid, pressures within the capillaries are at least 500 psi. It has been demonstrated that the inventive interconnect device will withstand pressures of up to at least 5,000 psi. 
       FIGS. 1-4  illustrate one embodiment of the capillary interconnect device. As depicted in  FIG. 1 , the device  50  includes (i) a lower interconnect stiffening or support plate  62 ; (ii) lower ferrule plate  70 ; (iii) manifold  68 ; (iv) upper ferrule plate  86 ; and (v) top interconnect plate  80 . The support plate  62  and top interconnect plate  80  ensure uniform sealing of device  50  as described further herein. Support plate  62  is provided with threaded wells  52  at both ends that receive screws  82  that hold the various parts of the capillary interconnect device  50  in proper orientation and fasten the parts of the device together. Support plate  62  has a linear array of apertures  56  through which capillaries  90  are inserted as described further herein. Both support plate  62  and top interconnect plate  80  are preferably made of a stiff material such as metal, e.g., stainless steel, or high strength ceramics. 
     Manifold  68  also has a linear array of orifices  72  that traverse the height of the manifold  68 . As further shown in  FIGS. 3 and 4 , each orifice defines an upper recess region  94  and a lower recess region  96 . The recess regions preferably are cavities with conical-shaped exterior surfaces; however, the cavities can have any external shape. The only limitation being that the contour of each interior surface substantially matches that of the exterior surface of the protrusions of the top and lower ferrule plates as described herein. As depicted in  FIG. 4 , the diameter of the recess regions  94 ,  96  at their narrow ends are slightly less than the corresponding initial diameters of the protrusions  74 ,  76 . This angle difference allows compressive forces to be applied onto the tip of each capillary. In a preferred embodiment, the inner surfaces of the recess regions  94 ,  96  define conical-shaped cavities suitably contoured to receive corresponding conical-shaped protrusions  74  of upper ferrule plate  86  and protrusions  76  of and lower ferrule plate  70 , respectively. As shown in  FIG. 4 , recess regions  94 ,  96  are connected by a narrow gap  98 . The height of the gap preferably ranges from 50 μm to 150 μm. Manifold  68  is preferably made of a rigid polymer material such as polyetherimide (PEI) sold under the tradename ULTEM by General Electric Co., polyether ether ketone, and acetal (e.g., DELRIN). 
     As shown in  FIGS. 1 ,  3 , and  4 , upper ferrule plate  86 , which mates with manifold  68 , also has a linear array of apertures  78  on its upper surface with each aperture defining a passage which traverses the height of the upper ferrule plate. (A capillary  92  is positioned in each passage.) The upper ferrule plate  86  has an underside with an array of conical-shaped protrusions  74  projecting from the underside such that each passage (shown in  FIG. 4  as being occupied by capillary  92 ) terminates at the end of a conical-shaped protrusion  74 . 
     The lower ferrule plate  70  is essentially identical to the upper ferrule plate  86  but its position is reversed. As shown in  FIGS. 1 ,  3 , and  4  lower ferrule plate  70 , which mates with manifold  68 , has a linear array of apertures on its lower surface with each aperture defining a passage which traverses the height of the lower ferrule plate  70 . (A capillary  90  is positioned in each passage.) The lower ferrule plate  70  has a topside with an array of conical-shaped protrusions  76  projecting there from such that each passage terminates at the end of a conical-shaped protrusion  76 . It is preferred that the upper and lower ferrule plates  86 ,  70  be made of material that is both deformable under mechanical compression and that is easy to machine or mold. 
     While this embodiment of the connector device has been illustrated using inlet and outlet capillaries without ferrules, the capillaries can also be attached preferably using one-piece ferrules. Furthermore, vials can also be employed and the connector device can be attached directly to a microscale device as further described herein. 
     Mechanical compression is applied to upper and lower ferrule plates  86 ,  70  by means of a rigid, top interconnect plate  80  which has an array of holes  84  which are aligned to the array of apertures of the upper and lower ferrule plates  86 ,  70 . Threaded walls  81  are drilled through the interconnect to provide passage for screws  82  that serve to exert mechanical compression on the assembly. 
     In operation, to connect a set of inlet capillaries  90  to a corresponding set of outlet capillaries  92 , the distal ends of the internal capillaries are inserted through the passages of the lower ferrule plate  70  and the channels of the manifold  68  until the tips of the capillaries reach the lower portion of gap  98 . Similarly, a set of outlet capillaries are inserted through the holes  84  of the top interconnect plate and through the passage of the upper ferrule plate  86  until their tips reach the upper portion of gap  98 . In this fashion, each outlet capillary is aligned with a corresponding inlet capillary. 
