JP4439916B2 - Interface members and holders for microfluidic array devices - Google Patents

Description

(Cross-reference of related applications)
This application claims the benefit of US Patent Application Publication No. 10 / 305,045 (filed November 26, 2002). This patent application is a partially pending application of U.S. Patent Application Publication No. 10 / 174,343 (filed on June 17, 2002) and U.S. Patent Application Publication No. 10 / 061,001 ( This is a partially pending application filed on July 30, 2002). This US Patent Application Publication No. 10 / 061,001 claims the benefit of US Patent Application Publication No. 60 / 341,069 (filed December 19, 2001). All of these documents are incorporated herein by reference in their entirety.
(Technical field)
The present invention relates to microfluidic devices, and more particularly to microfluidic array devices. The microfluidic array device can be used to deliver one or more samples through one or more nozzles formed as part of the microfluidic array device. Exemplary interface members and holders for holding the microfluidic device when the microfluidic device is used in a given application are also disclosed, along with exemplary uses for the microfluidic array device. For example, microfluidic array devices are suitable for operations designed for lab-on-a-chip functions including analysis of components in sample fluids by optical spectroscopy, mass spectrometry, and the like.

  There is growing interest in the development and manufacture of microscale fluid systems for obtaining chemical and biochemical information, and as a result of this attempt, microfluidics has worked on low-cost and versatile devices. For example, to name a few, it is considered to be a realization technology that provides for combination chemistry for drug lead discovery and large-scale protein profiling. In general, a microfluidic device (often referred to as a lab-on-a-chip device) is a flat device with one or more micron-sized channels formed therein, a reservoir, a valve, A flow switch or the like can be included. Microfluidic features are designed to perform complex laboratory functions such as DNA sequencing.

  Without the use of microfluidic devices, the aforementioned processes and the like are performed in a very time intensive and therefore costly manner. For example, in the biotechnology and pharmaceutical industries, large-scale protein profiling is usually hard work but is widespread. One particular application of microfluidic devices is to provide a microfluidic channel that represents a means to separate analytes in a mixture using techniques such as capillary electrophoresis and liquid chromatography.

  Traditionally, microfluidic devices are fabricated from substantially flat substrates using microfabrication techniques borrowed from the electronics industry such as photolithography, chemical etching, laser ablation techniques. When the microfluidic device is produced in this way, the microfluidic channel formed is placed parallel to the surface of one flat surface of the substrate, and the second flat substrate is bonded to the flat substrate containing the channel. To seal the channel. Techniques for detecting materials such as analytes that are placed in microfluidic channels are often primarily optical techniques. Traditionally, to transport fluid within a microfluidic device, liquid and particle electroosmosis, electrokinetics and / or pressure driven operations are used as a means for fluidly transporting such materials. Is needed.

  Although it is possible to produce a microfluidic structure with layered microfluidic channels by stacking multiple layers of a flat substrate, a common detection technique (optical based detection technique) Therefore, there is a limit to the practicality of manufacturing such a structure. This is because processing multiple layers of a flat substrate with multiple microfluidic separation channels in parallel is a reality because each microfluidic separation channel requires its own light source and detector. Because it is not the target.

  One detection technique that is rapidly becoming the optimal detection technique in the biotechnology and pharmaceutical industries is mass spectrometry (MS). There is more chemical information about the material under test (eg, analyte) obtained by mass spectrometry than with any other single detection technique. For example, even the molecular weight and chemical composition of analytes from small drug candidate molecules to large protein molecules can be successfully analyzed using mass spectrometry (MS) and related techniques referred to as MS-MS. In MS-MS, the molecular weight is obtained by ionizing and analyzing molecules in the first stage of the mass spectrometer. The same molecular ion (referred to as the “parent”) is then broken up in the mass spectrometer to produce “daughter” ions. Further analysis of the “daughter” ion yields the chemical component of the parent molecule.

  Although some progress has been made to interface microfluidic devices with mass spectrometers, there are still some drawbacks to overcome to make this interface process more practical. For example, one technique that has been considered involves drilling small holes. This hole is large enough to accommodate a glass or quartz capillary within the end of the microfluidic channel formed by the glass substrate, and the glass or quartz capillary is inserted into the drilled hole to allow the electrospray It functions as a nozzle for ionization. This approach is cumbersome and is not practical for high throughput operations where a large number of such holes must be drilled sequentially into the substrate.

  In another disclosed technique, a protrusion called an “electric pipette” extends from the edge of a substantially flat substrate. The microfluidic channel in this extended region is formed by two flat substrates, as is the case with the microfluidic channel formed in the rest of the microfluidic device. The outer diameter of the tip structure includes a thickness equal to the thickness of the two flat substrates. It is also disclosed to produce an array of nozzles using micromachining techniques such as deep ion reactive etching on a silicon wafer. However, when a silicon wafer is used as a substrate, the ability to operate each nozzle separately is severely limited because of the potential for breakdown due to the high voltage applied to the nozzles for generating electrical spray conditions. Also, the volume behind the nozzle produced by deep ion reactive etching is extremely difficult to access by means of conventional liquid handling equipment. It is also very difficult to integrate this silicon-based nozzle array with a microfluidic device, usually made of glass or polymer. The cost of making nozzles on silicon is also very high.

  Injection molding is being considered as a process for forming microfluidic devices. However, many limitations exist in connection with the above discussion of injection moldable microfluidic devices as well. For example, when forming microfluidic features using, for example, an injection molding process, it has been discussed that there are limitations on which size dimensions can be formed. Prior to the Applicant, it was not recognized and understood that microfluidic devices having microfluidic features with dimensions of less than 100 μm could be formed using an injection molding process. Therefore, the use of injection molding as a manufacturing process has been limited. This is because in many microfluidic applications, microfluidic features (eg, channels) possessed by microfluidic devices are required to be less than 100 μm in size, and more particularly less than 50 μm.

  Thus, microfluidic devices, particularly microfluidic array devices incorporating nozzles, that overcome the disadvantages of conventional microfluidic devices, and more particularly the disadvantages associated with the fabrication techniques of these devices and the use of such devices, are disclosed. It is desirable to provide.

(wrap up)
The present application relates generally to microfluidic devices. According to one aspect, a microfluidic device is provided and includes a first surface and an opposing second surface. At least one channel is formed in the body such that the channel extends from the first surface to the opposing second surface, the channel having an open reservoir portion formed in the first surface. The microfluidic device further includes at least one nozzle disposed along the second surface. The nozzles are in fluid communication with one channel such that each channel terminates in a nozzle opening formed as part of the nozzle tip. Unlike conventional microfluidic devices, a typical microfluidic device has one or more channels that open at each end to form a second surface in which a first surface and a nozzle are formed. It is formed substantially perpendicular to both the surface and the surface.

  According to another aspect, the nozzle is conical and the channel extends through the nozzle and terminates at the nozzle opening. In one exemplary embodiment, the outer diameter of the nozzle opening is 100 μm or less, preferably 50 μm or less, more preferably 20 μm or less. The outer diameter of the nozzle is less than about 150 μm, preferably about 100 μm or less, more preferably 50 μm or less, as measured at the tip. In another aspect of the present application, the microfluidic nozzle array device is formed by an injection molding process that allows the above dimensions of the microfluidic nozzle array device.

  In yet another embodiment, a member is provided for holding at least one microfluidic device and providing an interface between at least one microfluidic device and a second device. At least one microfluidic device has a plurality of reservoirs formed therein, the member includes an upper surface and a lower surface, and a plurality of open well members formed therein. Each well member is defined by a well wall and includes a first end and an opposing second end, the second end frictionally mating with at least one microfluidic device to at least a portion of the open well member And the microfluidic device reservoir are configured and dimensioned to be aligned with each other. Thus, the member not only corresponds to a means for removably holding at least one microfluidic device, but also corresponds to a means for increasing the effective volume of the reservoir of the microfluidic device. This is because the open well member that is aligned with the reservoir receives the sample that flows into the reservoir and eventually into the nozzle.

  Additionally and in accordance with other exemplary embodiments of the present application, an apparatus is provided that interfaces with a mass spectrometer for performing nanospray applications. The apparatus includes a microfluidic device having a body that includes a first surface and an opposing second surface. At least one channel is formed within the body and extends through the body from the first surface to the second surface, the channel extending along the second surface and a reservoir portion that opens at the first surface. And at least one nozzle. The nozzle is in fluid communication with the channel such that one end of the channel terminates in a nozzle opening formed as part of the tip of the nozzle. The apparatus is a holder having a frame disposed around the outer periphery of the microfluidic device so that the microfluidic device is securely held, and first and second holding members. The holding members are spaced apart and the frame can be placed between these members and held in place by these members, in which the sample is sprayed into the mass spectrometer inlet. A holder in which at least one nozzle for positioning is positioned.

  In other embodiments, the shield is coupled to at least one of the frame and the holder such that one side of the shield faces the second surface of the microfluidic device. At least one aperture is formed within the shield and the aperture is axially aligned with the tip of at least one nozzle. The shield is used as a means to prevent or control the formation of an electric field on the polymer nozzle array device. If the electrostatic field is not ejected from the insulating polymer surface during spraying, the stray electric field that accumulates on the insulating surface prevents the ions being sprayed from passing to the entrance of the analysis. This situation is overcome by the aforementioned shield.

  These and other features and advantages of the exemplary embodiments disclosed herein will become readily apparent from the accompanying drawings in conjunction with the following detailed description. In the drawings, like reference numbers indicate like elements.

  The foregoing and other features of the exemplary embodiments will become more readily apparent from the following detailed description and drawings that illustrate the embodiments. The drawings are not necessarily drawn to show an accurate appearance and are not necessarily proportional.

  Referring initially to FIGS. 1-2, an exemplary microfluidic device 10 according to one embodiment is illustrated. The microfluidic device 10 has a substrate body 20 (described in detail later) formed from a polymer material and at least one microfluidic channel 30 formed in the substrate body 20. More specifically, the substrate body 20 has a first surface 22 and an opposing second surface 24, and a microfluidic channel 30 is formed between the first and second surfaces 22, 24. The microfluidic channel 30 extends over the full thickness of the substrate body 20. Thus, the microfluidic channel 30 is open at both the first end 32 at the first surface 22 and the second end 34 at the second surface 24. The second end 34 of the microfluidic channel 30 is formed in a protrusion 50 formed on the second surface 24 of the substrate body 20. According to one exemplary embodiment, the protrusion 50 has a tapered shape (inner taper), is formed with a generally conical structure, and the open second end 34 is preferably conical. It is designed to be formed at the apex. The tapered protrusion 50 functions as a nozzle that delivers a sample (ie, liquid) to be filled into the microfluidic device 10.

  In contrast to conventional microfluidic devices, the microfluidic channel 30 is formed in the substrate body 20 because the microfluidic channel 30 is formed vertically in the substrate body 20 where the microfluidic channel 30 is preferably formed. It will be appreciated that the first and second surfaces 22, 24 are substantially perpendicular. As illustrated, a predetermined number of microfluidic channels 30 and nozzles 50 can be formed in one substrate body 20. The placement of the microfluidic channel 30 can be done according to any number of different patterns. For example, as illustrated in the exemplary embodiment of FIGS. 1 and 2 showing a preferred arrangement, a plurality of microfluidic channels / nozzles are in a regular array having a spacing that is the same as or similar to the spacing of the microtiter plates. Be placed. For example, if 96 microfluidic channels / nozzles are required, the 96 microfluidic channels / nozzles are arranged in an 8 × 12 grid with a spacing of about 9 mm between each microfluidic channel / nozzle structure. To do. In the case of a 384 microtiter array, the microfluidic channels / nozzles are arranged in a 16 × 24 grid with a spacing of about 4.5 mm. Although not for full scaling, FIG. 2 generally illustrates a cross section of a microfluidic channel / nozzle array with a spacing of about 4.5 mm.

  According to this exemplary embodiment, each nozzle 50 is made such that its dimensions are measured in microns. In FIG. 2, a particular configuration of nozzle 50 and microfluidic channel 30 is best shown. As illustrated, the first end 32 of the microfluidic channel 30 takes the form of a reservoir 60 (ie, an annular cavity) that tapers inwardly to the intermediate channel portion 36. The intermediate channel portion 36 is also tapered, and is tapered inwardly toward the second end 34 and the nozzle 50 formed on the second surface 24 of the substrate body 20. Thus, the dimensions of the microfluidic channel 30 are maximum at the first end where the reservoir is formed and minimum at the tip portion 52 of the nozzle 50 at the second end 34. According to one exemplary embodiment, the open second end 34 of the microfluidic channel 30 formed in the nozzle 50 has an inner diameter of about 100 μm or less, preferably 50 μm or less, more preferably 20 μm or less. Yes, the outer diameter of the nozzle is less than about 150 μm, preferably about 100 μm or less, more preferably about 50 μm or less as measured at its tip. The inner diameter of the microfluidic channel 30 gradually expands in the direction away from the nozzle 50 to about several hundred μm, the microfluidic channel 30 traverses through the thickness of the substrate body 20, and finally the microfluidic channel 30 is about 1 mm. At a first end 32 to define a reservoir. The length of the microfluidic channel 30 can be adjusted for a given application, depending on many factors such as the desired volume of the reservoir defined by the first end 32 and the thickness of the substrate body 20. . According to one exemplary embodiment, the microfluidic channel 30 is about 3 mm or more in length. However, it is understood that the dimensions described above are listed only to illustrate one exemplary embodiment, and that the microfluidic device 10 can be made to other dimensions.

The volume of the reservoir 60 must be such that it can accommodate the amount of sample material normally used in the application for which the microfluidic device is designed. For example, in the case of mass spectrometer analysis using an electrospray, the sample volume used is from sub-microliters up to 10 microliters. As will be described in detail later, after the sample material is contained in the reservoir 60, it is transported through the microfluidic channel 30 to the nozzle 50, where it is finally released through the open second end 34. The The outer diameter of the protruding nozzle 50 also increases correspondingly in the direction away from its tip portion 52. By forming the reservoir 60 or input port on the first surface 22 opposite the second surface 24 on which the nozzle 50 is formed, the sample can be easily fed into the microfluidic channel 30. This is made possible by injecting the sample into one or more reservoirs 50 and then transporting the sample through the associated microfluidic channel 30 using techniques detailed below. Turning to FIG. 3, the microfluidic device 10 can be fabricated such that it finds particular utility as an electrospray ionization means for analytes for mass spectrometer analysis. Electrical spraying is performed by applying a voltage to the nozzle 50 so that the liquid and analyte (“sample”) exit to a high electric field. For this particular application, the microfluidic device 10 includes a conductive region 70 formed on at least a portion of the nozzle 50, optionally the conductive region can extend onto the second surface 24. it can. For example, the area around the nozzle 50 that maximizes the end of each nozzle 50 is metallized by vapor deposition techniques, printing techniques, or other suitable techniques known in the art to form the conductive areas 70. In the illustrated embodiment, since the nozzle 50 is conical, the conductive region 70 is in the form of a ring-shaped metal layer with the nozzle 50 in the center. The thickness of the conductive region 70 varies depending on the exact application. However, the thickness of the conductive region 70 is such that when a voltage is applied to the conductive region 70, the sample material (i.e., liquid) in the microfluidic channel evaporates, and thus an electrical spray or nanospray application, such as a mass spectrometer. It must be sufficient to be used for electrospray ionization of analytes. In this example, the microfluidic device 10 is a nanosprayable electrical spray interface that can be disposable at low cost. This device can be made to accept multiple sample inputs and multiplex several separation instruments into a single mass spectrometer.

  Each conductive region 70 formed around the nozzle 50 is connected to one or more electrical contacts 80 formed on one edge of the substrate body 20. More specifically, the electrical contacts 80 are preferably in the form of conductive pads (ie, metallized tabs) formed on the second surface 24 of the substrate body 20. FIG. 3 illustrates one exemplary method of electrically connecting the conductive region 70 to the electrical contact 80. In this typical arrangement, one conductive region 70 is electrically connected to one electrical contact 80 via an electrical path 90. Electrical path 90 is merely an electrical path between conductive region 70 and electrical contact 80 and is thus formed from a conductive material (eg, metal). For example, the electrical path 90 can be in the form of a thin conductive coating. By reducing the outer diameter of the tip portion 52 of the nozzle 50 (for example, to about 50 μm to 80 μm), the voltage necessary for generating the spray is lowered. According to one exemplary embodiment, the voltage used to form the spray is about 5-6 KV for a tip portion 52 having an outer diameter of about 50-80 μm. Although larger sized outer diameters can be used, it is understood that this requires that a larger voltage be applied to the nozzle 50 in order to form a spray.

