JP2009052744A - Microfabricated elastomeric valve and pump system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of fabricating an elastomeric valve structure. <P>SOLUTION: The method of fabricating an elastomeric valve structure comprises: forming a first elastomeric layer 20 on top of a micromachined mold, the micromachined mold having a first raised protrusion which forms a first recess extending along a bottom surface of the first elastomeric layer 20; forming a second elastomeric layer 22 on top of a micromachined mold, the micromachined mold having a second raised protrusion which forms a second recess extending along a bottom surface of the second elastomeric layer 22; bonding the bottom surface of the second elastomeric layer 22 onto a top surface of the first elastomeric layer 20 such that a control channel forms in the second recess between the first and second elastomeric layers 20, 22; and positioning the first elastomeric layer 20 on top of a planar substrate such that a flow channel 32 forms in the first recess between the first elastomeric layer 20 and the planar substrate. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

(Cross-reference of related applications)
This non-provisional patent application is a partial continuation application of non-provisional patent application No. 09 / 826,583 filed on Apr. 6, 2001. This non-provisional patent application No. 09 / 826,583 is a partial continuation application of the non-provisional patent application No. 09 / 724,784 filed on Nov. 28, 2000. This non-provisional patent application No. 09 / 724,784 is a partial continuation application of the non-provisional patent application No. 09 / 605,520 filed on June 27, 2000. This patent application claims priority from the following previously filed provisional patent applications: US Provisional Patent Application No. 60 / 141,503 (filed Jun. 28, 1999), US Provisional Patent Application No. 60/147. 199 (filed Aug. 3, 1999), and US Provisional Patent Application No. 60 / 186,856 (filed Mar. 3, 2000). The texts of these prior provisional patent applications are incorporated herein by reference.

(A statement on the right to an invention made under research and development with financial support from the federal government)
The work described herein is supported in part by the National Institutes of Health grant number HG-01642-02. The US government may therefore have certain rights in the invention.

(Technical field)
The present invention relates to a microfabricated structure and a method of fabricating a microfabricated structure, and relates to a microfabricated system for adjusting fluid velocity.

(Background of the Invention)
Various approaches have been attempted in designing microfluidic pumps and microfluidic valves. Unfortunately, each of these approaches is subject to its own limitations.

  The two most common methods of fabricating micro-electromechanical (MEMS) structures such as pumps and valves are silicon-based bulk microfabrication (after lithographic patterning of single crystal silicon, three-dimensional structures A subtractive manufacturing process that etches to form a surface layer microfabrication (polysilicon, silicon nitride, silicon dioxide, and various layers of semiconductor-type materials such as various metals are successively added and patterned 3 Additive manufacturing method for producing a dimensional structure).

  The limitation of the first approach of silicon-based microfabrication requires a high working force of the semiconductor material used, which in turn results in a large and complex design. In fact, both bulk and surface micromachining methods are limited by the hardness of the materials used. Furthermore, the adhesive between the various layers of the manufactured device is also a problem. For example, in bulk microfabrication, wafer bonding techniques must be employed to provide a multilayer structure. On the other hand, in the case of surface micromachining, the thermal stress between the various layers of the device often limits the total thickness of the device to about 20 microns. Use of any of the above methods requires clean room manufacturing and meticulous quality control.

(Summary of the Invention)
The present invention demonstrates a system for manufacturing and operating microfabricated structures made from various layers of elastomers bonded together, such as on / off valves, switching valves, and pumps. is doing. The structures and methods of the present invention are ideally suited for controlling and channeling fluid motion.

  In a preferred aspect, the present invention utilizes a multilayer flexible lithography process to build a monolithic (ie monolithic) microfabricated elastomeric structure.

  The advantage of manufacturing the structure by bonding together multiple layers of soft elastomeric material is that the resulting device is only two orders of magnitude larger than a silicon-based device A point to be reduced is mentioned. Furthermore, further advantages of rapid prototyping, ease of manufacture and biocompatibility are also achieved.

  In a preferred aspect of the present invention, a separate elastomeric layer is manufactured on top of the microfabricated mold so that a recess is formed in each of the various elastomeric layers. By bonding these various elastomeric layers together, the recesses that extend along the various elastomeric layers form flow channels and control lines through the resulting monolithic monolithic elastomeric structure. In various aspects of the invention, the flow channels and control lines formed in the elastomeric structure can be actuated to function as a fine pump and fine valve, as described below.

  In a further optional aspect of the invention, the monolithic elastomeric structure is sealed to the top surface of the flat substrate, wherein the flow channel extends along the surface of the flat substrate and the bottom surface of the elastomeric structure. It is formed between existing recesses.