     The screws  82  are then tightened to assemble the interconnect device. As compressive forces are applied, the conical-shaped protrusions of the upper ferrule plate  86 , which are preferably made of a chemically inert material that readily deforms under mechanical compression, are inserted into the mating cavities or channels  72  of manifold  68 . As a result, the bottom surface of each conical-shaped body deforms around the outer surface of each capillary thereby supporting and securing the outlet capillary. Deformation of the conical-shaped bodies also provides a fluid tight seal. Similarly, the conical-shaped bodies of the lower ferrule plate  70 , which are also preferably made of a chemically inert material that readily deforms under mechanical compression, are inserted into the mating cavities or channels of manifold  68 . High pressure fluids can now flow through the two sets of capillaries. 
     The capillary interconnect device can also be employed to connect external capillaries and/or other fluid conduits directly to the inlet and/or outlet ports of a microscale device as illustrated in  FIGS. 5-8 . As depicted in  FIG. 5 , the device  10  includes (i) a lower interconnect stiffening or support plate  12 ; (ii) manifold  18 ; (iii) ferrule plate  24 ; and (iv) top interconnect plate  30 . The support plate  12  and top interconnect plate  30  ensure uniform sealing of device  10  as described further herein. Support plate  12  is provided with threaded wells  36  at both ends that receive screws  32  that hold the various parts of the capillary interconnect device  10  in proper orientation and that fasten the parts of the device together. Support plate  12  has an internal cavity or slot  16  that acts as a receptacle for a lower portion  20  of manifold  18 . Both support plate  12  and top interconnect plate  30  are preferably made of metal, e.g., stainless steel, or high strength ceramics. 
     As further shown in  FIGS. 7 and 8 , the lower portion  20  of manifold  18  fits into slot  16  of support plate  12  so that the lower planar surface of manifold  18  rests on the surface of substrate  14 , e.g., microfluidic chip. The substrate  14  includes a number of fluid channels  15  with inlet and/or outlet ports on the substrate surface. The manifold  18  is preferably made of a polymer material that is rigid and that will adhere to glass which is the material of many conventional microscale devices. A preferred material is a polyetherimide sold under the tradename ULTEM by General Electric Co. Preferably manifold  18  is bonded to substrate  14  with a suitable adhesive. 
     As shown in  FIGS. 5 and 8 , the top surface of manifold  18  has a linear array with recess regions  22  which are preferably cavities with conical-shaped, i.e., tapered, exterior surfaces  46 . It is understood that the cavities can have any shape, the only limitation being that the contour of each inner surface  48  substantially matches that of the exterior surfaces  46  of the protrusions from the ferrule plate as described herein. Preferably the two surface angles are not the same to permit enhanced deformation at the tip of the ferrule plate protrusions. As further shown in  FIGS. 7 and 8 , each conical-shaped cavity  22  is connected to channel sections  42 ,  44  that run to the bottom surface of the manifold. In this case, the diameter of the upper portion  44  of the channel is slightly larger than the remaining lower section  42 . 
     As shown in  FIGS. 5 ,  7 , and  8 , ferrule plate  24 , which mates with manifold  18 , also has a linear array of apertures  28  on its upper surface with each aperture defining passages  40  which traverse the height of the ferrule plate  24 . The ferrule plate  24  has an underside with an array of conical-shaped protrusions  26  projecting from the underside such that each passage  40  terminates at the end of a protrusion  26 . It is preferred that the ferrule plate  24  be made of material that is both deformable under mechanical compression and that is easy to machine or mold. Suitable materials include, for example, polyether ether ketone, high density polyethylene, or polyamide. A preferred material is a solid, abrasion resistant, self-lubricating, polyamide available under the trade name VESPEL from Du Pont Corporation. 
     Mechanical compression is applied to ferrule plate  24  by means of a rigid, top interconnect plate  30  which has an array of holes  34  that are aligned to apertures  28  of ferrule plate  24 . Threaded walls  31  are drilled through the interconnect plate to provide passage for screws  32  that serve to exert mechanical compression on the assembly. 
     As illustrated in  FIG. 7 , the interconnect device  10  can be employed to deliver and/or remove fluids from a microscale device  14 . The device  10  as assembled is preferably attached with adhesive on the upper surface of the microscale device  14  which has inlet and outlet ports that are connected to internal channels  15 . The dimensions and spacing of the ports match those of passages  42  such that the lower surface of device  10  can be attached, e.g., bonded with epoxy, directly onto the upper surface of the microscale device so that each passage  42  of device  10  will be aligned with an inlet and/or outlet port of channel  15  of microscale device  10 . In this fashion, no internal capillary is needed to connect device  10  to microscale device  14 , that is, passages  42  are in direct fluid communication with channels  15 . Capillary  91  is depicted as being positioned within one of the passages  42 . 