  It is understood that the plurality of conductive regions 70 can be electrically attached to one electrical contact 80 by using separate electrical paths 90 or by using an electrical path network or a complete metal coating. However, in this embodiment, when a voltage is applied to one electrical contact 80, a voltage is applied to each conductive region 70 that is electrically connected to one electrical contact 80. Thus, in this particular embodiment, no voltage can be selectively applied to individual nozzles 50.

  4-5, an exemplary microfluidic device 100 according to a second embodiment is illustrated. The microfluidic device 100 is similar in some respects to the microfluidic device 10 of FIGS. The microfluidic device 100 includes a substrate body 110. The substrate body 110 is made of a polymer material, and includes a first surface 120 and an opposing second surface 130. Unlike the embodiment illustrated in FIGS. 1-3, the first and second surfaces 120, 130 are not substantially flat surfaces, but rather a number of recesses and protrusions are formed in each surface 120, 130. In reality, it is non-flat.

  Inside the microfluidic device 100, at least one microfluidic channel 140 is formed between the first surface 120 and the second surface 130. The microfluidic channel 140 extends completely from the first surface 120 to the second surface 130 through the thickness of the substrate body 110. Thus, the microfluidic channel 140 is open at both the first end 142 on the first surface 120 and the second end 144 on the second surface 130. The first surface 120 includes a first peripheral wall 122 that extends around the outer periphery of the microfluidic device 100 at the first surface 120. In an exemplary embodiment, the microfluidic device 100 is generally rectangular. However, this is only one typical shape for the microfluidic device 100, and the microfluidic device 100 can assume any number of different shapes. One or more reservoir walls 124 are formed within the boundary of the first peripheral wall 122, and the number of reservoir walls 124 is equal to the number of microfluidic channels 140 formed in the substrate body 110. . Each reservoir wall 124 partially defines a reservoir 160 designed to receive sample material, and therefore reservoir wall 124 also defines a first end 142 of microfluidic channel 140. Both the first peripheral wall 122 and the one or more reservoir walls 124 extend above the generally flat surface 126 (ie, floor) of the first surface 120 in this embodiment. Thus, a substantial portion of the reservoir 160 defined at the first end 142 of the microfluidic device 140 is formed above the flat surface 126.

  The second end 144 of the microfluidic channel 140 is formed at a protrusion 170 that extends outward from the second surface 130. As in the previous embodiments, the protrusion 170 is preferably tapered (inner taper), has a generally conical structure, and the open second end 144 is conical. It is formed at the apex. As a result, the tapered protrusion 170 functions as a nozzle that can discharge the sample filled in the microfluidic channel 140 (eg, in the reservoir 160). Thus, nozzle 170 is part of the microfluidic channel structure. This is because the microfluidic channel 140 is formed through the microfluidic channel structure and terminates the nozzle opening.

  Second surface 130 is also not substantially flat, but rather includes a second peripheral wall 132 that extends at least partially along the periphery of second surface 130. The second surface 130 does not include a substantially flat floor surface 134. One or more nozzle base portions 180 are formed between the second peripheral walls 132, the number of nozzle base portions 180 being equal to the number of microfluidic channels 14. The nozzle base portion 180 is integrally formed with the floor surface 134 and extends outward from the floor surface 134, and in the illustrated embodiment, each nozzle base portion 180 has a generally annular shape. However, the shape of the nozzle base portion is not limited to an annular shape and can instead have any number of shapes. For example, a conical shape, a tapered shape, or some other regular or irregular shape. According to one embodiment, the plane that includes the upper edge of the second peripheral wall 132 generally intersects the interface between the nozzle base portion 180 and the nozzle 170. Accordingly, the nozzle 170 extends beyond the upper edge of the second peripheral wall 132. According to one embodiment, the diameter of the reservoir 160 is approximately equal to the outer diameter of the nozzle base portion 180. Accordingly, the outer diameter of reservoir wall 124 is greater than the outer diameter of nozzle base portion 180.

  In FIG. 5, a particular configuration of nozzle 170 and microfluidic channel 140 is best shown. As illustrated, the first end 142 of the microfluidic channel 140 is in the form of a reservoir 160. The distal end of the reservoir 160 has an inwardly tapered configuration leading to the intermediate channel portion 146. A substantial length of the intermediate channel portion 146 is formed in the nozzle base portion 180. The intermediate channel portion 146 also has a tapered configuration and tapers inwardly toward the nozzle 170 defined at the second end 144 of the microfluidic channel 140. Thus, the dimensions of the microfluidic channel 140 are largest at the first end 142 and smallest at the tip portion 172 of the nozzle 170. In one embodiment, the microfluidic features formed in the device 100 starting at the reservoir 160 and ending at the nozzle 170 have a generally cylindrical shape along its length. According to one exemplary embodiment, the open second end 144 of the microfluidic channel 140 formed in the tip portion 172 has an inner diameter of 100 μm or less, preferably 50 μm or less, more preferably 20 μm, The outer diameter of the nozzle is less than about 150 μm, preferably about 100 μm or less, more preferably about 50 μm or less, as measured at its tip. The inner diameter of the microfluidic channel 140 varies along its length due to its tapered configuration. For example, the inner diameter of the microfluidic channel 140 gradually expands in the direction away from the nozzle 170 to about several hundred μm, and the microfluidic channel 140 traverses through the thickness of the substrate body 110 and finally the microfluidic channel 140 is , About 1.5 mm in diameter to define the reservoir 160. The length of the microfluidic channel 140 can be adjusted to take into account the detailed configuration of the microfluidic device 100 and possible applications of the device 100. In one example, the length of the microfluidic channel 140 is about 3 mm. However, this varies depending on the thickness of the device 100, the amount of sample to be loaded into the device, and the like.

  As with the first embodiment, since the microfluidic channel 140 is formed substantially perpendicular to both the first and second surfaces 120, 130, the microfluidic channel 140 is a substrate. The body 110 is formed substantially vertically. The nozzle 170 extends beyond the plane that includes the trailing edge of the second peripheral wall 132, while the end of the reservoir wall 124 is preferably in the same plane that includes the trailing edge of the first peripheral wall 122. . With this orientation, a cover (eg, a thin polymer cover sheet) or seal member is placed across the trailing edge of the first peripheral wall 122 and the distal end of the reservoir wall 124 to provide a sample in the reservoir 160. The material can be effectively sealed. This will be described later.

  It will be appreciated that one of the advantages of device 100 is that it is formed as a single piece configuration, as opposed to a conventional device where multiple layers are bonded together. In such conventional devices, a microfluidic channel is closed by joining one layer onto another. In other words, two separate layers are required to define a complete channel. Since the device 100 is injection molded, a separate bonding layer is not required.

  It will be understood that the present configuration illustrated here with reference to FIGS. 1-5 is merely exemplary in nature and is only intended to convey exemplary embodiments. Depending on a number of different considerations, such as manufacturing considerations, various changes can be made to the microfluidic device. For example, the nozzle structure need not necessarily be conical. However, for ease of manufacture, a conical shape or the like is generally preferred.

  According to other aspects of this application, various manufacturing methods for manufacturing the microfluidic array devices illustrated in FIGS. 1-5 are disclosed herein. Generally speaking, the exemplary manufacturing process disclosed herein can produce microfluidic nozzle array devices with microscale nozzle dimensions (eg, nozzle tip opening diameter of 100 μm or less). , Preferably 50 μm or less, more preferably 20 μm or less, and the outer diameter of the nozzle is less than about 150 μm, preferably about 100 μm or less, and more preferably about 50 μm or less, as measured at its tip. The microfluidic array device is particularly suitable for an inexpensive manufacturing method. More specifically, the microfluidic array device of this application can be manufactured by injection molding a suitable thermoplastic material using conventional injection molding techniques. Suitable thermoplastics include polycyclic olefin polyethylene copolymers, polymethyl methacrylate (PMMA), polycarbonate, polyalkanes, polyacrylate polybutanol copolymers, polystyrene, and polyionomers such as Surlyn ™ And Bynel (trademark). Polycyclic olefin polyethylene copolymers are particularly suitable for use in injection molding processes. Various grades of such polymers are commercially available from Ticona under the trade name Topas ™ (which is a polyethylene polycyclic olefin copolymer). In addition, polybutyl terephthalate (PBT) can be used, as well as polyamides such as various grades of nylon (nylon 6-6, nylon, 6 nylon 6-12, etc.); polyoxymethylene (POM), and others As other resins, those having a melt viscosity comparable to PBT and other properties similar to other suitable polymers disclosed herein can be used. In general, polymers suitable for use in the present injection molding process include thermoplastic polymers with relatively low melt viscosities, and such polymers preferably have a high chemical purity (preferably the polymer is , Particulate additives do not exceed a few percent and are chemically inert). Other suitable polymers include thermoplastics blended with a lubricant (eg, a liquid crystalline polymer). Lubricants are added to facilitate flow, and therefore this additive functions as a processing aid. Other liquid crystalline polymers including polymers such as Zenite ™ (DuPont) can also be used. Also suitable are polymers (both commercial and non-commercial) with high chemical purity, high chemical resistance and thermal stability. For some applications, injection moldable elastomers may also be suitable.

  In order to produce the microfluidic array device using injection molding technology, a mold or mold insert must first be made. The following description of the mold is only typical for one type of mold configuration that has been oversimplified for that configuration to illustrate some details of the overall molding process. However, those skilled in the art can readily vary the mold structure and are determined by the desired configuration of the microfluidic device, more specifically, microfluidics based on the shape, dimensions, and characteristics of the microfluidic channel. It is understood that this is determined by the desired configuration of the channel.

  Molds are usually formed from multiple parts, which fit together to form an assembled mold. The mold or mold insert is typically formed as a negative impression whatever channel architecture or device feature is desired in the microfluidic array device. After the polymer material is injected into the mold, the polymer material is cured to form a microfluidic array device and is removed from the mold. Typically, the mold is formed from two mold dies that fit together in a shielded state, so that after the microfluidic device is formed and cooled sufficiently, the two mold dies are separated, Allows access to and removal of the microfluidic array device.

  The mold (ie, mold die) or mold insert can be prepared from any number of materials suitable for such use, such as metal, silicon, quartz, sapphire, and suitable polymer materials. Forming negative impressions of the channel architecture includes photolithographic etching, stereolithographic etching, chemical etching, reactive ion etching, laser processing, rapid prototyping, ink jet printing, and electroforming Can be done by technology. When using electroforming, the mold or mold insert is formed as a negative impression of the channel architecture by electroforming metal, and the metal mold is polished (preferably mirror finished).

  When a non-metallic mold is used for injection molding, the mold can be formed of a flat and hard material such as a Si wafer, a glass wafer, quartz, or sapphire. Forming the microfluidic design features in the mold can be done by photolithography, chemical etching, reactive ion etching, or laser processing (which is widely used in microfabrication equipment). In addition, some ceramics can be used to make molds or mold inserts.

  Molds can also be made from “rapid prototyping” techniques. This includes traditional ink-jet printing of designs, or direct writing of resists such as Su-8, direct fabrication of molds with photopolymers using stereolithography, direct three-dimensional fabrication using polymers, and various Other similar or related techniques using the material with the polymer are included. The resulting polymer-based mold is electroformed to yield a metal negative replica of the polymer-based mold. Metal molds are particularly suitable for polymer injection molding where the mold itself needs to be heated. One widely used metal for electroforming is nickel, although other metals can be used. Metal electroformed molds are preferably polished to a high or “mirror finish” before use as a mold for injection molding. This finish is comparable to that obtained by mechanical polishing or submicron to micron sized abrasives (eg diamond particles). The same degree of finish can be obtained using electropolishing and other forms of polishing. In addition, the metal mold surface should preferably be as flat and parallel as a Si, glass, quartz or sapphire wafer. In one exemplary embodiment, the metal mold is polished to a highly polished finish using 1 μm diamond particles to obtain a near mirror-like finish.

  Applicants have used a polymer microfluidic device having an array of micron-sized nozzle structures by using injection molding techniques with a mold made of hardened steel or other metal comprising: The diameter is 100 μm or less, preferably 50 μm or less, more preferably 20 μm or less, and the outer diameter of the nozzle is less than about 150 μm, preferably about 100 μm or less, more preferably 50 μm or less, when measured at the tip portion. It has been found that microfluidic devices can be manufactured. FIG. 6 is a perspective view of a mold structure 200 configured to injection mold a microfluidic nozzle array device as shown in FIG. 1 having the dimensions and characteristics described above. Again, the mold 200 is formed as a negative impression of the microfluidic device to be formed. The mold 200 includes a first mold die or portion 210 and a second mold die or portion 230. These are configured to be complementary to each other and fit together to form an injection molding assembly used to form a microfluidic nozzle array device similar to the device 10 illustrated in FIG. . The mold 200 is preferably formed by electrical discharge machining (EDM).

  The first mold die 210 has a first surface 212 that includes a substantially flat surface. A recessed portion 214 is formed in the first surface 212. The recessed portion 214 generally defines the external peripheral shape of the microfluidic device, and the depth of the recessed portion 214 defines the thickness of the microfluidic device (excluding the region where the nozzle is formed). Since microfluidic devices are typically square or rectangular in shape, the shape of the recessed portion 214 is the same or similar. For example, the illustrated recessed portion 214 has a substantially square shape. The first mold die 210 also includes a plurality of upstanding profiles 216 that are spaced across the floor of the recessed portion 214. The shape of each pin 216 directly corresponds to the shape of the microfluidic channel formed when the mold 200 is closed and polymer material is injected. More specifically, the base portion 217 of the pin 216 corresponds to the reservoir of the microfluidic channel. The middle portion 218 corresponds to the middle portion of the microfluidic channel, and the conical tip portion 219 of the pin 216 corresponds to the second end of the microfluidic channel formed in the tip portion of the nozzle. As a result, the dimensions of the pin 216 are largest at the base portion 217, and the pin 216 tapers inwardly to its conical tip portion 219. Since the spacing of the pins 216 is directly related to the spacing of the microfluidic channel / nozzle structure, the pins 216 are preferably spaced in an array.

  Next, referring to FIGS. The second mold die 230 is It has a first surface 232 that mates with the first surface 212 of the first mold die 210. The first surface 232 is Except that a plurality of apertures 234 are formed in the second mold die 230, It is substantially flat. The aperture 234 The pins 216 are arranged according to a predetermined pattern corresponding to the arrangement of the pins 216. The aperture 234 First and second mold dies 210, When 230 fit together, The pin 216 is sized to receive at least a portion of the conical tip portion 219 (in one embodiment, about 500 μm long). The outer shape of the aperture 234 itself is The aperture 234 is tapered on the inside; The lower portion 235 of each aperture 234 is conical to form a conical nozzle for the microfluidic device. According to one embodiment, First and second molds 210, 230 fit together, When pin 216 is received in aperture 234, The tip portion 219 of the pin 216 is Extends completely to the bottom of the aperture 234, Contact the body of the second die mold 210 that defines the closed end of the aperture 234. The mold 200 of FIG. Generally configured to produce the microfluidic device of FIG.

  FIG. 7 shows a cross-sectional view of a mold configured to produce the microfluidic device 100 of FIG. For ease of explanation and simplification, the reference numbers of FIG. 6 are carried over to the description of FIGS. This is because each of these illustrated molds includes first and second mold dies. It is understood that the features formed as part of the first and second mold dies 210, 230 determine the size and shape of the resulting microfluidic device features.

  Accordingly, when the first and second mold dies 210, 230 are closed and any preparatory steps necessary for the injection molding process are taken, the first mold die 210 and the second mold die 220 are The first surfaces fit closely together to effectively seal the recessed portion 214 and the polymer material (usually resin) is injected into a closed space defined in part by the recessed portion 234. Is understood. In FIG. 7, the first and second mold dies 210, 230 are in a closed position, and the tip 219 of the pin 216 is within the aperture 234, more specifically within the conical lower portion 235 of the aperture 234. Sectional drawing which shows a mode that was accepted is shown. Since the first and second mold dies 210, 230 are the resulting negative impression of the microfluidic device, the microfluidic channel takes the shape of a pin 216, and the nozzle of the microfluidic device has a conical bottom 235. More precisely, the nozzle is formed by a resin that completely fills the space between the tip portion 219 of the pin 216 and the tip portion of the conical lower portion 235. As described above, in this embodiment, the tip portion 219 of the pin 216 and the tip of the second mold die 230 formed in the conical lower portion 235 are in contact with each other.