  In one preferred aspect, the monolithic elastomeric structure is constructed by first casting each layer of elastomer separately from a microfabricated mold, and then bonding these two separate layers of elastomer together. The The elastomer used is a two-component addition curable material, and the bottom elastomer layer preferably has one component in excess, but the top elastomer layer preferably has the other component in excess. In an exemplary embodiment, the elastomer used is silicone rubber. The two layers of elastomer are cured separately. Each layer is cured separately before the top layer is placed over the bottom layer. The two layers are then glued together. Each layer preferably has an excess of one of the two components so that reactive molecules remain at the interface between the two layers. The top layer is assembled to the top surface of the bottom layer and then heated. The two layers are irreversibly bonded so that the interfacial strength approaches or equals that of the bulk elastomer. This results in a monolithic three-dimensional patterned structure consisting of two layers of elastomers bonded together as a whole. Additional layers can be added by simply repeating the same process, but in this case each new layer has an opposite “polar” layer and is cured together so that Combined.

In a second preferred aspect, a first photoresist layer is deposited on the top surface of the first elastomer layer. The first photoresist is then patterned, leaving a pattern of lines or lines of photoresist on the top surface of the first elastomer layer. Next, another layer of elastomer is added and cured to encapsulate a pattern of photoresist lines or lines. A second photoresist layer is added, patterned, and another layer of elastomer is added and cured to encapsulate the photoresist line or pattern of lines in a monolithic elastomeric structure. This process can be repeated, adding more encapsulated patterns and elastomer layers. The photoresist is then removed, leaving the flow channel (s) and control line (s) in the space occupied by the photoresist. This process can be repeated to create an elastomeric structure having multiple layers.

  The advantage of patterning appropriately sized features (> / = 10 microns) using a photoresist method is that a high resolution transparent film can be used as a contact mask. This allows a single researcher to typically do all of this within 24 hours to design, print, pattern the mold, and create a new set of cast elastomeric devices.

  A further advantage of any of the above embodiments of the present invention is that due to its monolithic properties, ie integral properties (ie, all layers are composed of the same material), interlayer adhesion failure and thermal stress. These problems are completely avoided.

  A further advantage of the preferred use of the present invention of a silicone rubber or elastomer such as RTV615 manufactured by General Electric is that it is transparent to visible light and allows multiple optical tandems to be used in a variety of microfluidic devices. To enable optical information interrogation of channels or chambers. A suitably formed elastomeric layer can act as a lens and an optical element so that the bonding of the layers allows the creation of a multilayer optical column. Furthermore, GE RTV615 elastomer is biocompatible. Even in the presence of small particulates in the flow channel, the closed valve forms a good seal because it is soft. Silicone rubber is also biocompatible and is particularly inexpensive when compared to single crystal silicon.

  Monolithic elastomeric valves and pumps also avoid many of the practical issues affecting fluid systems based on electroosmotic flow. As a typical example, electroosmotic flow systems suffer from bubble formation around the electrodes, and the flow is strongly dependent on the composition of the flow medium. Foam formation places strict restrictions on the use of electroosmotic flow in microfluidic devices, making it difficult to build a function-integrated device. Typically, the magnitude of the flow, and even the direction of flow, typically depends in a complex manner on ionic strength and ion type, the presence of surfactant, and the charge on the walls of the flow channel. Furthermore, since electrolysis occurs continuously, a final volume of buffer that resists pH changes can also be achieved. Furthermore, electroosmotic flow always occurs in competition with electroperistalsis. Since different molecules may have different electroperistaltic mobilities, unwanted electroperistaltic separation can occur in electroosmotic flow. Finally, electroosmotic flow cannot be readily utilized to stop flow, interrupt diffusion, or balance pressure differentials.

  A further advantage of the present monolithic elastomeric valves and pumps is that they can operate at very high speeds. For example, the present invention uses an aqueous solution therein to achieve a reaction time for the valve on the order of 1 millisecond, allowing the valve to open and close at speeds near 100 Hz or above 100 Hz. In particular, a non-limiting list of circulation speed ranges for opening and closing the valve structure includes between about 0.001 and 1000 ms, between about 0.01 and 1000 ms, between about 0.1 and 100 ms. And between about 1 and 10 ms. This circulation rate depends on the composition and structure of the valve used for the particular application and method of operation, and circulation rates outside this listed range are therefore within the scope of the present invention.

  A further advantage of the present pumps and valves is that the pumps and valves operate quickly due to their small dimensions and become resistant due to their flexibility. Furthermore, when the pump and the valve are linearly closed with a differential applied pressure, this linear relationship allows the flow rate of the fluid to be adjusted and the valve to be closed despite the high back pressure.

  In various aspects of the invention, a plurality of flow channels extend through the elastomeric structure, and the second flow channel extends across the first flow channel and above the first flow channel. In this aspect of the invention, the elastomeric film separates the first flow channel and the second flow channel. As described below, this downward movement of the membrane (due to the pressurized second flow channel or the oppositely activated membrane) blocks the flow through the lower flow channel.