     In operation, in one embodiment, a set of external capillaries are connected by inserting their proximal ends through holes  34  of the top interconnect plate  30  and through apertures  28  of the ferrule plate  24  until their tips bottom out at the upper channel section  44  of the manifold. In this fashion, each external capillary serves as a source of fluid to the microscale device or as a conduit through which fluid is removed from the microscale device. As the screws  32  are tightened and the compressive forces applied as shown in  FIG. 5 , the conical-shaped protrusions  26  of ferrule plate  24 , which are preferably made of a chemically inert material that readily deforms under mechanical compression, are inserted into the mating conical-shaped cavities  22  of manifold  18 . As a result, as shown in  FIG. 8 , the bottom surface  46  of each conical-shaped protrusion deforms around the outer surface  48  of the conical-shaped cavities. Deformation of the conical-shaped protrusions also provides a fluid tight seal around the capillary to the microscale device. 
       FIGS. 10 and 11  also depict the threaded, one-piece ferrule. The ferrule includes an adapter body  112  having an hexagonal nut  114  on one side and an elongated member  110 ,  118  on the other side. End portion  118  of the elongated member is tapered. The ferrule has internal bore  120 ,  122  that runs the length of the ferrule from inlet  128  to outlet  116 . Preferably, as shown in  FIG. 11 , the proximal portion  122  of the bore is broader to facilitate insertion of a capillary tube into the wider distal portion  120  of the bore. The wall of the bore at the tapered end will collapse directly against the tube as compressive forces are created as the ferrule is screwed into the threaded conical-shaped cavity. This effectively prevents the capillary tube from extruding during high pressure operations. 
     Each ferrule is machined from a block of material to fabricate a single, integral piece ferrule. The bore is formed using conventional drills and threads are machined preferably on the exterior of the non-taper portion  110  of the elongated member. When using the ferrule, no flange is needed. In addition, a mating sleeve is not needed since the bore will collapse against the tube under compressive force. By “mating sleeve” is meant an extra tube that is inserted into the bore of the ferrule before the capillary tube that will be transferring a fluid of interest is inserted through the bore of the mating sleeve. Mating sleeves having an outer diameter that matches the inner diameter of prior art ferrules are used quite often but are not needed with the inventive ferrule. Machining permits exact tolerance to be maintained to improve fittings function. Because the ferrules are fabricated by machining, that is, they are not made by molding, a wide range of materials, including plastics, ceramics, and metals, for example, can be used depending on the expected operating conditions, e.g., temperature, pressure, and type of fluids the ferrule will be exposed to. The ferrules are reusable and can be finger-tightened to provide a seal that can withstand a minimum pressure of 5,000 psi. 
     The ferrule is particularly suited for high pressure operations to connect capillary tubes in microfluidic applications and therefore the ferrule is dimensioned accordingly. In this regard, referring to the ferrule shown in  FIG. 11 , the diameter of the distal portion  120  of the bore is preferably 0.0145 in. (0.368 mm) to 0.015 in. (0.38 mm) and the diameter of the proximal portion  122  of the bore is typically 0.018 in. (0.46 mm) to 0.020 in. (0.51 mm). 
     While the embodiments illustrated show a plurality of capillary interconnections oriented linearly the device can be used for a single capillary interconnection and could be equally effective in a circular orientation to interconnect capillary bundles. Moreover, the interconnect device can be used to connect at least two substrates together. 
     The reusable interconnecting device can be employed to provide fluid type communication between two sets of capillaries regardless of what the capillaries are ultimately connected. Typically, at least one or more of the capillaries from one set will be connected to a substrate which refers to any microfluidic device that has an integrated network of microfluidic channels disposed therein. The particular design or configuration of the internal structure of the substrate is not critical. Such substrates are also referred as microfluidic or microscale wafers or chips. 
     The substrate includes microfluidic channels, e.g., sealed enclosed groove, depression, and tube, which are adapted to handle small volumes of fluid. Typically, the channel is a tube, channel or conduit having at least one subsection with at least one cross-sectional dimension of between about 0.1 microns and 500 microns, and typically less than 100 microns. 
     The substrate is preferably fabricated from glass, quartz, silicon or plastic by conventional techniques including LIGA (an acronym for the German for lithography, electroplating, and molding), deep x-ray lithography, silicon surface micromachining and lithography, electric discharge machining, and direct laser additive fabrication. In addition, commercially available substrates can be modified with appropriate dimensioned inlet and/or outlet ports as further described herein. The substrate may include reaction cells, reservoirs, and other structures that are interconnected by a network of microchannels and a series of micropumps. Such substrates are further described in U.S. Pat. No. 5,846,396 to Zanzucchi, et al. which is incorporated herein. 
     Conventional mechanical pumps can be employed to transport liquid fluids through the capillaries although a preferred method employs a high pressure hydraulic system that has no moving parts for converting electric potential to hydraulic force and for manipulating fluids which are described in U.S. Pat. Nos. 6,013,164 to Paul, et al., 6,019,882 to Paul, et al., 6,224,728 to Obomy, et al., and 6,277,257 to Paul, et al., and 6,290,909 to Paul, et al., which are incorporated herein by reference. 
     Although only preferred embodiments of the invention are specifically disclosed and described above, it will be appreciated that many modifications and variations of the present invention are possible in light of the above teachings and within the purview of the appended claims without departing from the spirit and intended scope of the invention.