  The mold 200 is intended to be used many times over a long period of time to produce a large number of microfluidic devices, and thus the materials selected to manufacture the mold 200 are accordingly Must be done. In other words, the material must be selected so that microscale features can be formed in the microfluidic device and the mold 200 can be used to form multiple microfluidic devices. One material that is suitable for use in the manufacture of mold 200 is hardened steel. When conventional machining techniques such as metal turning or electrical discharge machining (EDM) are used, the dimensions of the tip portion 219 of the pin 216 that forms the nozzle opening may be limited. For example, manufacturing considerations may limit the dimensions (ie, diameter and length) of tip portion 219. Depending on available manufacturing techniques, the nozzle outer diameter can be formed to about 50 μm. This is because the resin can be injection molded in the space between the tip portion 219 and the conical lower portion 235. Depending on the area, this space is only on the order of about 15 μm due to the desired dimensions of the nozzle and microfluidic channel.

  Although the first mold die 210 is illustrated as being square, as long as the shape of the first mold die 210 and the second mold die 230 allows these two components to fit together, It is understood that the first mold die 210 can be formed in any number of different shapes.

  However, there are techniques available for injection molding nozzle openings with dimensions smaller than those previously described. FIG. 8 illustrates one possible injection molding arrangement for accomplishing this task to produce a nozzle having a nozzle opening that is even smaller than the tip portion 219 of the pin 216. In FIG. 8, after assembling the first and second mold dies 210, 230, there is a gap 240 between the tip portion 219 and the conical lower portion 235. When the polymer material (ie, resin) is injected into the conical lower portion 235 (in the molten state), the pressure of the injected resin is adjusted so that the resin does not fill the entire space in the gap 240; Since there is not enough pressure to move the resin to the lowest portion of the lower portion 235, an opening (space) remains at the tip of the resulting molding nozzle. If this technique is used, the diameter of the tip portion 219 of the pin 216 can be made larger than 20 μm. This is because the nozzle opening and nozzle profile are no longer defined by the dimensions of the corresponding part of the mold, but rather by the combination of mold dimensions, gap dimensions, and injection pressure. In this way, the pin 216 need not be manufactured so that the tip portion 219 is on the order of 20 μm to form a nozzle opening of the same size. Alternatively, the diameter of the tip portion 219 can be larger than the diameter of the nozzle opening that is ultimately formed in the nozzle as a result of the injection molding process.

  FIG. 9 illustrates one exemplary method of overshooting the injected resin into a gap 240 formed between the tip portion 219 and the tip of the conical lower portion 235. The nozzle opening 215 is defined by the pressure used for pouring the molten resin and the size of the gap 240. By controlling these parameters, the size of the nozzle opening can be controlled.

  Injection molding as a manufacturing technique for polymer parts is mass production at low cost. However, considerable costs are involved in the fabrication of the mold itself, especially for microfluidic nozzle designs that have micron-sized features and are therefore demanding designs in terms of creating the mold. Because the microfluidic nozzle array device is arranged to have the same pattern as the microtiter plate, it is possible to fill the reservoir of the microfluidic channel with a robotic commercially available liquid dispensing device. If possible, a large number of small microfluidic nozzle array devices (ie, subunits) can be tiled or combined to form a large structure. This is because the microtiter plate is composed of regularly spaced sample input points in the grid pattern. For example, after forming a microfluidic nozzle array device, combine with each other to produce a structure with the desired number of sample reservoirs (also referred to as sample wells or sample inputs) to accept the desired number of samples. be able to. For example, some common microfluidic devices contain a 96 sample reservoir (8 × 12 grid); a 384 sample reservoir (16 × 24 grid); and a 1536 sample reservoir (32 × 48 grid). . Arranging like tiles can be done by many known conventional means including, for example, permanently joining adjacent tiles together by melt bonding, welding, adhesives, and the like. In other words, any method or technique for joining and bringing together polymer structures can be used if preferred. The subunit structure can be formed as separate subunit tiles (FIGS. 17-18), or the subunit structure can be in the form of a long strip containing multiple rows of nozzles. For example, the strip can be formed to include two rows of spaced nozzles.

  Alternatively, the user can be provided with a base plate having a number of features formed therein so that the nozzle subunit structure can be inserted into and retained by the base plate. For example, the base plate can accommodate a predetermined receptacle that receives the nozzle subunit structure. Receiving is performed such that the nozzle subunit structure is securely held within the base plate and arranged according to the desired pattern. One or both of the base plate and nozzle subunit structure can accommodate a coupling feature to obtain a coupling connection between the base plate and the nozzle subunit structure. In this embodiment, the base plate functions as a base on which the final microfluidic nozzle array device can be constructed. The configuration is done by placing a number of nozzle subunit structures together and then securely holding these subunit structures within the base plate. FIG. 17 illustrates one exemplary structure for removably holding the nozzle subunit in a connected state. This structure will be described in detail later in the description of the third embodiment.

  Multiple nozzle / subunit structures arranged like tiles or otherwise combined, There are many advantages to be gained by having a larger size microfluidic nozzle array device. First, Mold manufacturing costs for smaller nozzle / subunit structures are: Rather than the cost of manufacturing the mold for the entire grid of microfluidic nozzles, Virtually small. Also, the cost of mold replacement when only one pin in the mold is damaged is substantially reduced. Second, The usefulness of the nozzle array It becomes more flexible. The experiment If not all the reservoirs (eg 96) of the microfluidic device to be filled are needed, Only the number of nozzles you need or close to it, Can be inserted into the base plate. at the same time, With this configuration, It is still possible to distribute samples using a robot. By way of example and according to one exemplary embodiment, One nozzle / subunit structure contains four reservoirs, So if your experiment requires only 60 reservoirs, Only 15 nozzle / subunit structures are inserted into the base plate. In this way In order to greatly reduce or completely eliminate unused reservoirs, The possible waste or inefficiency associated with each microfluidic device is eliminated or greatly reduced.

  Third, if the microfluidic nozzle array device is used for electrical or nanospraying in front of the mass spectrometer inlet, a common configuration is to place the nozzle spray "off axis" That is, the nozzle spray is placed in a direction perpendicular to the input. Often there is not enough space in front of the inlet to accommodate the microtiter plate because the nozzle needs to be placed in the immediate vicinity of the inlet (eg, typically within an inch). FIG. 10 illustrates how a tiled microfluidic nozzle array microtiter plate can be used in an off-axis configuration for electrical spraying. A tiled microfluidic nozzle array 300 arranged in a 96-well microtiter plate configuration is divided into strips 302 having two rows of 12 nozzles 310 each. One of the strips 302 is cut from the other and otherwise removed and transferred to a nozzle mount (not shown) in front of the mass spectrometer inlet 330 of the mass spectrometer 340 (as indicated by arrow 320). . The nozzle mount holds the strip 302 and has at least an xy translation stage at the mass spectrometer inlet 330 for spraying the sample material contained in the microfluidic channel associated with the selected nozzle. Each nozzle can be arranged at an optimal position. The direction of spray is perpendicular to the mass spectrometer inlet 330. In the schematic of FIG. 10, the nozzle 310 is located below the center line of the mass spectrometer inlet 330 and the spray is in a direction out of the surface of the drawing. The use of strips 302 that are still felt in future applications will depend on whether the entire combined strip 302 structure is used or what the application requirements are in terms of the exact application and the number of nozzles 310 required. Thus, it is understood that this is possible by either removing one or more strips 302 for use in a given application.

  The microfluidic nozzle array device disclosed herein is suitable for use in many different types of applications.

  For illustrative purposes only, some typical applications will be disclosed with reference to the microfluidic nozzle array device 100 illustrated in FIGS. However, it is understood that any device disclosed herein can be used in place of device 100.

  The microfluidic nozzle array device 100 is particularly suitable for use in nanospray / electrospray applications. Electrospray is a technique that allows a liquid sample to be evaporated and ionized for mass spectrometry. The electrospray process is performed at ambient pressure. In a conventional electric spray, a liquid sample is sent to the inlet of a mass spectrometer using a capillary having a relatively large inner diameter (that is, about 50 μm). The liquid flowing out of the capillary is subjected to an electric field generated by applying a high voltage (for example, 4 to 5 KV) to the metal conductor near the capillary opening and the ground plane opposite to the capillary opening, or vice versa. Evaporates under the influence. Dry nitrogen flows through the concentric piping to the capillary to help spray the liquid flowing out of the capillary. The liquid flow inside the capillary is generally driven by a pump such as a syringe pump.

  When the nozzle array of the microfluidic device 100 is used as a separate nanospray source, the reservoir 160 on the opposite side of the nozzle opening is filled with the sample to be sprayed. Prior to spraying, it is necessary to seal the reservoir so that the reservoir is liquid tight. In other words, the open end of the reservoir 160 (ie, the open first end 142 of the microfluidic channel 140) must be sealed. Sealing the open end of the reservoir 160 can be done in many different ways, each providing a satisfactory fluid tight seal of the reservoir and allowing the sample to be transported into the channel 140. Figures 11-13 illustrate a number of exemplary methods for providing the desired fluid tight seal of the reservoir.

  For example, FIG. 11 illustrates a first sealing technique in which the opening of the reservoir 160 (ie, the first end 142 of the microfluidic channel 140) is sealed with an elastic cover sheet 400. The elastic cover sheet 400 is preferably in the form of a masculine polymer cover sheet. In the microfluidic nozzle array device 100, the polymer cover sheet 400 is coupled to the reservoir wall 124 such that the polymer cover sheet 400 extends completely over the open end of the reservoir 160. A force is applied to the polymer cover sheet 400, such as with a mechanical plunger 410, pushing the sample along the length of the microfluidic channel 140 and finally the nozzle opening (the first of the microfluidic channel 140. Out of the second end 144) in a continuous stream (shown roughly at 430). The discharged continuous sample liquid stream is then evaporated under the influence of an electric field. The general direction of movement of the polymer cover sheet 400 and the plunger 410 is indicated by arrows 420.

  FIG. 12 illustrates another sealing technique. According to this technique, a movable seal member 400 is provided, which includes a seal base 422 for sealing the reservoir opening and a rod or plunger 444 attached to the seal base 442. Is formed. Since the size of the seal base 442 is larger than the size of the open end of the reservoir 160, the seal base 442 fits the reservoir wall 124 and spans the entire open end of the reservoir 160. The seal base 442 is formed of a suitable elastic material so that the seal base can be partially deformed when a force is applied. This elasticity allows the seal base 442 to function as a temporary diaphragm that seals the reservoir when the seal base 442 is directed inside the reservoir 160 itself.

  When the seal base 442 is pushed down in the direction toward the nozzle 170, the seal base 442 is forced into the first end of the microfluidic channel 140 (which is also the inlet of the reservoir 160). Deforms when In the illustrated embodiment, the seal base 442 includes a flange 446 that has a diameter greater than the diameter of other portions of the seal base. Therefore, when the seal base is inserted into the reservoir, the flange 446 is in intimate contact with the inner surface of the reservoir wall 124 to form a liquid tight seal between the seal base and the reservoir. When the seal base 442 is inserted into the reservoir 160 and moves through it toward the nozzle, the seal base 442 effectively pushes the sample toward the second end 144 of the microfluidic channel 140, The sample is discharged from the nozzle opening defined there. There may be an air gap between the sample (eg, liquid) in the reservoir 160 and the seal base 442, or a vent (not shown) may be incorporated into the seal base 442 to seal the seal. Air can also be pushed out of the reservoir 160 as the sample is pushed through the microfluidic device by the base 442. Vents can be made using conventional venting techniques such that the vents allow air passage while being impermeable to liquid flow, so that the sample It is prevented from flowing out of the reservoir 160 through the vent hole.

  It will be appreciated that the plunger 444 can either be manually operated or be part of an automated system including an actuator or the like that controls the operation of the plunger 444. By connecting all the plungers 444 to a common actuator or link, at start-up, the plungers 444 can all be driven simultaneously and the sample can be transported through individual channels to individual nozzles simultaneously.

  With reference to FIG. 13, yet another sealing technique for providing a fluid conveying member 450 is illustrated. Member 450 has a hollow portion and is generally shaped to be complementary to the shape of reservoir 160 so that member 450 fits the top edge of reservoir wall 124. Member 450 includes a distal end 452 that is initially located near the open end of reservoir 160. At the end 452, a gasket 460 is provided, and in the illustrated embodiment, the gasket 460 is in the form of a seal O-ring or the like. The gasket 460 provides a seal between the distal end 452 and the reservoir wall 124 and serves to prevent the sample from flowing out between this interface when transported as follows. Because member 450 is at least partially hollow, gasket 460 is disposed around a hole extending through member 450.

  In this embodiment, the sample is moved through the microfluidic channel 140 by flowing fluid through the member 450 (more specifically, the hole), effectively pushing the sample through the microfluidic channel 140 to the nozzle 170; Sample is discharged from nozzle 170 in a continuous stream 430. The fluid is preferably a high pressure gas, such as air or dry nitrogen gas, delivered from a source in fluid communication with the piston bore. The direction of fluid flow is shown schematically at 470. In other embodiments, the fluid is a liquid sample and can be fed into the microfluidic channel 140 to continuously push the liquid through the nozzle.

  It will be appreciated that a protective cover (not shown) may be placed at the distal end 452 of the fluid conveying member 450 to prevent the sample from contacting the inner surface of the piston hole. The protective cover must be permeable to fluid flowing through the holes and into the reservoir 160 to transport the sample along the microfluidic channel 140. For example, the protective cover can be in the form of a thin polymer coating that is permeable to gas and at the same time impermeable to liquid flow. In this way, the sample cannot come into contact with the holes themselves. It is not necessary to use such a protective cover. This is because the injected fluid can flow through member 450 and push the liquid sample by applying a force to the air gap between the sample and the surrounding structure.

  Further, conventional fluid delivery mechanisms can be used with device 100. In this embodiment, the stopper is inserted into the reservoir 160. A hole communicating with the reservoir 160 is formed through the stopper. The capillary is inserted through the hole and a liquid sample is injected into the reservoir through a capillary from a source outside the capillary. In this embodiment, the sample is not stored in reservoir 160, but rather is delivered to channel 140 by being injected into reservoir 160 through a capillary.

  As described above, the front surface of the nozzle array is made conductive by a thin coating of metal or conductive polymer. When an appropriate strength electric field is applied to the nozzle (eg, by the arrangement illustrated in FIG. 3), the liquid and the analyte it carries (ie, the sample) evaporate as it is ejected through the nozzle opening. Liquids suitable for use in electrospray mass spectrometry include (but are not limited to) acetonitrile, ammonium acetate, and other volatile liquids. Since the inner diameter of the nozzle is less than about 20 μm, the amount of material to evaporate out of the nozzle is less than that normally used in conventional electric spray operations. Moreover, since the outer diameter is 50 μm, an electric field sufficiently strong to evaporate is generated even with an applied voltage lower than about 6 KV.

  Therefore, it is not necessary to use an atomizing gas to support the evaporation process. However, if nebulization gas is required, a channel for flowing dry nitrogen gas through the nozzle openings can simply be added to the polymer substrate mounted in front of the nozzle array. FIGS. 14-15 are plan and cross-sectional views, respectively, showing the microfluidic nozzle array device 500 combined with a substrate 510 having a gas conduit 520 formed therein for spraying. The microfluidic nozzle array device 500 can be similar or identical to any of the exemplary microfluidic array devices previously disclosed herein. A gas outlet 522 is formed so as to be concentric with one nozzle 530. A substrate 510 having atomized gas channels can be made during the injection molding process by the injection molding process used for the nozzle array device 500 itself. Alternatively, the substrate 510 can be made first and later attached (eg, bonded) to the nozzle array device 500 as a separate component. The substrate 510 can be attached in any number of different ways, including (but not limited to) using an adhesive along the boundary zone or melting and joining the two members.

  In some cases, the nozzle array may not need to be adapted to the microtiter plate sample well configuration. For example, the sample can be delivered to the nozzle by the eluent of a high performance liquid phase gas chromatography (HPLC) column. The reservoir size in the nozzle array can be formed to any size, so the reservoir size can be any size where the open end of the reservoir divides one end of the HPLC column or the HPLC eluent for mass spectrometry. Can be configured to accept piping. The reservoir side of the nozzle array can also consist of injection molded features for splitting the eluent for mass analysis. In this case, the driving force through which the liquid sample specimen flows through the nozzle opening is a liquid flow due to the pressure driving of HPLC. Neither a pressure diaphragm nor an external pressure induction mechanism is required.