  In any preferred aspect of the system, a plurality of individually addressable valves are formed connected together to the elastomeric structure and then actuated sequentially to achieve peristaltic pumping. . Networked control system or multiplexed control system, selectively addressable valves arranged in a latticed valve, networked reaction chamber system or multiplexed reaction chamber system And a more complex system comprising a biopolymer synthesis system.

  One embodiment of a microfabricated elastomeric structure according to the present invention comprises an elastomer block formed therein with first and second microfabricated recesses, this portion when a portion of the elastomer block is actuated. Comprises a portion of an elastomeric block that is deflectable.

  One embodiment of a method of microfabricating an elastomeric structure includes microfabricating a first elastomer layer and microfabricating a second elastomer layer; placing the second elastomer layer on top of the first elastomer layer; 2 bonding the bottom surface of the elastomer layer onto the top surface of the first elastomer layer.

  A first alternative embodiment of a method of microfabricating an elastomeric structure includes forming a first elastomeric layer on top of a first microfabricated mold, the first microfabricated mold comprising at least a first A raised protrusion, the first raised protrusion forming at least one first channel on the bottom surface of the first elastomer layer. The second elastomer layer is formed on top of the second microfabricated mold, the second microfabricated mold having at least one second raised protrusion, the second raised protrusion being at least one first raised protrusion. Two channels are formed in the lower surface of the second elastomer layer. The bottom surface of the second elastomer layer is bonded onto the top surface of the first elastomer layer, so that at least one second channel is enclosed between the first elastomer layer and the second elastomer layer.

  A second alternative embodiment of a method for microfabricating an elastomeric structure in accordance with the present invention includes forming a first elastomer layer on a substrate top, curing the first elastomer layer, and first sacrificial layer first. Depositing on the upper surface of the elastomer layer. A portion of the first sacrificial layer is removed, so that a first pattern of sacrificial material remains on the upper surface of the first elastomer layer. A second elastomer layer is formed over the first elastomer layer, thereby enclosing a first pattern of sacrificial material between the first elastomer layer and the second elastomer layer. The second elastomer layer is cured and then the sacrificial material is removed, thereby forming at least one first recess between the first elastomer layer and the second elastomer layer.

An embodiment of a method for operating an elastomeric structure in accordance with the present invention includes providing an elastomer block formed therein with a first microfabricated recess and a second microfabricated recess, wherein the first microfabricated recess and the first microfabricated recess. The two microfabrication recesses are separated by a part of this structure, and when one of the first recess and the second recess is pressurized, the part of this structure is the other of the first recess or the second recess. Bendable. One of these recesses is pressurized so that a portion of the elastomeric structure separating the second recess from the first recess can deflect to the other of these two recesses.

  In any other preferred aspect, a magnetic or conductive material can be added to create a layer of magnetic or conductive elastomer, thus allowing the fabrication of all elastomeric electromagnetic devices.

(Detailed description of the invention)
The present invention has a variety of microfabricated elastomeric structures that can be used as pumps or valves. A method of producing a preferred elastomeric structure is also specified.

(Method for producing the present invention)
Two specific methods of manufacturing the present invention are presented here. It should be understood that the present invention is not limited to production by one or the other of these methods. Rather, other suitable methods of manufacturing the microstructure are also contemplated, including modifications of the method.

  FIGS. 1-7B illustrate the sequential steps of the first preferred method of manufacturing the microstructure (which can be used as a pump or valve). FIGS. 8-18 illustrate the sequential steps of the second preferred method of manufacturing the present microstructure (which can also be used as a pump or valve).

  As described below, the preferred method of FIGS. 1-7B involves utilizing a pre-cured elastomer layer that has been assembled and bonded. Conversely, the preferred method of FIGS. 8-18 involves curing each layer of elastomer “in place”. In the following description, “channel” refers to a recess in an elastomeric structure that may contain a fluid or gas flow.

(First exemplary method)
Referring to FIG. 1, a first microfabricated mold 10 is provided. The microfabricated mold 10 can be manufactured by a number of conventional silicon processing methods, including but not limited to photolithography, ion-milling, and electron beam lithography.

  As can be seen, the microfabricated mold 10 has raised lines or protrusions 11 extending along it. The first elastomer layer 20 is cast on the top of the mold 10 so that a first recess 21 is formed in the lower surface of the elastomer layer 20 as shown (the recess 21 is a protrusion in size). 11).

  As can be seen in FIG. 2, the second microfabricated mold 12 is presented with the raised protrusions 13 extending along the body. The second elastomer layer 22 is cast on the top surface of the mold 12 as shown in the figure, and the recess 23 is formed on the bottom surface corresponding to the dimension of the protrusion 13.