  The microfluidic nozzle array device disclosed herein is also particularly adapted for use as a nozzle array for optical spectroscopy. Each microfluidic channel in a nozzle array device terminates with a nozzle opening having an inner diameter of 20 μm or less, and the substrate of the nozzle array device is generally formed from a polymer material that is hydrophobic, so the microfluidic channel The internal liquid will not drip or be released from the nozzle without applying external force. When either ultraviolet or visible light is incident on the reservoir side of the array, the light exits the nozzle opening and conveys optical spectroscopic information of the analyte contained in the liquid in the microfluidic channel. In this way, the microfluidic channel and the nozzle opening provide a light detection system that does not use an optical window. This is an important advantage. This is because the microfluidic nozzle array device need not be made to incorporate an optical window formed from an optical material into its design. This reduces the structural complexity for the microfluidic nozzle array device, and also reduces the cost and complexity for fabrication of the microfluidic nozzle array device.

  The 96 microtiter nozzle plates filled with samples can be placed in an ultraviolet reader for the 96 microtiter plates, and the spectrophotometric information for each sample can be obtained by the reader. it can. Conventional microtiter plates used for UV spectrophotometry have to form the bottom of the sample well with a special UV transparent material to hold the sample in the well and transmit UV light simultaneously Otherwise, a microtiter plate made of quartz must be used. Thus, by using a microtiter nozzle plate array plate according to one exemplary embodiment, two detection techniques for the sample in the plate require that the sample be transferred to another additional plate. It becomes possible without.

  FIG. 16 is a cross-sectional view showing how the microfluidic nozzle array device 100 can be used for UV spectrophotometry. FIG. 16 illustrates a partial microfluidic nozzle array device 100 showing two nozzle structures to illustrate how to use the microfluidic nozzle array device 100 in UV spectrophotometry. . In this exemplary arrangement, UV light is emitted from the source 540, travels toward the microfluidic nozzle array device 100 and is incident on the reservoir side 120. The UV light travels through the reservoir 160 and continues along the length of the microfluidic channel 140. Both reservoir 160 and microfluidic channel 140 contain samples (eg, liquids and analytes). The UV light travels through the nozzle opening 144 and reaches the detector 550. The detector 550 is arranged to face the side of the microfluidic nozzle array device that houses the nozzle 170. The spectrophotometric information of the specimen transmitted by the UV light is detected by the detector 550 of the UV reader. Thus, the configuration of vertically oriented microfluidic channels can advantageously perform UV spectrophotometry in a simple and convenient manner. This is because the microfluidic nozzle array device 100 can be easily placed between the UV light source and the detector 550 of the UV reader. Similarly, transmission fluorescence spectroscopy can be performed using the microfluidic nozzle array device 100.

  Unlike conventional microfluidic devices where optical windows formed from optical materials are fabricated in the device, the substrate body of the microfluidic nozzle array device need not be formed of an optically transparent material. . As a result, the complexity of the fabrication process is reduced because this requirement does not exist in microfluidic nozzle array devices.

  The microfluidic nozzle array device disclosed herein can also be used in a wide variety of other applications where similar conventional devices are commonly used. For example, a microfluidic nozzle array device can be used to spot an array of DNA or protein on a substrate. This is an alternative to using the conventional capillary suction method currently used with metal capillaries. Currently, DNA array spotting is primarily performed by “sucking” DNA fragments into the open ends of a metal capillary. In order to spot within the array configuration on the glass slide, the split ends of the capillaries are pushed slightly onto the glass slide using a robotic arm or the like to facilitate the deposition of DNA fragments. Metal capillaries tend to “jump” out of the glass slide as soon as they are lifted from the glass slide. As a result of this phenomenon and other factors, it is well known that some 20% of the spots in the array are incomplete. For example, either the spot is bare or the amount of deposited material is insufficient. Spotting is usually performed using an expensive machine with rows of 8-12 capillaries, and the capillaries are rinsed and reused for different DNA samples.

  The microfluidic nozzle array device disclosed herein has a nozzle opening smaller than a conventional nozzle configuration (for example, 20 μm or less), and the microfluidic nozzle array device is smaller than a conventional metal capillary. Many advantages can be realized by using a device. First, the injection molded microfluidic nozzle array device can be discarded after each deposition. This eliminates the time-consuming rinsing process and eliminates the risk of cross-contamination because the device is not reused. Second, DNA or protein molecules are adsorbed on the metal surface, but not on the walls of the polymer nozzle. Spotting is therefore more complete when molecules leave the polymer nozzle and are deposited on the glass slide. Third, since a two-dimensional nozzle / spotter can be manufactured at low cost, the speed of the spotting operation is greatly increased. Fourth, depositing DNA or protein molecules from a polymer nozzle by pumping the molecules from the nozzle with high pressure air and / or an electric field for electrospray using one of the devices described above. Can help.

  Microfluidic nozzle array devices can also be used for spotting matrix assisted laser desorption ionization (MALDI) plates, pipette replacement, and capillary spotting methods. In the case of matrix-assisted laser desorption and ionization mass spectrometry, the main analytical technique for protein molecules and high molecular weight fragments, the molecules to be analyzed are deposited on the matrix material layer and are usually UV-evaporable by a UV laser. Absorbing molecule. In this way, the target molecule is carried into the gas phase and ionized together with the matrix molecule. Conventionally, metal (usually aluminum) MALDI plates are manually spotted using a micropipette, more recently using a capillary. Using a metallized polymer nozzle for spotting increases the efficiency of the ionization process. First, the matrix material is electrosprayed onto an aluminum MALDI plate. The aluminum MALDI plate is held at ground potential while the metal coated nozzle is held at a high voltage. Or vice versa. The molecules of interest are then electrosprayed onto the matrix material in a new nozzle. Spraying allows matrix molecules and target molecules to be mixed more uniformly with each other, thus increasing the efficiency of laser-assisted desorption and ionization. Also, spotting of the MALDI plate may be performed using a two-dimensional array of nozzles to obtain high throughput. Thus, the density of the nozzle array can be greatly increased, and as a result, the density of the spotting array can be increased. Therefore, more test or experimental sites can be provided on the substrate as a result of the increased spotting density. It is also understood that an electric field can be used to assist the spotting process. The electric field can be generated by using the arrangement illustrated in FIG. 3 or by some other type of suitable arrangement.

  It is further understood that pipette tips for nano to picoliter dispensing can be made using manufacturing methods disclosed herein based on injection molding techniques. In other words, by producing a mold and injecting resin into the mold, the pipette tip has a long main body and a tip opening whose inner diameter is less than about 20 μm (the outer diameter of the tip is less than about 50 μm). A pipette tip can be formed that ends at a).

The following examples serve only to illustrate some embodiments of the present microfluidic array device and are not intended to limit the scope of the invention in any way.
Example 1
A polymer microfluidic nozzle array device is fabricated using the techniques disclosed herein and first a mold designed for the injection molding process is provided. The mold is made of metal, and the conical surface of the mold that defines the nozzle portion of the microfluidic device is polished with diamond paste to form a highly polished surface. More specifically, the conical surface is polished with 1 μm diamond particles to achieve a near mirror finish for a nozzle formed as part of a microfluidic device. Fabrication of the microfluidic device involves injecting polybutyl terephthalate (PBT) into a closed mold, then curing the formed structure, and finally removing the molded microfluidic nozzle array device from the mold. Do by removing. The microfluidic nozzle array device is formed such that the average outer diameter of the nozzle is about 60 μm and the average inner diameter of the tip (ie, the diameter of the nozzle opening) is less than about 20 μm.

  By polishing the conical surface of the mold defining the nozzle, the outer surface of the nozzle becomes very smooth and the outer diameter of the nozzle is more constant between nozzles and between mold runs. By providing a smooth, highly polished surface in the conical portion, resin flow friction is reduced, resulting in increased accuracy and efficiency of the injection process. These techniques provide advantages when forming very small dimension structures such as the nozzles of the present microfluidic devices having microscale features.

The microfluidic nozzle array device is then used as an electrical spray device to spray a liquid sample that is placed in a microfluidic feature formed in the microfluidic nozzle array device. As already detailed, the nozzle serves to spray the liquid sample into a fine mist by evaporation induced by an electric field. In this embodiment, a voltage between 5 and 6 KV is applied to a conductive region formed around the nozzle tip to obtain the required electric field. The evaporated and ionized sample is then injected into the inlet of the analytical mass spectrometer.
(Example 2)
A polymer microfluidic nozzle array device is fabricated using the techniques disclosed herein and first a mold designed for the injection molding process is provided. The mold is made of metal, and the conical surface of the mold that defines the nozzle portion of the microfluidic device is polished with diamond paste to form a highly polished surface. More specifically, the conical surface is polished with 1 μm diamond particles to achieve a near mirror finish for a nozzle formed as part of a microfluidic device. Fabrication of the microfluidic device involves injecting polybutyl terephthalate (PBT) into a closed mold, then curing the formed structure, and finally removing the molded microfluidic nozzle array device from the mold. Do by removing. The microfluidic nozzle array device is formed such that the average outer diameter of the nozzle is about 60 μm and the average inner diameter of the tip (ie, the diameter of the nozzle opening) is less than about 20 μm. The mold is configured to form a microfluidic nozzle array strip having two rows of 12 nozzles each.

As soon as the molded microfluidic nozzle array strip is removed, the above process is repeated to form one or more other microfluidic nozzle array strips. The microfluidic nozzle array strips are then placed side by side and adjacent strips are removably secured to each other by applying an adhesive (eg, an adhesive) to the edges of each strip. More specifically, after heating the edges so that the polymeric material is soft, adjacent strips are aligned along these edges to produce a melted bond between the two touched edges. . Preferably, the melted bond between adjacent strips includes a weak portion (eg, a score line or the like can be formed along the bond, or of the bonded interface portion between two strips. As a result, one strip can be easily pulled away from the other. Paste any remaining microfluidic strips in the same way to form a single, tiled microfluidic nozzle array device with weak portions between adjacent microfluidic devices joined together . The number of microfluidic nozzle array strips joined to the desired overall size of the microfluidic nozzle array device, more specifically to the desired overall number of reservoirs and nozzles per each microfluidic device. Dependent. In use, a single, tiled microfluidic nozzle array device is divided into two or more parts. These can be used or further divided into smaller additional microfluidic devices.
(Example 3)
A polymer microfluidic nozzle array device is fabricated using the techniques disclosed herein and first a mold designed for the injection molding process is provided. The mold is made of metal, and the conical surface of the mold that defines the nozzle portion of the microfluidic device is polished with diamond paste to form a highly polished surface. More specifically, the conical surface is polished with 1 μm diamond particles to achieve a near mirror finish for a nozzle formed as part of a microfluidic device. Fabrication of the microfluidic device involves injecting polybutyl terephthalate (PBT) into a closed mold, then curing the formed structure, and finally removing the molded microfluidic nozzle array device from the mold. Do by removing. The microfluidic nozzle array device is formed such that the average outer diameter of the nozzle is about 60 μm and the average inner diameter of the tip (ie, the diameter of the nozzle opening) is less than about 20 μm. The mold is configured to form a microfluidic nozzle array strip having two rows of 12 nozzles each.

  As soon as the molded microfluidic nozzle array strip is removed, the above process is repeated to form one or more other microfluidic nozzle array strips. FIG. 17 roughly illustrates the concept of multiple nozzle subunit structures arranged in tiles or otherwise combined into a large size microfluidic nozzle array device. A base plate 600 is provided and serves as a means for receiving a number of nozzle subunit structures (shown generally at 610). Receiving is performed such that the nozzle subunit structure 610 is releasably connected to the base plate 600. More specifically, the base plate 600 is a frame-like member and has a predetermined number of holding rails 620. The holding rails 620 are attached to the pair of end walls 630 at their ends. The rails 620 are spaced from each other such that an open slot 640 is formed between adjacent rails 620.

  As illustrated in FIGS. 17 and 18, each rail 620 has a number of clamping features 650 formed as part of the rail 620 and spaced along the length of the rail 620. The clamp feature 650 includes sidewalls 652 spaced from each other and defining a retention slot 660 therebetween. The side walls 652 are disposed parallel to each other and extend upward from the floor 652 of the clamp feature 650. The distance between the inner surfaces of the side walls 652 provides a friction fit between the side walls of the nozzle and subunit structure 610 so that the structure 610 can be secured to the base 600 and at the same time the structure 610 can be easily removed from the base 600. Selected as possible. Accordingly, the distance between the inner surfaces of the sidewalls 652 is equal to or slightly greater than the width of the sidewalls of the structure 610 received in the retention slot 660 between the sidewalls 652.

  Alternatively, the retention slot 660 can be formed between two sidewalls 652 spaced from each other with the entire length of the rail 620 having a “U-shaped” cross section. In this embodiment, the entire rail 620 functions as a locking member instead of a separate clamp feature 650 that is spaced along the length of the rail 620.

  In the illustrated embodiment, each nozzle subunit structure 610 includes four nozzles 612 and four reservoirs (not shown) on the opposite side of the structure 610. For illustrative purposes only, the nozzle 612 is illustrated as facing away from the clamp feature 650 (so that the nozzle 612 is in a plane above the clamp feature 650). However, the structure 610 can be releasably connected to the base 600 such that the nozzle 612 faces in the opposite direction. In other words, the reservoir at the opposite end of the microfluidic channel faces away from the clamp feature 650 and lies in a plane above the clamp feature 650.

  Connecting the nozzle subunit structure 610 to the base 600 in a releasable manner means that two opposing side walls 611 of one nozzle subunit structure 610 face two adjacent rails facing each other with an open slot 640 therebetween. This is done by inserting it into the holding slot 660 of 620. One side wall 611 can be inserted first and then the other side wall 611 can be inserted into the other retaining slot 660, or after both side walls 611 are aligned with the slot 660, the nozzle-subunit structure is pushed down. The side wall 611 can also be effectively placed in the holding slot 660. Both the nozzle subunit structure 610 and the base 600 are preferably formed of plastic material, and the dimensions of the structure are carefully selected so that a frictional fit occurs when the sidewall 611 is received in the retention slot 660. When sidewall 611 is received in retention slot 660, nozzle 612 and reservoir are received in open slot 640 so that these elements are not obstructed by base 600. In other words, since the reservoir opening is not blocked, it is possible to place the sample into the reservoir otherwise, and the nozzle opening is not blocked so that the sample can be discharged.

  In one embodiment, the base 600 is formed of a polymer material and is manufactured using an injection molding process such that the base 600 is formed as a unitary structure. Friction fit is one way to releasably connect the nozzle subunit structure 610 to the base 600, but using a small amount of adhesive at the interface between the sidewall 611 and the clamp feature 650, a variety of It may be ensured that the nozzle / subunit structure 610 stays in place during an application (such as when the base 600 may need to be turned over). Further, depending on the application, it may be necessary to apply a force to the back of the nozzle subunit structure 610 (eg, to start a plunger in the reservoir), so that when this force is applied, the nozzle subunit structure 610 , It is desirable to stay in place and not disengage from the base 600. Any suitable number of pressure-sensitive adhesives can be used. It will be appreciated that one type of adhesive is a releasable adhesive that allows the nozzle subunit structure 610 to be removed from the base 600.

  FIG. 19 illustrates a base 600 of another embodiment that is very similar to the configuration illustrated in FIGS. In this embodiment, the clamp feature 650 is configured to receive two sidewalls 611 of adjacent nozzle subunit structures 610. That is, the distance between the inner surfaces of the side walls 652 is selected such that the width of two side walls 611 arranged in close contact with each other is approximately equal to or slightly smaller than the distance between the inner surfaces of the side walls 652. ing. In other words, the slot 660 is configured to receive and hold two side walls 611 of adjacent nozzle subunit structures 610. In order to removably couple the nozzle subunit structure 610 to the base 600 according to this embodiment, after placing one sidewall 611 in the slot 660, the other sidewall 611 of the adjacent nozzle subunit structure 610 is In the slot 660 next to the other side wall 611. This provides a friction fit and ensures that both adjacent nozzle and subunit structures 610 are held in place. Unlike the embodiment of FIGS. 17-18, in this embodiment, two sidewalls 611 need to be placed in one slot 660 in order to effectively couple each nozzle subunit structure to the base 600. .

  It will be appreciated that other members may be used in addition to the clamp members described above. For example, each clamp member can be comprised of a spring biased clip to receive the sidewall 611 in a frictional manner and maintain and hold the sidewall 611 in a releasable manner. The clip can be composed of two opposing plates connected at one end via a hinge to bias the plates in the direction of each other. After receiving the side walls 611 at opposite ends of the plate and inserting the side walls 611 between the plates, the side walls 611 between the plates are directed toward the hinged end. The biasing action between the plates ensures that the side wall 611 is securely gripped between the plates, while at the same time it can be removed simply by overcoming the biasing force and lifting the side wall 611 upwards away from the plate.

  FIG. 20 illustrates still another base 700. The base 700 aligns or otherwise combines a number of nozzle subunit structures into a larger size microfluidic nozzle array device and one of the microfluidic nozzle array devices. This is to increase the volume of the reservoir forming the part. The base plate 700 is formed of a plastic material, preferably a plastic material that can be injection molded. As previously mentioned, the low cost of forming the base plate 700 by injection molding without compromising the overall integrity of the base plate 700 or the micro-scale features formed as part of the base plate 700. A method is obtained.

  In this particular embodiment, the base plate 700 is similar to a conventional microtiter plate with a particular configuration on the surface that accepts a robotic dispensing pipette, for example 96 wells. Base plate 700 can be formed in many different shapes. However, the base plate 700 generally includes an upper surface 702 and an opposite lower surface 704. The base plate 700 has a large number of open end wells 710 formed therein and arranged according to a predetermined pattern. The upper end 712 of the well 710 partially defines the upper surface 702 of the base plate 700, while the lower end 714 of the well 710 is spaced from the lower surface 704. The well 710 has a tapered configuration in that the width of the upper end 712 is larger than the lower end 714 of the well 710. It will be appreciated that the well 710 can be formed with any number of different cross-sectional shapes, and in one exemplary embodiment, the well 710 has a generally annular shape (ie, a circular cross-section).

  Base plate 700 is configured to hold at least one microfluidic nozzle array device, such as device 100 illustrated in FIG. For purposes of explanation, it will be described that base plate 700 is used to hold device 100. However, it is understood that devices having different features and / or configurations can be used as long as the device has retention features that can be coupled to and retained by the base plate 700. More specifically, the device 100 has many features formed therein for coupling with the lower end 714 of the well 710. For example, the first surface 120 of the device 100 includes a reservoir wall 124 that partially defines a reservoir 160. In the exemplary embodiment, the reservoir wall 124 has an annular shape because the reservoir 160 itself is such shaped. The first surface 120 is configured such that the reservoir wall 124 is raised relative to a portion of the periphery of the first surface 120. Therefore, the member can be fitted around the outer surface of the reservoir wall 124.

  The base plate 700 is configured to allow easy coupling of one or more devices 100 to the base plate 700 so that a large number of small devices 100 can be combined into a large grid device 100. Such a coupling between the device 100 and the base plate 700 is virtually releasable in that any one of the devices 100 can be easily removed and / or replaced. In order to couple one or more devices 100 to the base plate 700, the placement of each device 100 is performed such that the reservoir 160 is aligned with a well 710 formed in the base plate 700. Because the inner diameter of the lower end 714 of the well 710 is slightly larger than or approximately equal to the outer diameter of the reservoir wall 124, the lower end 714 of the well 710 fits snugly onto the reservoir wall 124, so that the device 100 can be Can be combined.

  Since the wells 710 are disposed throughout the base plate 700, there is a corresponding well 710 for each reservoir 160, and when the device 100 is securely coupled to the base plate 700, the device 100 There is at least one well 710 aligned with each of the reservoirs 160. Since there is a corresponding well 710 for each reservoir 160 of the device 100, the base plate 700 serves to actually increase the volume of the reservoir 160 because the well 710 serves as an extension of the reservoir 160. Fulfill. In other words, the reservoir 160 can be filled through the well 710 and any amount of sample overflowing from the reservoir 160 is only stored in the well 710. Since the sample is ejected through nozzle 170 in the manner described above, the sample from well 710 is fed into reservoir 160 to replace the dispensed amount. Increased reservoir volume behind each nozzle 170 increases other advantages to the base plate 700 and the effective size of the reservoir in that the device 100 can accommodate and adapt to robotic dispensing equipment. That ability exists. This is illustrated in FIG. The figure shows that the volume that contains the sample (eg, liquid) in each well 710 is much larger than if samples were received using only the reservoir 160 of the nozzle array.

  Alternatively, the lower end 714 can interface with the reservoir wall 124 in a different manner in that the lower end 714 is received within (between) the reservoir walls 124. In other words, the outer diameter of the lower end 714 is selected to be slightly less than or approximately equal to the inner diameter of the reservoir wall 124. In this embodiment, the lower end 714 is snugly received within the reservoir wall 124 to ensure that the device 100 is coupled to the base plate 700.

  Whether the lower end 714 is received within the reservoir wall 124 or the lower end 714 is disposed around the reservoir wall 124, in both cases, the coupling at the junction between the lower end 714 and the reservoir wall 124 causes a fluid tightness. And a hermetic bond is formed for gases at pressures up to several pounds per square inch (psi).

  As illustrated in FIG. 20, when the device 100 is coupled to the base plate 700, the lower surface 704 protrudes beyond the nozzle 170 (eg, extends downward) and has a chamfered edge 705. The tip of the nozzle 170 is protected without interfering with the function of the nozzle 170. The lower surface 704 should extend below the nozzle tip to prevent damage to the nozzle tip and allow the base plate 700 to fit flush with the flat surface. This may be the case when the base plate 700 is attached to an instrument such as an electrospray device or a spectrophotometer. Also, the protruding corner of the base plate 700 protects the tip of the nozzle 170 during handling.

  In embodiments where the base plate 700 functions as an interface plate for a robotic dispensing device, the base plate 700 is of a height that complements a conventional robotic dispensing device. In one exemplary embodiment, the base plate 700 includes 96 open end wells 710 arranged in a standard 8 × 12 grid configuration. The overall height of the base plate 700 and the nozzle array device 100 can be formed to match the height of a standard microtiter plate. In this way, the reservoir volume can be varied and selected in view of the predetermined application of the device 100. For example, without the need to change the mode design of the nozzle array device 100, the combined volume of the well 710 and the reservoir 160 is about 370 μl as in one of the standard volumes for 96 well plates. As such, or to some other desired volume, the base plate 700, more specifically its well 710, can be formed. In other words, the effective volume of the reservoir 160 can be changed by changing the dimensions of the well 710 as opposed to having to prepare various devices 100 having reservoirs 160 of different volumes.

  Furthermore, attaching the device 100 with an array of nozzles with 384 well spacing to 96 well plate attachments, using only one of every four nozzles at each lower end 714 of the well 710. If attached, it is possible. Thus, not all wells 710 and / or reservoirs 170 need be used in any given application. A further advantage of arranging the base plate 700 like a tile is that the existing commercial seal mat and its robotic seal mechanism can be applied directly to the base plate 700 without major changes. .

  The upper end 712 of the wall 710 is configured to fit a pierceable seal mat 725. The pierceable seal mat 725 is disposed over the entire upper surface of the base plate 700 so that at least the upper end 712 of the well 710 is covered by the pierceable seal mat 725. Puncturable seal mats 725 are known in the art and can be obtained from many commercial sources. A pierceable seal mat 725 can be used to prevent evaporation of sample liquid from the well 710, but the base plate 700 is being modified in preparation for transfer to one instrument such as a mass spectrometer. .

  That is, base plate 700 incorporates an open-ended well 10 similar to an open-ended tube and has a first diameter at one end (eg, lower end 714) for interfacing with reservoir wall 124 of device 100. However, the second diameter at the other end is selected such that the opening at this end is the same as a conventional well in the microtiter plate 700. Advantages gained by the base plate 700 include increased sample storage volume, improved reservoir sealing with commercially available seal mats, and improved handling of the nozzle array device 100. In addition, since the base plate 700 is preferably manufactured by an injection molding process, the cost of the base plate 700 is also relatively low.

  FIG. 21 illustrates another embodiment for effectively increasing the volume of the reservoir 160 of the device 100. More specifically, an open end conduit member 800 is mated with the reservoir 124 to effectively increase the volume of the reservoir 160. The conduit member 800 in one exemplary embodiment is a piece of tubing having an open first end 802 and an open second end 804. The pipe 800 can be configured so that the dimensions are the same along its length, or the pipe 800 can be configured such that the dimension of one end is larger than the other end. . In the latter embodiment, the pipe 800 has a tapered configuration. Shown in FIG. 21 is a slightly tapered configuration of a pipe 800 in which the dimensions of the first end 802 attached to the reservoir wall 124 are spaced above the first surface 120 of the device 100. A pipe 800 that is smaller than the second end 804 arranged with the

  In one embodiment, the inner diameter of the first end 802 is slightly greater than or approximately equal to the outer diameter of the reservoir wall 124 so that the first end 802 fits snugly around the reservoir wall 124. (E.g., to provide a liquid and air tight junction between the device and the pipe 800). Alternatively, the first end 802 can be received within the reservoir 160 because the outer diameter of the first end 802 is slightly less than or approximately equal to the inner diameter of the reservoir wall 124, so that the device 100 and piping 800 can be securely coupled.

  The pipe 800 can be formed of any number of materials normally used for forming pipes, such as plastic materials and rubber materials. As in the embodiment illustrated in FIG. 20, the pipe 800 effectively increases the volume of the reservoir 160 because the pipe 800 functions as an extension of the reservoir 160. This results in the advantages described above with respect to the base plate 700.

  FIG. 22 illustrates yet another embodiment base plate 900 that is similar or identical in construction to the base plate 700. The difference between the arrangement illustrated in FIG. 22 and the arrangement illustrated in FIG. 20 is that the configuration of the base plate 900 is different from the nozzle array configuration of the device 100, and the configuration of the base plate 700 and the device 100 is as follows. In contrast to what was intended to fit each other. For example, the base plate 900 can be in an 8 × 12 96-well grid configuration, while the nozzle array device spacing can be associated with 384-well plate spacing. In other words, the number of reservoirs 160 is greater than the number of wells 710 so that each reservoir 160 is not aligned or matched with the corresponding well 710. However, each well 710 is preferably aligned with one reservoir 160. That is, such a base plate configuration is configured to use only the selected reservoir 160, as opposed to using all of the reservoir 160, and allows the base plate and / or nozzle array device to be used for a particular application. There is no need for custom configuration.

  In the embodiments of FIGS. 20-22 described above, the nozzle array is compatible with the microtiter plate configuration, but the size of the nozzle array components is small, and a large number of nozzle array devices are gathered together like a tile. Can be used to line up. Advantageously, each embodiment provides a means for increasing the effective volume of the reservoir of the nozzle array device. This is because the well formed in the plate effectively and reliably couples with one end of the reservoir so that the sample can be injected into the well, so that the sample is in the reservoir and finally This is because it is fed into the nozzle tip. By increasing the effective volume of the reservoir, the nozzle array device can be made more compatible with robotic dispensing equipment.

  Next, still another embodiment of the present invention will be illustrated with reference to FIGS. In FIG. 23, a general mass spectrometer setup is schematically shown. The mass spectrometer includes a mass spectrometer unit 1000 and a conventional electric spray needle assembly 1010. The electrospray needle assembly 1010 is used to convert a liquid sample into a vapor jet by a technique commonly referred to as electrospray ionization (ESI). The electrospray needle assembly 1010 sprays the sample at a flow rate of about 5 microliters / minute or more, depending on the exact application and operating parameters. The electrospray needle assembly 1010 can be attached and secured to the mass spectrometer unit 1000 to ionize the liquid sample to form a vapor jet. The vapor jet is partially received in the inlet port of the mass spectrometer 1000. For example, the mass spectrometer 1000 has an inlet cone 1030 that is configured to receive a portion of the vapor jet formed by the electric spray needle assembly 1010. Extending through the interior of the inlet cone 1030 is an inlet opening for receiving a steam jet.

  In electrospray ionization, the analyte solution is passed through a capillary at atmospheric pressure into a small diameter tip 1012 held at a high voltage (eg, several KV). The effect of the electric field as the solution exits the tip 1012 is to generate a spray of strongly charged droplets, which are potential (and pressure) gradients, in this case an analyzer that is a mass spectrometer unit 1000 Go down towards. The tip 1012 is typically spaced from the inlet cone 1030 and is positioned such that the opening formed through the tip 1012 is not axially aligned with the opening formed through the inlet cone 1030. Instead, the tip 1012 is positioned so that its longitudinal axis is perpendicular to the axis through the opening of the inlet cone 1030. Further, when the electrospray needle assembly 1010 is fixed in position relative to the mass spectrometer unit 1000, the opening formed through the tip 1012 and the opening formed through the inlet cone 1030 are typically In the same plane.

  Electrospray ionization is very inefficient. This is because the electrospray ionization feature allows the analyte solution flow rate to be relatively high so that a sufficient amount of sample is received in the inlet cone 1030 so that the mass spectrometer unit 1000 can function properly. That is why. For example, it is common for only about 4% of the sprayed analyte solution to be trapped within the inlet cone 1030, which results in a significant amount of sample due to the high sample flow rate of the analyte solution in electrospray ionization applications. It will be wasted.

  Because of the aforementioned and other imperfections, nanospray is an attractive alternative to electrospray ionization and is increasingly becoming so. Nanospray is a technique used in mass spectrometry to convert a liquid sample into a vapor jet using substantially less sample compared to conventional electrospray ionization. As mentioned above, the sample flow rate through the nanospray nozzle is typically well below 1 microliter / minute. However, there are many disadvantages that must be overcome to realize the benefits of nanospray. For example, one of the problems encountered when a user attempts to use the mass spectrometer unit 1000 for both nanospray and electrical spray applications is to use an existing apparatus with a nanospray device. In some cases, the user needs to remove the conventional ESI fixture and insert the selected nanospray device in place. In other words, the conventional electrospray needle assembly 1010 must be removed from the mass spectrometer unit 1000 so that the nanospray device can be secured to the same framework that supports the electrospray needle assembly 1010. This is a very time consuming task. This is because each assembly is typically bolted to the frame that secures the mass spectrometer unit, so to remove one assembly, the user unscrews the assembly and puts the other in place. This is because it must be bolted. The time required to set up and run the analysis must account for the time required to verify that the correct instrument is in place, including the aforementioned Multiple bolting / rebolting steps may be required. Furthermore, such an arrangement cannot use a “universal” nanospray device that can be used with various types of mass spectrometer units. This is because the nanospray device must be bolted onto the mass spectrometer unit framework.

  As best shown in FIGS. 24, 25, 29, and 30, the universal problem is solved so that the change from ESI to nanospray application can be made easier and less time consuming. A simple holder device 1100 is provided. The holder device 1100 is for use with a predetermined size nozzle array device, such as the nozzle array device 100, and includes a frame 1110 that receives the device 100. As already detailed, device 100 is in the form of a small plastic tip and includes a nozzle array therein. The frame 1110 is preferably made of a plastic material and has an opening 1112 formed therein. The opening 1112 complements the outer periphery of the device 100 in shape and size so that the device 100 has no or little space in the opening 1112 between the device 100 and the frame 1110. Are arranged as follows. Preferably, the dimensions of device 100 and opening 1112 are such that a close friction fit occurs between device 100 and frame 1110. In addition, the use of a bonding support agent such as a pressure-sensitive adhesive (adhesive) can ensure that the device 100 continues to be held in a predetermined position within the opening 1112 of the frame 1110. In one embodiment, each device 100 and frame 1110 is square or rectangular.

  It is also understood that the device 100 and the frame 1110 can be formed as a single integral part by a common injection molding process. This eliminates the steps of placing the device 100 in the frame 1110 and ensuring that the two are coupled together.

  As illustrated in FIGS. 23, 24, and 30, the holder device 1100 also has a holder 1120 for securely holding the frame 1110 in place, so that the device 100 can be connected to the mass spectrometer unit 1000 and more. Specifically, it can be properly aligned with the inlet cone 1030. The holder 1120 can be any number of different shapes as long as it includes a flat platform 1130. According to one exemplary embodiment, the holder 1120 is generally L-shaped in that it includes a support portion 1132 that intersects and is integral with one end of the flat platform 1130. That is, the support portion 1132 and the flat platform 1130 are disposed at right angles to each other, giving the holder 1120 a substantially L-shaped configuration. In one exemplary embodiment, the holder 1120 is formed of a single piece of plastic, such as plexiglass material.