  As can be seen in the sequential steps illustrated in FIGS. 3 and 4, the second elastomer layer 22 is then removed from the mold 12 and placed on the top surface of the first elastomer layer 20. As shown, a recess 23 extending along the bottom surface of the second elastomer layer 22 forms a flow channel 32.

  Referring to FIG. 5, separate first elastomer layer 20 and second elastomer layer 22 (FIG. 4) are then bonded together to form a monolithic (ie, monolithic) elastomer structure 24. is doing.

  As seen in the continuous process of FIGS. 6 and 7A, the elastomeric structure 24 is then removed from the mold 10 and placed on the top surface of the flat substrate 14. As can be seen in FIGS. 7A and 7B, the recess 21 forms a flow channel 30 once the elastomeric structure 24 is in close contact with the flat substrate 14 at its bottom surface.

  The elastomeric structure forms a reversible hermetic seal using almost any smooth and flat substrate. The advantage of forming a seal in this way is that the elastomeric structure can be peeled off, cleaned and reused. In a preferred aspect, the flat substrate 14 is glass. A further advantage of utilizing glass is that the glass is transparent and allows optical information response between the elastomeric channel and the reservoir. As an alternative, the elastomeric structure can be bonded onto the flat elastomeric layer in the same manner as described above to form a permanent high strength bond. This may prove advantageous when higher back pressure is utilized.

  As can be seen in FIGS. 7A and 7B, the flow channel 30 and the flow channel 32 are positioned at an angle with respect to each other so that the small film 25 of the substrate 24 separates the top surface of the flow channel 30 from the bottom of the flow channel 32. It is preferable to be in a state where

  In a preferred aspect, the flat substrate 14 is glass. The advantage of utilizing glass is that the elastomeric structure can be peeled, cleaned and reused. A further advantage of utilizing glass is that optical sensing can be employed. As an alternative, the flat structure 14 can be the elastomer itself, but this may prove advantageous if higher back pressure is utilized.

  The fabrication method just described can be varied to form a structure having a membrane composed of a different elastomeric material than that which forms the channel walls of the device. This modified manufacturing method is shown in FIGS.

  Referring to FIG. 7C, a first microfabricated mold 10 is provided. The microfabricated mold 10 has raised lines or protrusions 11 extending along it. In FIG. 7D, the first elastomer layer 20 is cast on the top of the first microfabricated mold 10 so that the top of the first elastomer layer 20 is flushed over the raised lines or protrusions 11. This can be achieved by carefully controlling the volume of elastomeric material spun onto the mold 10 relative to the known height of the raised line 11. Alternatively, the desired shape can be formed by extrusion.

  In FIG. 7E, a second microfabricated mold 12 having raised protrusions 13 extending along it is also provided. A second elastomer layer 22 is cast on the top of the second mold 12 as shown, so that a recess 23 is formed on its lower surface corresponding to the dimensions of the protrusion 13.

  In FIG. 7F, the second elastomer layer 22 is removed from the mold 12 and placed on top of the third elastomer layer 222. The second elastomer layer 22 is bonded to the third elastomer layer 20 using techniques described in detail below to form an integral elastomer block 224. At this point in the process, the recess 23 previously occupied by the raised line 13 forms a flow channel 23.

In FIG. 7G, the elastomer block 224 is disposed on top of the first microfabricated mold 10 and the first elastomer layer 20. The elastomeric block and the first elastomeric layer 20 are then bonded together to form a unitary (ie, monolithic) elastomeric structure 24 having a membrane composed of another elastomeric layer 222.

  When the elastomeric structure 24 is sealed at its bottom surface to a flat substrate in the manner described above in connection with FIG. 7A, the recess previously occupied by the raised line 11 forms a flow channel 30.

  The variant manufacturing method illustrated above in combination with FIGS. 7C-7G offers the advantage of allowing the membrane portion to be composed of a material other than the remaining elastomeric material of this structure. This is important. This is because the thickness and elastomeric properties of the membrane play an important role in the operation of the device. Moreover, this method allows another elastomeric layer to be easily subjected to a conditioning step before being incorporated into the elastomeric structure. As discussed in detail below, examples of potentially desirable conditions include incorporating magnetic or conductive species to enable operation of the membrane and / or changing this elasticity to change its elasticity. Incorporation of dopants into the film may be mentioned.

  Although the above method has been exemplified in combination with the step of forming elastomer layers of various shapes formed by replication molding on the top of the microfabricated mold, the present invention is not limited to this technique. Other techniques may be utilized to form separate layers of shaped elastomeric material that are bonded together. For example, the shape layer of elastomeric material may be formed by laser cutting or injection molding, or by a method that utilizes chemical etching and / or a sacrificial material, as discussed below in combination with the second exemplary method. obtain.