  The flat platform 1130 is connected to the support portion 1132 at its first end 1134, and at the second end 1136, the device / frame combination is held fixed in place. More specifically, at or near the second end 1136, the first and second retaining members 1140, 1142 are spaced apart from each other, with a space 1144 for receiving the frame 1110 therebetween. Is formed. The first and second holding members 1140, 1142 can comprise any number of different types of members that are configured to fit and hold members therebetween. By way of example and according to one exemplary embodiment, the first and second retaining members 1140, 1142 are simply long rails that are formed as part of or secured to the top surface of the flat platform 1130. is there. The rails 1140 and 1142 are arranged parallel to each other such that a parallel slot or space 1144 is formed therebetween. The dimensions of the space 1144 supplement the dimensions of the frame 1100 so that the frame 1100 can be received and retained within the space 1144. For example, the width of the space 1144 can be approximately equal to the width of the frame 1100 so that when the frame 1100 is placed in the space 1144, a positive friction fit is formed between these components, Or it can even be very slightly smaller than the width of the frame 1100. Because the holder 1120 is intended to be reused with other frames 1100, the frame 1100 can be removed from the holder 1120 so that the user can insert and secure the other frame 1100 into the rails 1140, 1142. It must be.

  When the device 100 is securely held in place between the rails 1140, 1142, the device 100 is oriented perpendicular to the flat platform 1130. In other words, the device 100 stands up between the rails 1140, 1142. The height of the rails 1140, 1422 is a height that does not interfere with spraying the sample through a nozzle formed as part of the device 100. That is, the rails 1140 and 1142 typically do not extend above the bottom end of the frame 1100 and therefore do not hide the bottom nozzle. The lengths of the illustrated rails 1140 and 1142 are such that they do not extend above the end of the frame. However, this is not important and the opposite configuration is equally applicable.

  As best shown in FIGS. 24, 25, and 30, the frame 1100 also preferably has positioning and retention features formed as part of one or more faces of the frame 1100. In one exemplary embodiment, one face of frame 1100 includes four posts 1160 spaced at each corner of frame 1100. The illustrated frame 1100 has a generally square shape, so the distance between any two posts 1160 is substantially the same. Two of the posts 1160 function as positioning and retention features by mating with one of the rails 1140, 1142. More specifically, two lowest-order posts 1160 are formed on the frame 1100 and are spaced apart from each other, so that one of the rails 1140 and 1142 can be rubbed between the lowest-order posts 1160. The frame 1100 is positioned on the holder 1120, and the frame 1100 is positioned and locked by being locked in place. Each post 1160 is sufficiently high to fit in one of the rails 1140, 1422 in a manner that limits the lateral movement of the frame 1100. In other words, the post 1160 prevents the frame 1100 from moving laterally, whether the user attempts to apply a lateral force to the frame 1100 or is accidentally applied. Thus, in order to place or remove the frame 1100 in the holder 1120, the user must push or lift the frame 1100 downward while the individual rails 1140, 1422 are located between the posts 1160. . The post 1160 also serves to protect the nozzle 150 when the device 100 is turned upside down and the surface with the outwardly extending nozzle 150 becomes the ground contact surface. In the absence of the post 1160, the tip of the nozzle 150 corresponds to the lowest point of the device 100, so that the tip may hit the surface and be damaged and / or destroyed. In the state with the post 1160, the post 1160 corresponds to the lowest point of the device 100, so the post 1160 first hits the ground instead of the nozzle tip hitting the ground. Thus, the post 1160 serves to protect the nozzle 150. Therefore, the length of the post 1160 must be greater than the height of the nozzle 150.

  As shown in FIGS. 24 and 25, the frame 1100 includes tabs 1101 for handling the frame 1100. For example, the tab 1101 extends outward from one end of the frame 1100 so that the user can easily grasp the user member when the user is inserting the frame 1100 into or out of the holder 1120. ing. That is, when the frame 1100 is inserted into the holder 1120, the tab 1101 is positioned on the upper end of the frame 1100 so that the user can easily access the tab 1101. Accordingly, when the user lowers the frame 1100 into the holder 1120, the user grasps the frame 1100 with the tab 1101, and conversely, the user grasps the tab 1101 and removes the frame 1100 from the holder 1120. The illustrated tab 1101 is square, but the tab 1101 can be any other number of shapes, such as an ellipse, a triangle, a variant, and the like.

  The remaining portion of the flat platform 1130 can be used as a support surface to hold other components that can be used in various nanospray applications. As an example and as detailed below, a capillary device 1300 (shown in the embodiment illustrated in FIG. 30) that can be used to ionize and inject the sample into the reservoir 160 of the various nozzles 150 of the device 100. Can be supported by a flat platform 1130.

  If the holder 1120 is to be securely connected to the framework that supports the other components of the mass spectrometer unit 1000, the configuration and positioning of the holder 1120 ensures that the frame 1100 is held between the rails 1140 and 1142. Occasionally, at least one nozzle 150 of the nozzle array is designated as a targate nozzle positioned proximate the inlet cone 1030 of the mass spectrometer unit 1000 to inject a sample into the inlet cone 1030. If a sufficient amount of sample injected into the nozzle 150 is carried into the inlet cone 1030, the exact position of the device 100 is changed. For example, in the embodiment shown in FIG. 23, the axis through the tip opening formed in the nozzle 150 is perpendicular to the axis through the inlet cone 1030, similar to the manner in which a conventional electric spray device is placed. However, the nozzle tip opening need not be in the same plane as the opening formed in the inlet cone 1030. In contrast, the device 100 can be locked in the holder 1120 such that the nozzle 150 is positioned slightly above the inlet cone 1030 (the axis of the nozzle tip opening is perpendicular to the axis of the inlet cone 1030). In other words, FIG. 23 is an example of an arrangement of nanospray devices in the source region of the mass spectrometer unit. The nanospray device is positioned so that the nozzle 150 points toward the inlet cone 1030. Because the amount of sample sprayed by the nanospray nozzle 150 is substantially less than that of the ESI, the spray can be directed to the inlet cone 1030 without applying a large amount of vapor to the mass spectrometer unit 1000. FIG. 29 shows an alternative arrangement in which the axis through the nozzle opening is parallel to the axis through the opening of the inlet cone 1030 and possibly axially aligned with this axis.

  The nanospray apparatus includes a holder 1120 and accesses the source region of the mass spectrometer unit 1000 through a cutout portion of a transparent cover surrounding the source region. For different types of mass spectrometer units 1000, different covers with appropriate cutouts must be made and replaced with the original cover. However, it is possible to operate the mass spectrometer without enclosing the source region with a cover, but it is generally preferable to have a cover due to the presence of high pressure and relatively high temperature in the source region. Understood.

  As shown in FIG. 30, the nanospray device may be coupled to an automatic positioning system 1400 so that the nanospray device can be easily taken to an appropriate position relative to the mass spectrometer unit 1000. preferable. More specifically, the system 1400 preferably includes an automated robotic robot that is movable in x, y, and z directions so that at least selected nozzles 150 of the nozzle array can be adjusted relative to the position of the inlet cone 1030. System.

  There are many commercially available robotic systems 1400 suitable for use with the present invention. Typically, the robot system 1400 has at least an x, y, z coordinate drive system to adjust the device 100 until the appropriate x, y, z coordinates are determined and stored in the programmable system. It has become. Because the device 100 has a number of nozzles 150 that can be used for a given experiment or application, the system 1400 maps the x, y, z coordinates of the nozzles 150. This can be based on user input information such as nozzle array size. For example, if a device 100 with 96 nozzles 150 arranged in an 8 × 12 grid is selected, the user selects the grid array size (8 × 12) as the robot system 1400 user interface ( For example, a coordinate map is generated and the relative coordinate positions of all the nozzles 150 are indicated. The robotic system 1400 can receive other information regarding other parameters or features of the overall system, such as the type of mass spectrometer unit 1000, and the optimality of the spray nozzle 150 (one of the nozzles in the array). The x, y, z coordinates are determined and the robotic device 1400 moves the device 100 to set the spray nozzle 150 to the optimal coordinates.

  As soon as the spray nozzle 150 completes the spray operation, the robot system 1400 moves the device 100 to place the other one of the nozzles 150 in the optimal x, y, z coordinates. Thus, when the spray operation is complete, each nozzle 150 is set to the optimal x, y, z coordinate so that a sufficient amount of sample is injected into the inlet cone 1030 for each spray operation. In one exemplary embodiment, the robot system 1400 has a base that is movable in at least two directions. The movement is performed by being guided along, for example, a guide rail. In addition, a robot arm or the like is connected to the base, and is similarly movable in one or more directions. Preferably, the robot arm is movable in many directions, and one end of the support portion 1132 is connected to the robot arm so that the holder 1120 is supported by the robot arm, and thus the movement of the robot arm is controlled by the holder. It changes directly to the movement of 1120.

  Determining the optimal x, y, z coordinates depends on many different parameters, so that the goal of having a sufficient jet can be realized. Some of these parameters include electrical spray characteristics and nozzle tip opening diameter, and the user preferably observes the mass spectrometer unit 1000 when injecting a liquid sample. By changing the applied voltage, the jet profile of the sample liquid can be changed. Thus, changing any of the above parameters in addition to others can change the jet of the liquid sample and ensure that a sufficient amount of liquid sample is injected into the inlet cone 1030. The device 100 can be positioned above the inlet cone 1030 such that individual nozzles 150 point downward toward the inlet cone 1030 (see FIG. 23), but the axis through the nozzle opening is the inlet The device 100 can also be positioned so that it is axially aligned with the axis through the cone 1030 (see FIG. 29). In this embodiment, the nozzle tip is spaced from the opening in the inlet cone 1030 such that a sufficient amount of ionized sample is injected into the opening extending through the inlet cone 1030. It has become.

  As best illustrated in FIGS. 26-28 and 31-32, according to one aspect of the invention, the frame 1100 is metallized in a selected region and the inner surface of at least one of the rails 1140, 1422 is metallized. Thus, an appropriate voltage potential (eg, ground potential in one example) is applied to the frame 1100 of the device 100 when the frame 1100 is placed in the space 1144 between the rails 1140 and 1142. The high voltage required for spraying may also be applied to the liquid in the nozzle 150 through a metallized path from the reservoir 160 behind the nozzle 150 to the inner surface on the other side of the space 1144. Alternatively, a high voltage can be applied through a separate electrode located in the reservoir 160 behind the nozzle 150.

  For example, in the embodiment shown in FIGS. 26-28 and 31-32, the inner surface of one of the rails 1140, 1142 is metallized to form a conductive metallized path on the frame 1100, and the device 100 By functioning as a means for grounding or as a means for applying a high voltage to device 100, nanospray applications can be implemented. A first conductive path (electrical path) 1143 is formed on the flat platform 1130. The first conductive path 1143 includes a first end 1145 and a second end 1147. Second end 1147 terminates at rail 1140 and is in electrical contact with the conductive material on the inner surface. The second conductive path (electrical path) 1151 is also formed on the flat platform 1130. Second conductive path 1151 includes a first end 1153 and a second second end 1155. Second end 1155 terminates in rail 1142 and is in electrical contact with the conductive material on the inner surface. Preferably, the first conductive path 1143 is formed along one side edge of the flat platform 1130 and the second conductive path 1151 is on the opposite side edge of the flat platform 1130. Is formed. Each of the first ends 1145, 1153 can terminate in a contact pad or enlarged region adapted to connect to either a high voltage source or ground. The first and second conductive paths 1143, 1151 can be formed using any number of conventional techniques. For example, using a printing process to place the conductive material according to a defined path. Since one of the paths 1143 and 1151 functions as a high-voltage path and the other paths 1143 and 1151 function as ground paths, the two paths cannot intersect.

  In one embodiment, a conductive metallized path extends from the edge of the frame 1100 and traverses the device 100 to the reservoir behind the nozzle 150, thus causing the high voltage to flow to the liquid behind the nozzle 150. Applied to ionize the sample as it passes through the nozzle 150. Each nozzle reservoir 160 has an associated unique metallized path to the edge of the frame 1100 so that when the frame 1100 is placed in the space 1144, the metallized formed at the edge of the frame 1100. A path can be placed in electrical contact with one of the metallized inner surfaces of rails 1140, 1142. Alternatively, branching the metallized path into several branches a single metallized line at the edge of the frame 1100 into two or more metallized lines to reach two or more reservoirs 160 can do. This type of arrangement is advantageous when there is a need to simultaneously apply voltages to a particular group of nozzles or when there are a significant number of nozzles 150 and each reservoir 160 associated with each reservoir is a frame This is the case when the metallized lines are quite dense at the edges of the frame 1100 when they have their own unique metallized lines that extend to the edges of 1100. The metallized surfaces of individual rails 1140, 1142 are then operatively connected to a high voltage source, and the other rail 1140, 1422 is grounded by any number of conventional techniques. This includes, for example, forming a metallized surface on the other rail 1140, 1142 and connecting the metallized surface to ground. It is also understood that the other rails 1140, 1142 need not be grounded by including a metallized inner surface. This is because there are many other ways to obtain ground. For example, by bringing the device 100 and the entrance cone 1030 in close proximity, the entrance cone 1030 can function as a ground without contacting the frame 1100.

  The amount of conductive material disposed on one or more inner surfaces of the rails 1140, 1422 and its exact pattern can vary from application to application. For example, the exact pattern of conductive material on each rail 1140, 1422 depends on the pattern of conductive paths formed on the frame 1100. In other words, the two conductive surfaces must fit together to form an electrical path between them. 26 to 27 illustrate a state in which the device 100 is not disposed in the holder 1120, and FIG. 28 illustrates a state in which the holder 1120 securely holds the device 100 between the rails 1140 and 1142. Illustrate. FIG. 28 also illustrates a state where the lateral movement of the device 100 is prevented by the posts 1160 located on both sides of the front rail 1140.

  Alternatively, neither the frame 1000 nor the inner surfaces of the rails 1140, 1142 are provided with a conductive metallized coating, but rather a wire or the like can be inserted directly into the liquid sample placed in the reservoir 160. Multiple ends of the wire are connected to a high voltage source to expose the liquid sample to a high voltage state through the wire in operation. This serves to ionize the liquid sample when it moves from the reservoir 160 through the nozzle 150 to the tip opening. The frame 1100 can be grounded using any number of techniques, including, for example, an entrance cone 1030 that functions as a ground for the device 100 to be proximate to the device 100.

  FIG. 29 illustrates a nanospray device interface 1660 in combination with the mass spectrometer unit 1000. A mounting mechanism 1610, such as a positioning system 1400, is provided that translates x, y, z, and a holder 1120 is securely attached thereto. In this embodiment, electrical contacts such as conductive paths 1143 and 1151 are formed on the holder 1120. Since the holder 1120 is supported at least in part by the mounting mechanism 1610, the translational movement of the mounting mechanism 1610 translates into movement of the holder 1120.

A cover 1620 of the mass spectrometer unit 1000 is disposed around the inlet cone 1030 and the frame 1100 and functions in the manner described above. In this embodiment, the device 100 is vertically oriented and positioned directly opposite the inlet cone 1030 and the target nozzle 150 delivers a sufficient amount of ionized spray into the opening formed through the inlet cone 1030. In addition, in another embodiment illustrated in FIGS. 24, 25, 30, a metallized capillary 1300 is used and its metallized tip portion is positioned in or proximate to reservoir 160. Has been. The capillary 1300 serves to inject a liquid sample into the reservoir 160. A high voltage is applied to the conductive portion through a metal or other conductive coating on the capillary 1300 so that the injected sample is charged. As the liquid sample flows out of the capillary into the microfluidic channel and into the nozzle 150, the liquid sample 150 becomes charged when it comes into contact with a conductive coating held at a high voltage at the opening of the capillary. When using a metallized or conductive capillary 1300, the capillary 1300 can be supported by a capillary holder 1310 (parallel to the microfluidic device 100) connected to the flat platform 1130 of the holder 1120, and the liquid sample can be Injecting into the capillary 1300 in a conventional manner, the metallized portion of the capillary 1300 is operably connected to a high voltage source. When using the metallized capillary 1300, there is no need to form a metallized path inside the device 100. This is because the high voltage source is connected to the capillary 1300 and not to the device 100.

  31 to 32 illustrate an embodiment in which an electrical path (electrode arrangement) is formed on the nozzle device 100 and the frame 1100. FIG. 31 is a plan view of the reservoir side of one exemplary embodiment, where the frame 1100 in which the device 100 is disposed includes tabs 1101 to facilitate handling of the frame 1100. In the exemplary embodiment, device 100 includes four nozzles 150, along with their corresponding reservoirs. A pair of external conductive paths 1181 are formed across the device 100 and the frame 1100. More specifically, an external conductive path 1181 extends along the two edges 1183, 1185 of the device 100. One end of the external conductive path 1181 ends at or near the entrance to the microfluidic channel connecting the reservoir 160 to the nozzle 150. The other end of each path 1181 extends from edge 1187 across frame 1100 to conductive tab 1191 formed at the edge of frame 1100. The conductive tab 1191 is preferably larger in size than the path 1181. As a result, the conductive tab 1191 is configured with an increased area of conductive material for making electrical contact with one or more electrodes formed as part of the device holder 1120. The conductive path 1181 and the conductive tab 1191 can be formed of any number of conductive materials if suitable. This is, for example, a noble metal coating or other material that can be printed according to a desired pattern on the surface of the device 100 and the frame 1100.

  A pair of internal conductive paths 1193 are formed across the device 100 and the frame 1100. The formation is performed at a location similar to, but different from, the external conductive path 1181. More specifically, the external conductive path 1181 extends from the remaining two reservoirs 160 to the edge 1187 and is formed between the two external conductive paths 1181. Like the external conductive path 118, each internal conductive path 1193 terminates at or near the entrance to the microfluidic channel formed through one reservoir 160. The other end of each path 1193 extends from edge 1187 across frame 1100 to conductive tab 1191 formed at the edge of frame 1100. Since the reservoir 160 associated with the internal conductive path 1193 is closer to the edge 1187, the length of the internal conductive path 1193 is shorter than the length of the external conductive path 1181. Each external conductive path 1181 is formed such that a relatively long straight portion does not interfere with the other reservoir 160 along one of the edges. In this embodiment, four conductive tabs 1191 are formed along the edges of the frame 1100, one for each of the conductive paths associated with one reservoir 160. Tabs 1191 are spaced apart from one another. However, the exact spacing and placement of the tabs 1191 is not important, rather it is a matter of design choice.

  FIG. 32 is a cross-sectional view through one nozzle of the device 100 according to another embodiment. As shown, the device 100 includes a nozzle 150 and a reservoir 160. According to one embodiment, a capillary 1195 is provided for pumping a liquid sample into the nozzle 150. The capillary 1195 is connected at one end to a liquid sample source. On the other hand, the other end is disposed through the microfluidic channel 30 formed through the nozzle 150. A conductive coating 1196 is disposed on a part of the capillary 1195. Preferably, the conductive coating 1196 is formed along the outer surface of the capillary 1195 from the point inside the end 1197 where the capillary 1195 enters the microfluidic channel behind the nozzle 150 to the end 1197 itself. In other words, the conductive coating 1196 is formed along the end portion of the capillary 1195. Capillary 1195 also includes an electrical contact 1198 that is electrically connected to a high voltage source. An electrical contact 1198 is connected to the capillary 1195 at a point along the conductive coating 1196 so that an electrical connection can be established between the high voltage source and the capillary 1195. Preferably, the diameter of the microfluidic channel 30 is approximately or equal to the outer diameter of the conductor coated capillary 1195 so that the capillary 1195 passes through the back of the reservoir 160 into the nozzle 150 and through the nozzle 150. A liquid-tight seal is assured when placed at the nozzle tip. By flowing a liquid sample through capillary 1195 and simultaneously applying a high voltage to conductive coating 1196 through electrical contact 1198, the liquid sample can be vaporized and ionized for use in nanospray applications.

  FIG. 33 illustrates a microfluidic device 1800 according to yet another aspect of the present invention. Microfluidic device 1800 is very similar to device 100. Therefore, only the differences between the two devices are described below. That is, the microfluidic device 1800 is a microfluidic device formed of a plastic material that is injection molded to form a structure in which an array of nozzles is formed as part thereof. In contrast to device 100, device 1800 is configured to be able to supply more than one nozzle 1810 from one reservoir 160. More specifically, each reservoir 160 has a base floor 1820 that is actually the interface between the reservoir 160 and two or more nozzles 1810. Base floor 1820 is preferably a flat floor. Many openings are formed in the base floor 1820, each opening corresponding to an inlet to one of the nozzles 1810. The microfluidic channel portion 1812 that forms each nozzle 1810 tapers inwardly at the distal end to define a nozzle tip 1814 that terminates in the nozzle opening 1816. Thus, nozzle opening 1816 is an opening formed along one side of device 1800 and the other side includes a much larger opening corresponding to the inlet to reservoir 160.

  Preferably, each nozzle opening 1816 has a diameter of about 20 to about 50 μm. The nozzle openings 1816 can be arranged in a regular or irregular configuration, wherein the spacing between the nozzle openings 1816 is preferably greater than 50 μm and up to about several hundred μm or more. In the cross-sectional view of FIG. 32, a large number of nozzles 1810 are arranged linearly, for example, along a row. Device 100 can be configured to include only one reservoir 160 such that a plurality of nozzles 1810 are in fluid communication with one reservoir 160 and one reservoir supplies a plurality of nozzles 1810 with a liquid sample.

  In yet another aspect of the present invention, an improved process for spraying liquid from droplets into a vapor jet using a polymer nozzle array device, such as device 100, is provided. Spraying liquid with the help of an electric field through a narrowed opening is a well-known process for generating a vapor jet for various applications. In mass spectrometer applications, a vapor jet carrying ions of a molecule of interest is sent into the mass spectrometer unit 1000 where the molecular ion mass is obtained. From the molecular mass, the chemical properties of each molecule are obtained. In the prior art, an electric field large enough to generate a vapor jet is obtained by a narrow opening or nozzle with a small radius. This is because the electric field at the nozzle is inversely proportional to the nozzle radius. Some examples of such nozzle devices include glass capillaries with one end tapered to a diameter of less than 30 μm and the outer surface at the tapered end as an electrode and micromachined silicon nozzle. It is intended to function. When the silicon nozzle is fabricated on a flat substrate, the liquid sample coming through the nozzle is charged with a high voltage while the outer surface of the nozzle 150 is held at a ground potential. The wall of the nozzle 150 can be approximately 12.5 μm thick, and the electric field generated by the distance between the charged liquid and the ground potential of the outer wall of the silicon nozzle (ie a distance of approximately 12.5 μm) causes the nozzle An additional electric field is generated that is comparable in strength and intensity to that generated by the diameter. In both of these cases, the physical dimension of the nozzle radius is important in determining whether the electric field strength generated by a given applied voltage is sufficient to evaporate the liquid into a jet.

  The disadvantages of the above process are as follows. (1) The outer diameter of the nozzle 150 must be very small, i.e. less than 35 μm, so that expensive manufacturing processes such as microfabrication techniques including photolithography and reactive ion etching, or one nozzle 150 A laser pulling that can be formed by each pull is required. (2) When the outer diameter of the nozzle 150 is limited to less than 35 μm, the inner diameter of the nozzle 150 inevitably decreases to 10 μm. These inner diameters lead to clogging of the nozzle with a liquid sample in which a large number of large molecules are suspended. (3) Since the outer diameter of the nozzle is small, the nozzle is easily broken and easily damaged during daily handling.

  The process is suitable for using the polymer nozzle device 100 to apply a voltage to the liquid to spray the liquid through the nozzle 150 in the form of droplets, vapor jets, or multiple vapor jets. While the liquid placed behind the nozzle 150 is pumped through the nozzle 150 by liquid or gas pressure means, a sufficiently high voltage, usually in the range of about ± 1 to 3.5 KV, is located behind the nozzle 150. The liquid to be applied is applied through electrodes. The electrode may be inserted into a space behind the nozzle 150 (eg, reservoir 160) or a precious metal coating such as gold in the area behind the nozzle 150 that contacts the electrode before the liquid sample exits the nozzle opening. It may be a built-in electrode formed by deposition. As the liquid exits the nozzle opening, the entire tip of the liquid, known as the tailor cone due to the effect of the electric field formed at the liquid tip, is sprayed out of the nozzle opening. When the applied voltage is increased, the spray shape changes from a large droplet having a diameter of several hundred μm to a fine droplet of mist or vapor. For mass spectrometry, a spray with fine droplets or vapor is preferred. When the liquid in a droplet evaporates with or without the aid of a desolvent gas (usually nitrogen gas flowing into the jet droplet from the opposite direction), the ions confined in each droplet are fine Released from the droplet. The ions are then analyzed by entering the mass selector of the mass spectrometer.

  There are alternative processes for operating the nozzle device to obtain ions from a liquid sample for mass analysis. In the process described above, the liquid sample is continuously pumped through the nozzle opening while a high voltage is applied to the liquid sample to obtain a fine droplet spray. In an alternative process, a liquid sample placed in a microfluidic channel behind the nozzle is not pumped through the nozzle. That is, the liquid flow rate through the nozzle is zero. A high voltage is applied to the liquid sample through the conductive end of the capillary as shown in FIG. The electric field acting on the droplets in the microfluidic channel causes evaporation and ionization of the liquid sample. The ions formed during this process do so without being constrained by the large number of sprayed droplets. These ions thus formed leave the microfluidic channel through the nozzle opening 150 and travel to a lower potential on the reference electrode at the entrance of the mass spectrometer for analysis. In this way, with less than 200 nl of sample initially contained within the microfluidic channel, a sufficient amount of ions for mass analysis can be generated continuously for over 20 minutes. This mode of operation is particularly beneficial when only nano-scale quantities of samples that require high-precision analysis during long-term measurements are available for measurement.

  In the prior art, there is a similar mode of nanospray for liquid samples in capillary tubes that are tapered at the end of the spray and have very small openings (usually a few μm in diameter). This is realized without using any external pumping means. Using small capillary tubes with such tapered ends creates a number of problems because these tapered ends are very fragile and susceptible to destruction and damage. . Therefore, filling such a tube with a liquid sample is very troublesome. In addition, the small tapered opening at its tip tends to clog. In the disclosed process, the liquid sample contained within the microfluidic channel is placed there, with the help of a robust method such as a robotic liquid distributor, or the end portion of a standard capillary tube. This may be done by dipping in a liquid sample container and taking out the droplets. If a standard capillary tube is used, the capillary tube does not have a tapered configuration at one end, but preferably is substantially the same width along its entire length. For example, a tubular capillary member is suitable for use. It is possible to use structures other than capillary tubes, as long as the ends of the structure are electrically charged and the shape and size of the ends are such that a liquid sample droplet can be formed there. I understand that.

  A drop of liquid sample, preferably less than 200 nl, is initially held at the flat open end of the capillary tube in the microfluidic channel of the nozzle device and extends beyond this end. The relative surface tension and other properties of the liquid sample and the hydrophobicity of the polymer microfluidic channel favor the formation of small droplets (liquid tip) at the end of the capillary tube. On the outer surface of the capillary tube, a conductive layer is formed at least at an end portion where a droplet is formed. After the capillary tube is inserted through the reservoir portion into the channel and into the nozzle so that the droplet is contained within the nozzle, the capillary tube conductive layer is coupled to a high voltage source and the voltage source Is activated to generate an electric field, thereby generating an electric field at this end. When a high voltage is applied to the capillary tube, the droplet (liquid sample) extends to form a conical shape, the tip of which evaporates, and ions of the sample molecules and very fine nanoscale or picoscale liquid Drops are formed and charge is carried. In contrast to vapor jets generated in conventional nanospray applications, the present invention does not have a liquid spray component defined in much the same way as in conventional nanospray applications. Instead, the release consists of ions and very small droplets (eg, nanoscale or smaller dimensions). Advantageously, this results in eliminating or substantially reducing the need for a drying mechanism to dry the droplets and release the ions. In the case of conventional nanospray applications, a solvent removal gas is very often required to dry the droplets by flowing dry nitrogen gas into the vapor jet. That is, the method reduces the time and cost associated with pumping the sample through the capillary and also drying the droplets, and provides a less complex mechanism that consumes very little sample material. The The detailed mechanism of this ion generation method is not surely known. Another possibility is that a corona discharge occurs at the electrode in the partially filled microfluidic channel.

  One of the other differences between this technology (whether pumped or not) using polymer nozzle devices and conventional nanospray technology is that the electric field to evaporate and ionize the liquid sample Instead of the actual tapered structure of the tube, it is formed by the liquid tip (liquid sample droplet) due to its shape and position. Formation of the liquid tip is facilitated by the material properties of the microfluidic channel that contains droplets that are preferably materials that are not wetted by the liquid water-soluble sample. A polymer material or a material covered with a polymer layer is a suitable material. Materials with good thermal conductivity are also suitable, as are polymeric materials with impregnated electrical and thermal conductive additives such as carbon and metal particles. In the process disclosed above, the diameter of the polymer nozzle opening affects the voltage required to produce a given liquid spray. When the nozzle opening has a diameter of 20 to 30 μm, a fine spray of 40% methanol / 60% water can be formed by setting the applied voltage between ± 2 to 2.5 KV. When spraying at a diameter of about 50 μm, the applied voltage can be larger and can be about ± 3 to 3.5 KV. As soon as spraying begins, the voltage can be lowered to about 1.3 KV to maintain the spray. The nozzle outer diameter can vary between 50 and 150 μm. The outer diameter of the polymer nozzle can be greater than 150 μm.

  The reference electrode or the counter electrode can be arranged 0.5 mm to several mm from the nozzle opening. The closer the counter electrode is to the nozzle opening, the smaller the voltage applied to the liquid in order to start spraying. If the counter electrode is about 0.5 mm away from the nozzle opening by more than 1 mm, the required voltage difference is in the range of several hundred volts.

  The advantages of this process are as follows. (1) It is possible to produce nozzles with various inner diameters so as to meet the requirements of the flow velocity range and the contents of the liquid sample without greatly affecting the applied voltage. (2) A sufficiently fine structure can be formed in nozzles made from various polymer materials by micro injection molding technology for polymers, and injection molding is a low cost manufacturing technology. (3) Using a nozzle having a relatively large outer diameter, it is possible to generate a fine jet whose characteristics are comparable to those of a jet generated by a small nozzle, and the possibility of physical damage to the nozzle due to the large outer diameter Minimize.

  The inner diameter of the nozzle can be made large enough to spray droplets of viscous liquids such as polymer solutions and can be applied to array spotting and polymer nanospray particle production. Organic arrays used in inductive LED displays, conventional dies used in conventional ink jet printing, and other materials that require fine or nanoscale droplets can be sprayed using these array devices. By doing so, it is possible to realize high speed together with high resolution droplets. This design configuration thus overcomes the aforementioned disadvantages associated with the prior art.

  34-35, as described above, spraying liquid through a narrowed opening with the aid of an electric field is a well-known process for generating a vapor jet for various applications. . In mass spectrometry applications, a vapor jet carrying ions of a molecule of interest is sent into a mass spectrometer where the mass of molecular ions is obtained. From the molecular mass, the chemical properties of each molecule are identified.

  Each of the aforementioned polymer nozzle array devices (e.g., device 100) has a relatively large surface area proximate to a spray containing multiple ionic species. These charged species can strike the polymer surface of the nozzle array device and generate an electrostatic field. The electrostatic field changes in an unpredictable manner as the number of charged species impinging on the polymer surface during spraying increases. If the charge is not drained from the insulating polymer surface in any way, stray electric fields accumulate on the insulating surface, thus preventing the ions being sprayed from entering the entrance cone 103 of the mass spectrometer 1000. If the build-up of the stray electric field is sufficiently large, the electric field sensed by the droplet at the nozzle tip becomes small, and the spray is completely stopped.

  There are many different techniques or means for preventing or controlling the formation of an electric field on a polymer nozzle array device. The following are some typical means of suppressing or controlling the build-up of the electric field on the polymer nozzle array surface. It is understood that one or more of the following methods of discharging stray field build-up can be incorporated into a nozzle array device. First, the surface of the polymer nozzle array device can be coated with a layer of high resistivity (eg, about 1 GΩ) conductive material. The material can be a thin layer coating of a noble metal, or a salt layer coating. Suitable salts for use can be selected from sodium iodide, rubidium iodide, silver halide, barium sulfate and the like. Second, an appropriate value capacitor can be electrically connected between the polymer nozzle array device surface and electrical ground. The capacitor is charged by stray ions and charges from the electrons and discharges the charges to electrical ground at controlled intervals. Third, a salt solution containing sodium iodide and rubidium iodide can be added to the sample liquid for spraying to allow the salt layer to coat the device surface and remove stray charges during spraying. can do. Fourth, an antistatic agent can be added to the polymer resin during the injection molding process so that the resulting polymer nozzle device has antistatic properties. The antistatic agent can be a highly conjugated polymer, such as polyaniline. Similarly, a pre-mixed commercially available antistatic polymer resin, such as that supplied by HiTech (Hebron, KY), is used to form a polymer nozzle array with suitable antistatic properties. The device may be injection molded. The preferred antistatic polypropylene is particularly suitable.