(Second exemplary method)
A second specific method of producing an elastomeric structure that can be used as a pump or valve is demonstrated in the sequential steps shown in FIGS.

  In this aspect of the invention, the flow is achieved by first patterning the photoresist on the surface of the elastomeric layer (or other substrate that can include glass), leaving the raised lined photoresist where the channel is desired. A channel and a control channel are defined. Next, a second layer of elastomer is added thereon and the second photoresist is patterned over the second layer of elastomer leaving a raised lined photoresist where a channel is desired. . A third layer of elastomer is deposited thereon. Finally, the photoresist is removed by dissolving it from the elastomer with a suitable solvent, and the void formed by the removal of the photoresist becomes a flow channel through the substrate.

  Referring initially to FIG. 8, a flat substrate 40 is presented. A first elastomer layer 42 is then deposited on the top surface of the flat substrate 40 and cured. Referring to FIG. 9, a first photoresist layer 44A is then deposited on the top surface of the elastomer layer. Referring to FIG. 10, a portion of the photoresist layer 44A is removed so that only the first line of photoresist 44B remains as shown. Referring to FIG. 11, a second elastomer layer 46 is subsequently deposited on the top surface of the first elastomer layer 42 and on the first line of photoresist 44B, as shown, A first line of photoresist 44B is encapsulated between the first elastomer layer 42 and the second elastomer layer 46. Referring to FIG. 12, an elastomeric layer 46 is cured on the layer 42 to bond the layers together, resulting in a monolithic elastomeric structure 45.

Referring to FIG. 13, a second photoresist layer 48 </ b> A is deposited on the elastomeric structure 45. Referring to FIG. 14, a portion of the second photoresist layer 48A is removed and a second photoresist line 48B is formed on the top surface of the elastomeric structure 45 as shown.
Leave only. Referring to FIG. 15, as shown, the elastomeric structure 45 (consisting of the second elastomer layer 42 and the first line of photoresist 44B) and the top surface of the second photoresist line 48B. A third elastomer layer 50 is then deposited on top of each other, thereby encapsulating a second line of photoresist 48B between the elastomeric structure 45 and the third elastomer layer 50.

  Referring to FIG. 16, a third elastomer layer 50 and an elastomer structure 45 (consisting of a first elastomer layer 42 and a second elastomer layer 46 bonded together) are then bonded together. A monolithic elastomeric structure 47, through which photoresist lines 44B and 48B penetrate, as shown. Referring to FIG. 17, photoresist lines 44B and 48B are then removed (eg, with a solvent) and a first flow channel 60 and a second flow channel 62 are provided in place, as shown. The elastomer structure 47 is passed through. Finally, referring to FIG. 18, the flat substrate 40 can be removed from the bottom surface of the monolithic monolithic structure.

  The method described in FIGS. 8-18 utilizes the generation of a photoresist encapsulated in an elastomeric material to produce a patterned elastomeric structure. However, the method according to the present invention is not limited to utilizing a photoresist. Other materials such as metals can also serve as a sacrificial material to be removed, selective to the surrounding elastomeric material, and this method is still within the scope of the present invention. For example, as described in detail below in combination with FIGS. 35A-35D, gold selective to the RTV615 elastomer can be etched utilizing a suitable chemical mixture.

(Preferred layer and channel dimensions)
Microfabrication refers to the size of the features of the elastomeric structure fabricated according to embodiments of the present invention. In general, deformation of a microfabricated structure of at least one dimension is controlled to the micron level with at least one dimension that is microscopic (ie, 1000 μm or less). Microfabrication typically includes semiconductor or MEMS fabrication techniques, such as photolithography and spin coating, designed for the creation of feature dimensions at the microscopic level, and includes microfabricated structures of at least some dimensions These dimensions require a microscope that reasonably resolves / images the structure.

In a preferred aspect, the flow channels 30, 32, 60 and 62 preferably have a width to depth ratio of about 10: 1. A non-limiting list of other ranges of width to depth ratios according to embodiments of the present invention is 0.1: 1 to 100: 1, more preferably 1: 1 to 50: 1, more Preferably from 2: 1 to 20: 1, and most preferably from 3: 1 to 15: 1. In an exemplary aspect, the flow channels 30, 32, 60 and 62 have a width of about 1 to 1000 microns. An enumeration of other non-limiting flow channel widths according to embodiments of the present invention is 0.01 to 1000 microns, more preferably 0.05 to 1000 microns, and more preferably 0. .2 to 500 microns, more preferably 1 to 250 microns, and most preferably 10 to 200 microns. Exemplary channel widths are 0.1 μm, 1 μm, 2 μm, 5 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm. 180 μm, 190 μm, 200 μm, 210 μm, 220 μm, 230 μm, 240 μm and 250 μm, 160 μm
including.