  Fifth, and as illustrated in FIGS. 34-35, a conductive shield 1900 made of a metal sheet or metal-coated insulator is connected to the nozzle tip and mass spectrometer inlet (eg, inlet cone 1030 in FIG. 23). Can act as a physical barrier to catch the sprayed droplets (the droplets could otherwise fall onto the surface of the nozzle array device 100) . The shield 1900 must have an aperture 1910 and be positioned approximately 1 mm from the nozzle tip. The aperture 1910 must be large enough to allow the start of the spray to pass. Figures 34-35 illustrate one exemplary arrangement of the shield 1900. In this configuration, shield 1900 is held at a distance defined by the height of post 1160 on frame 1100 of device 100. Although the distance between the shield 1900 and the nozzle tip varies depending on the length of the post 1160, this distance is preferably less than 1 mm. In other words, the shield 1900 can be attached to the post 1160 and spread across the device 100 to form an aperture 1910 associated with each nozzle 150 in the shield 1900. In one exemplary configuration, the dimensions of the shield 1900 can vary, but the thickness of the shield 1900 is about 0.005 inches to 0.010 inches.

  There are many different ways to attach the shield 1900 to the post 1160. For example, a sticky or adhesive material can be applied to the location of post 1160 and / or selected shield 1900. In addition, the shield 1900 can include a number of hubs equal to the number of posts 1160. Each post 1160 mates with a hub to removably couple shield 1900 to post 1160, thereby coupling shield 1900 to frame 1100 and microfluidic nozzle array device 100. In one exemplary embodiment, each hub is in the form of a hollow protrusion (eg, a tube-like structure) that extends outward from the inner surface of the shield 1900 toward the frame 1100. The shield 1900 is attachably coupled to the frame 1100 by inserting a post 1160 into the hollow interior of the hub to ensure that the two portions are coupled together. If it is desired to remove the shield 1900, the shield 1900 can simply be pulled from the post 1160. Having a shield removable from the microfluidic device 100 and holder 1120 allows for compatibility of individual components. For example, the configuration of shield 1900 depends on the configuration of device 100, and more specifically on the number and placement of nozzles 150. This is because one aperture 1910 is required for one nozzle 150. That is, if the device 100 has the first array arrangement, the first shield 1900 is required. If the device 100 has a second array arrangement that is different from the first arrangement, a second shield 1900 may be required. Further, since the shield 1900 is not rigidly connected to the holder 1120 or formed integrally with the holder 1120, the holder 1120 can be used with many different shields 1900 and the microfluidic device 100. Can do.

  In an alternative embodiment, shield 1900 is removably coupled to holder 1120 using a mechanical fastener. For example, the shield 1900 can have a fastening tab extending outwardly therefrom to receive a fastener fixedly attached to the holder 1120 itself, so that the shield 1900 is secured to the holder 1120 but Can be removably attached. In other words, the shield is removably attached to the holder 1120 using a fastener such as a screw. In this embodiment, the shield 1900 is preferably in a position such that the inner surface of the shield 1900 fits the post 1160 after the shield 1900 is securely secured to the holder 1120. This is desirable because the post 1160 can then be used to place the shield 1900 at an appropriate distance from the nozzle tip. Thus, regardless of the actual configuration of the shield 1900, evenly placing the shield 1900 at a predetermined distance from the nozzle tip ensures that the shield 1900 fits the post 1160 after the shield 1900 is secured to the holder 1120. By doing so, it becomes possible. In this embodiment, the shield 1900 can be placed above the rail 1140 or on a flat platform 1130. The shield 1900 can also be fabricated as an integral part of the post 1160 in that the frame 100, post 1160, and shield 1900 can be integrally attached thereto using a molding process.

  In yet another embodiment, the rail 1140 can be configured with a longitudinal groove extending therein. The longitudinal groove is sized so that the shield 1900 can be snugly received therein to securely couple the shield 1900 to the holder 1120. In other words, the friction fit between the shield 1900 and the rail 1140 ensures that the shield 1900 is held in a vertical position and parallel to the microfluidic device 100. Again, when the shield 1900 is securely held in the groove of the rail 1140, the shield 1900 preferably fits the post 1160 for the reasons described above. In this embodiment, the shield 1900 is removable because it can be easily pulled out of the groove in the rail 1140.

  Sixth, and as illustrated in FIG. 36, the nozzle array device 100 reduces the amount of plastic perpendicular to the spray direction by placing through holes 1930 in the surface of the array device 100. it can. In this embodiment, the body of the nozzle cone (nozzle 150) is made longer so that the distance between the nozzle tip and the flat surface of the nozzle array device 100 perpendicular to the spray direction is maximized. can do.

  It is understood that the above-described means for suppressing or controlling the build-up of the electric field on the surface of the polymer nozzle array can be used in combination with any of the microfluidic nozzle array devices disclosed herein. The

  Although the invention has been particularly shown, described, shown and described with reference to preferred embodiments, it is to be understood that various changes in form and details may be made without departing from the spirit and scope of the invention. Understood by the vendor.

FIG. 1 is a top perspective view showing a microfluidic device having an array of nozzles incorporated therein according to a first exemplary embodiment. FIG. 2 is a cross-sectional view taken along line 2-2 of FIG. FIG. 3 is a plan view showing the microfluidic device according to FIG. 1, illustrating the arrangement of the electrodes around the nozzle and the connection between the electrodes and the electrical contacts formed on one edge of the microfluidic device. Yes. FIG. 4 is a top perspective view showing a microfluidic device having an array of nozzles incorporated therein according to a second exemplary embodiment. FIG. 5 is a cross-sectional view of the microfluidic device according to FIG. FIG. 6 is a perspective view showing a typical mold used for manufacturing the microfluidic device of FIG. FIG. 7 is a cross-sectional view showing the first and second dies in the closed position used for manufacturing the microfluidic device of FIG. FIG. 8 is a cross-sectional view illustrating the first and second dies of the mold, illustrating another embodiment in which a gap is formed between the pins of the first mold and the nozzle forming features of the second mold. ing. FIG. 9 is a cross-sectional view illustrating a mold arrangement for producing micron sized nozzle openings. FIG. 10 is a top view showing a tile arrangement in which each strip is formed from a number of interconnected strips including an array of nozzles, one of the strips being removed and placed in proximity to the mass spectrometer. . FIG. 11 is a cross-sectional view of one microfluidic channel / nozzle arrangement, with a member having a polymer cover sheet that can be inserted into and moved within the reservoir to release the sample through the nozzle opening. The sample reservoir is sealed. FIG. 12 is a cross-sectional view of one microfluidic channel / nozzle arrangement, with a member having a resilient seal base that can be inserted into and moved within the reservoir to release the sample through the nozzle opening. The sample reservoir is sealed. FIG. 13 is a cross-sectional view showing one microfluidic channel / nozzle arrangement, in which the sample is drawn by a piston device with a hole extending through it to inject fluid into the sample reservoir and release the sample through the nozzle opening. The reservoir is sealed. FIG. 14 is a plan view showing a typical microfluidic nozzle array device. FIG. 15 is a cross-sectional view taken along line 14-14. 16 is a cross-sectional side view showing the microfluidic device of FIG. 5 used in UV spectrophotometry. FIG. 17 is a plan view showing a holding base for releasably holding a number of microfluidic nozzle / subunit structures. 18 is a cross-sectional view taken along line 18-18 in FIG. FIG. 19 is a plan view showing a holding base according to another embodiment for detachably holding a number of microfluidic nozzle subunit structures. FIG. 20 is a cross-sectional view illustrating an interface plate that can be used to assemble at least one microfluidic device having an array of nozzles. FIG. 21 is a cross-sectional view illustrating a microfluidic device having an array of nozzles with open end piping attached to a reservoir. FIG. 22 is a cross-sectional view illustrating an interface plate according to another embodiment that can be used to assemble at least one microfluidic device having an array of nozzles. FIG. 23 is a plan view showing a mass spectrometer unit and an apparatus for arranging a microfluidic device having an array of nozzles in the mass spectrometer unit regardless of its structure. FIG. 24 is a front view showing the microfluidic device of FIG. FIG. 25 is a side view showing the microfluidic device of FIG. FIG. 26 is a plan view showing a holder for securely holding the microfluidic device of FIG. FIG. 27 is a side view showing the holder of FIG. FIG. 28 is a plan view showing a state in which the microfluidic device is securely held in the holder of FIG. FIG. 29 is a side view showing the nanospray device interface of the unit in the mass spectrometer. FIG. 30 is a perspective view showing a holder for securely holding a microfluidic device and coupled to an apparatus that moves the microfluidic device to an extent that it can be positioned with respect to the mass spectrometer unit. FIG. 31 is a front view showing a microfluidic device having an array of nozzles and a plurality of electrodes formed thereon. FIG. 32 is a cross-sectional view through one nozzle and its associated reservoir of a microfluidic device according to another embodiment provided with a conductive capillary. FIG. 33 is a cross-sectional view through a microfluidic device to show a plurality of nozzle openings delivered from a single reservoir. FIG. 34 is a front view illustrating a microfluidic device having a frame according to another exemplary embodiment. 35 is a side view showing the microfluidic device and frame of FIG. FIG. 36 is a front view showing a microfluidic device having a frame according to still another embodiment.

Claims (21)

A body having a first surface and an opposing second surface, wherein at least one channel is formed therein and extends through the body from the first surface to the second surface; A body having a reservoir portion that opens at a surface;
At least one nozzle disposed along a second surface, wherein the nozzle is in fluid communication with the channel, wherein one end of the channel terminates in a nozzle opening formed as part of the nozzle; Comprises an injection molded article comprising a nozzle formed from an injection moldable polymer article;
Here, the outer diameter of the nozzle is Ru der about 150μm or less, disposable microfluidic devices.   The microfluidic device of claim 1, wherein the channel is cylindrically shaped along at least a substantial length thereof, and the channel is defined by a seamless cylindrical surface.   The microfluidic device of claim 1, wherein the channel is internally tapered such that the channel dimension is maximum within the reservoir portion and minimum at the nozzle opening.   The microfluidic device of claim 1, wherein the channel is formed in the reservoir portion such that the channel is substantially perpendicular to both the first and second surfaces.   The microfluidic device of claim 1, wherein the at least one nozzle extends beyond the second surface and is substantially conical.   The microfluidic device according to claim 5, wherein an outer diameter of the nozzle is about 50 μm or less.   The microfluidic device according to claim 1, wherein an outer diameter of the nozzle opening is about 50 μm or less.   The microfluidic device of claim 1, wherein a portion of the channel formed in the nozzle and ending in the nozzle opening is tapered inwardly toward the nozzle opening. The microfluidic device of claim 1, wherein the at least one channel and the at least one nozzle are arranged in a geometric array.   The microfluidic device of claim 1, further comprising a conductive region formed around an outer periphery of at least one nozzle on the second surface.   The microfluidic device of claim 10, wherein the conductive region is formed of a metal and is electrically connected to the electrical contact.   The channel has a first portion whose inner channel surface is parallel, the first portion at least partially defining a reservoir portion and extending to the first surface, the channel further comprising a non-inner channel surface. The microfluidic device of claim 1, having a second portion in a parallel relationship, the second portion extending from the first portion to the nozzle opening. A body having a first surface and an opposing second surface, wherein at least one channel is formed therein and extends from the first surface to the second surface through the body, the channel receiving the sample A body having a reservoir portion opening at a first surface for
At least one nozzle integrally formed with the body and disposed along and extending beyond the second surface, the nozzle being defined by a substantially non-parallel outer surface, the number of nozzles being the number of channels Each nozzle has a portion of a channel formed therethrough, each channel ending within the nozzle opening of the nozzle, the diameter of the nozzle opening being about 100 μm or less and the outer diameter of the nozzle being A disposable microfluidic device comprising: a nozzle portion defined by a non-parallel surface that is approximately 150 μm and the channel portion formed in the nozzle terminates at one end with the formation of the nozzle opening; Wherein the device is formed of a polymeric material.   14. The microfluidic device of claim 13, wherein the diameter of the nozzle opening is about 150 [mu] m or less and the outer diameter of the nozzle is about 100 [mu] m or less.   14. The microfluidic device of claim 13, further comprising a device for sealing the reservoir portion and for transporting the sample from the reservoir portion through the channel to a nozzle opening from which the sample is discharged. A seal in the form of a deformable elastic polymer cover sheet initially disposed over the open end of the reservoir portion, the seal being attached to the first surface and along the first surface Further comprising a seal and a mechanical plunger for engaging the polymer cover sheet;
When the mechanical plunger is driven to the extended position, the polymer cover sheet is deformed to form a seal with the inner surface of the reservoir portion to force the sample to flow toward the nozzle opening and release the sample there The microfluidic device according to claim 13. The transport device includes a displaceable member, the displaceable member including a base around which a deformable seal extends, the base initially disposed over the open end of the reservoir portion with a mechanical plunger on the base. Connected,
When the mechanical plunger is driven to the extended position, the base is received into the reservoir portion and the flange forms a seal with the inner surface of the reservoir portion to force the sample to flow toward the nozzle opening. The microfluidic device according to claim 15, which discharges a sample. The transport device comprises a member through which a hole is formed, a gasket disposed at the end of the member, the gasket forming a seal between the member and the reservoir portion;
16. The microfluidic device of claim 15, wherein the member is introduced into the reservoir portion to communicate with a source of fluid that forces the sample to flow toward the nozzle opening and releases the sample there. A detection system for detecting one or more characteristics of a sample, comprising:
A body having a first surface and an opposing second surface, wherein at least one channel is formed therein and extends through the body from the first surface to the second surface; A body having a reservoir portion that opens at a surface and at least one nozzle formed integrally with the body and extending along and extending along the second surface, the nozzle being a non-parallel outer surface The number of nozzles is equal to the number of channels, each nozzle having a portion of the channel formed therethrough, and each channel is within a nozzle opening formed as part of the nozzle. The diameter of the nozzle opening is about 100 μm or less and the outer diameter of the nozzle is about 150 μm or less, and the channel portion formed by the nozzle ends at one end together with the formation of the nozzle opening. And injection molding the microfluidic devices of the disposable formed nozzle, an injection moldable polymeric material with defined by the tapered inner surface that,
A detector for receiving a sample emitted from the microfluidic device through its nozzle opening, the detector analyzing the emitted sample and providing information regarding one or more characteristics of the sample; Including detection system. A device that interfaces with a mass spectrometer to perform nanospray applications,
A disposable microfluidic device including a body having a first surface and an opposing second surface, wherein at least one channel is formed within the body and passes through the body from the first surface to the second surface. And the channel has a reservoir portion that opens at the first surface and at least one nozzle disposed along the second surface, the nozzle in fluid communication with the channel, with one end of the channel at the nozzle Ending in a nozzle opening formed as part of the tip of the device, wherein the device comprises a microfluidic device formed from a polymer material;
A frame disposed around the outer periphery of the microfluidic device to ensure that the microfluidic device is held therein;
A holder having first and second holding members, wherein the first and second holding members are disposed at a sufficient interval, and a frame is disposed between these members, and a predetermined position is set by these members. A holder in which at least one nozzle for spraying the sample into the inlet of the mass spectrometer is positioned in the holding position ;
Here, the outer diameter of the nozzle is about 150 μm or less . A body having a first surface and an opposing second surface, the body having at least one channel formed therein, and from the first surface to the second surface, A body extending through the body, the channel having a reservoir portion that is open at the first surface;
At least one nozzle disposed along a second surface and having the channel length formed therethrough, whereby one end of the channel is formed as the distal end of the nozzle Ending at the opening, the device comprises an injection molded polymer article comprising: at least one nozzle formed from an injection moldable material, and wherein the channel length formed by the nozzle has a variable diameter ;
Here, the outer diameter of the nozzle is Ru der about 150μm or less, disposable microfluidic devices.

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