The flow channels 30, 32, 60 and 62 have a depth of about 1 to 100 microns. A non-limiting list of depths of other ranges of flow channels according to embodiments of the present invention is 0.01 to 1000 microns, more preferably 0.05 to 500 microns, more preferably 0.2 to 250 microns, and more preferably 1 to 100 microns, more preferably 2 to 20 microns, and most preferably 5 to 10 microns. Exemplary channel depths are 0.01 μm, 0.02 μm, 0.05 μm, 0.1 μm, 0.2 μm, 0.5 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 7.5 μm, 10 μm, 12. Including 5 μm, 15 μm, 17.5 μm, 20 μm, 22.5 μm, 25 μm, 30 μm, 40 μm, 50 μm, 75 μm, 100 μm, 150 μm, 200 μm and 250 μm.

  This flow channel is not limited to these specific size ranges and examples given above, and the force required to deflect the membrane, as will be fully described below in connection with FIG. Can vary in width to affect the size of. For example, extremely narrow flow channels having a width on the order of 0.01 μm may be useful in optics and other applications as described in detail below. Elastomeric structures that include portions having channels that are even larger than those discussed above are also contemplated by the present invention, and examples of applications that utilize such wider flow channels include fluid containers and mixing channel structures.

  The elastomer layer 22 can be cast thick for mechanical stability. In the illustrated embodiment, layer 22 is 50 microns to several centimeters thick, and more preferably about 4 mm thick. A list of non-limiting thickness ranges of elastomer layers according to other embodiments of the invention is between about 0.1 microns to 10 cm, 1 micron to 5 cm, 10 microns to 2 cm, 100 microns to 10 mm. .

  Thus, the membrane 25 of FIG. 7B separating the flow channels 30 and 32 has a typical thickness between about 0.01 microns and 1000 microns, more preferably 0.05 to 500 microns, more preferably Is 0.2 to 250, more preferably 1 to 100 microns, more preferably 2 to 50 microns, and most preferably 5 to 40 microns. As such, the thickness of the elastomer layer 22 is about 100 times the thickness of the elastomer layer 20. Exemplary film thicknesses are 0.01 μm, 0.02 μm, 0.03 μm, 0.05 μm, 0.1 μm, 0.2 μm, 0.3 μm, 0.5 μm, 1 μm, 2 μm, 3 μm, 5 μm, 7.5 μm 10 μm, 12.5 μm, 15 μm, 17.5 μm, 20 μm, 22.5 μm, 25 μm, 30 μm, 40 μm, 50 μm, 75 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 400 μm, 500 μm, 750 μm, and 1000 μm.

  Similarly, the first elastomer layer 42 may have a preferred thickness that is approximately equal to the thickness of the elastomer layer 20 or 22, and the second elastomer layer 46 may have a preferred thickness that is approximately equal to the thickness of the elastomer layer 20. The third elastomer layer 50 may have a preferred thickness that is approximately equal to the thickness of the elastomer layer 22.

  As described herein, the lateral dimensions of the features of the microfabricated device according to embodiments of the present invention may be different from those defining the non-airlastomer mold features or on the elastomeric material. Can be precisely controlled using lithographic techniques either directly in defining the sacrificial features. Similarly, feature dimensions in the vertical direction can be varied and controlled through formation that can be defined utilizing flow channels, and can be achieved with precise control through the development of resists and other sacrificial materials.

For example, FIG. 71A shows a cross-sectional view of a mold 7600 that features topographic features 7602a and 7602b of different heights Y and Y ′, respectively. Features 7602a and 7602b can be generated directly through patterning of multiple resist layers 7604 and 7606, as shown in FIG. 71A. Upon removal of the elastomeric material 7608 from the mold 7600 of FIG. 71A, an elastomeric layer 7610 shown in FIG. 71B that features flow channels 7612 having portions 7612a and 7612b of different heights Y and Y ′ may be formed.

  Embodiments of the present invention may utilize positive or negative resist materials to form different height features. Embodiments of the present invention may utilize a photoresist or electron beam resist material.

  71A-B show the creation of varying height features through multiple resist layer patterning, the use of a resist material directly in the mold is not required by the present invention. In an alternative embodiment, multiple patterned layers of resist may serve as a mask for removal of underlying substrate material to different depths. Upon removal of the patterned resist, features of varying depth in the substrate can define the molded portion.

  Further, FIGS. 71A-71B illustrate the creation of varying height molded features utilizing multiple resist layers, but this is also not required by embodiments according to the present invention. In an alternative embodiment, a gray scale resist can be used. During development, the thickness of the gray scale resist reflects the intensity of incident radiation during exposure. Varying the intensity of such incident radiation can result in the formation of different height features from a single layer of resist material.

(Technology and materials for constructing multilayer flexible lithography)
(Soft lithography bonding)
Elastomer layers 20 and 22 (or elastomer layers 42, 46, and 50) are chemically bonded together utilizing the chemical properties that are inherent to polymers with patterned elastomer layers. It is preferable. Most preferably, the bond comprises a two component “addition cure” bond.

  In a preferred aspect, the various layers of elastomer are constrained together with heterogeneous bonds with the layers having different chemical properties. Alternatively, homogenous bonds where all layers have the same chemical properties can be used. Third, the respective elastomer layers can be glued together with an adhesive instead if desired. In a fourth aspect, the elastomeric layer can be a thermosetting elastomer that is bonded together by heating.

  In one aspect of homogenous bonding, the elastomeric layer is composed of the same elastomeric material having the same chemical entity in one layer that reacts with the same chemical entity in the other layer to bond the layers together. The In one embodiment, the bonds between the polymer chains of similar elastomeric layers can be obtained from activation of the crosslinker by light, heat, or a chemical reaction with another chemical species.

Alternatively, in a heterogeneous aspect, the elastomeric layer is composed of different elastomeric materials with a first chemical entity in one layer that reacts with a second chemical entity in another layer. In one exemplary heterogeneous aspect, the bonding method used to bind the respective elastomer layers together may include bonding the two layers of RTV 615 silicone together. RTV615 silicone is a two-part addition cured silicone rubber. Part A contains vinyl groups and catalyst, and part B contains silicon hydride (Si-H) groups. A typical ratio for RTV 615 is 10A: 1B. For bonding, one layer can be made of 30A: 1B (ie, excess vinyl groups) and the other can be made of 3A: 1B (ie, excess Si—H groups). Each layer is cured separately. When the two layers are brought into contact and heated at an elevated temperature, they irreversibly bond to form a monolithic elastomeric substrate.

  In an exemplary aspect of the invention, the elastomeric structure is formed utilizing an aliphatic urethane diacrylate such as (but not limited to) Sylgard 182, 184, or 186, or Ebecryl 270 or Irr245 (from UCB Chemical). .

In one embodiment of the present invention, a two-layer elastomeric structure was made from pure acrylic urethane Ebe270. The thin bottom layer was spin coated at 8000 rpm at 170 ° C. for 15 seconds. The top and bottom layers are made up of Electrolite corporation
Was initially cured under ultraviolet light for 10 minutes under nitrogen using a Model ELC 500 device manufactured by AA. This assembled layer was then cured for an additional 30 minutes. The reaction was catalyzed by a 0.5% vol / vol mixture of Irgacure 500 manufactured by Ciba-Geigy Chemicals. The resulting elastomeric material showed moderate elasticity and adhesion to glass.

  In another embodiment according to the present invention, a two-layer elastomeric structure was made from a combination of 25% Ebe270 / 50% Irr245 / 25% isopropyl alcohol for the thin bottom layer, and pure acrylated urethane Ebe270 as the top layer. . This thin bottom layer was initially cured for 5 minutes and the top layer was initially cured for 10 minutes under UV light under nitrogen using a Model ELC 500 device manufactured by Electrolite Corporation. This assembled layer was then cured for an additional 30 minutes. The reaction was catalyzed with a 0.5% vol / vol mixture of Irgacure 500 manufactured by Ciba-Geigy Chemicals. The resulting elastomeric material showed moderate elasticity and adhered to the glass.

  Alternatively, other bonding methods can be used, including activating the elastomeric surface, for example by plasma exposure, so that the elastomer layer / substrate bonds when placed in contact. For example, one possible approach to bonding together elastomeric layers composed of the same material is described by Duffy et al., “Rapid Prototyping of Microfluidic Systems in Poly (dimethylsiloxane)”, Analytical Chemistry (1998), 49, Described and incorporated herein by reference. This paper discusses the process of exposing a polydimethylsiloxane (PDMS) layer to an oxygen plasma to cause oxidation of this surface, which results in an irreversible bond when the two oxide layers are placed in contact.

  Yet another approach for bonding together successive layers of elastomers is to take advantage of the adhesive properties of uncured elastomers. Specifically, a thin layer of uncured elastomer such as RTV 615 is applied on top of the first cured elastomer layer. A second cured elastomer layer is then placed on top of the uncured elastomer layer. The thin center layer of uncured elastomer is then cured to create a monolithic elastomeric structure. Alternatively, the uncured elastomer can be applied to the bottom of the first cured elastomer layer, and the first cured elastomer layer can be placed on top of the second cured elastomer layer. Curing the central thin elastomeric layer again results in the formation of a monolithic elastomeric structure.

As described above in FIGS. 8-18, when the encapsulation of a sacrificial layer is employed to create an elastomeric structure, the bonding of the continuous elastomeric layer results in the uncured elastomer, the precured elastomeric layer, and above. Can be achieved by pouring over any sacrificial material patterned. Bonding between the elastomeric layers occurs by interpenetrating and reacting the polymer chains of the uncured elastomer layer with the polymer chains of the cured elastomer layer. Subsequent curing of the elastomeric layer creates a bond between the elastomeric layers and creates a monolithic elastomeric structure.

  Referring to the first method from FIGS. 1 to 7B, the first elastomer layer 20 can be made by spin coating the RTV mixture on the microfabricated mold 12 at 2000 rpm for 30 seconds and has a thickness of about 40 microns. obtain. The second elastomer layer 22 can be made by spin coating the RTV mixture on the microfabricated mold 11. Both layers 20 and 22 can be separately baked or cured at about 80 ° C. for 1.5 hours. The second elastomer layer 22 can be bonded onto the first elastomer layer 20 at about 80 ° C. for about 1.5 hours.

  The microfabricated molds 10 and 12 can be a photoresist patterned on a silicon wafer. In an exemplary aspect, Shipley SJR 5740 photoresist was spun at 2000 rpm, patterned as a mask with a high resolution transparent film, and then developed to obtain a reverse channel about 10 microns high. When baked at about 200 ° C. for about 30 minutes, the photoresist flows back and the reverse channel is rounded. In a preferred aspect, the mold can be treated with trimethylchlorosilane (TMCMS) vapor for about 1 minute before each use to prevent silicone rubber adhesion.

  Using a variety of multilayer soft lithographic construction techniques and materials described herein, the present invention creates channel networks of up to 7 separate elastomeric layer thicknesses (each layer is approximately 40 μm thick). Experimentally successful. It is foreseeable that devices with more than 7 separate elastomeric layers will be bonded together.

  While the above discussion focuses on a method for bonding together successive horizontal elastomeric layers, in an alternative embodiment according to the present invention, bonding further occurs between the vertical interfaces of different portions of the elastomeric structure. obtain. One embodiment of such an alternative approach is shown in FIGS. These show a cross-sectional view of a process for forming such a device that utilizes the separation of elastomeric structures along the flow channel section.

  FIG. 55A shows a cross section of two devices 6000 and 6010 that include first elastomer layers 6002 and 6012, respectively. First elastomer layers 6002 and 6012 cover the surface of second elastomer layers 6004 and 6014, thereby defining each flow channel 6006 and 6016. The first elastomeric layer 6002 includes a first elastomeric material and the second elastomeric layer 6004 includes a second elastomeric material configured to bond with the first elastomeric material. Conversely, the first elastomer layer 6012 includes a second elastomer material and the second elastomer layer 6014 includes a first elastomer material.

  FIG. 55B shows the results of cutting devices 6000 and 6010 along vertical lines 6001 and 6011 extending along the length of flow channels 6006 and 6015, respectively, to form half structures 600a-b and 6010a-b. Show.

  FIG. 55C shows a half of the first half 6000a coupled to the second half 6010b to form the device 6008 and the first half 6010a coupled to the second half 6000b to form the device 6018. Shows the result of crossing and combining structures. This reassembly is made possible by a bond between the first elastomeric material and the second elastomeric material.

  The bonding method described herein can be useful for assembling multiple chips together edge to form a multi-chip module. This is particularly advantageous for the production of microfluidic modules, each having a specific function, which can be assembled from component chips as desired.

  The above description focuses on combining continuous layers with the function of horizontally oriented channels, but creating layers with horizontally oriented channels, and then layers in a vertical position It is also possible to align the vertically oriented layer and bond the vertically oriented layer to the horizontally oriented layer. This is shown in FIGS. This figure shows a cross-sectional view of a method of joining a vertically oriented microfabricated elastomeric structure to a horizontally oriented microfabricated elastomeric structure.

  FIG. 68A shows a first horizontally oriented microfabricated elastomeric structure 7300. FIG. This microfabricated elastomeric structure 7300 includes a control channel 7302 formed in the first elastomeric layer 7304 that covers the surface of the flow channel 7306 and is separated from the flow channel 7306 by a membrane 7308 formed from the second elastomeric layer 7310. The second elastomer layer 7310 also defines a vertical via 7312 in communication with the flow channel 7306, and the first elastomer layer 7304 does not extend completely beyond the top of the second elastomer layer 7310. A second horizontally oriented microfabricated elastomeric structure 7320 is similarly formed in the third elastomer layer 7324, covers the flow channel 7322, and is flow channel 7326 by a membrane 7328 formed from the fourth elastomer layer 7330. Including a control channel 7322 separated from the control channel 7322.

  FIG. 68B shows the second microstructured structure 7320 oriented vertically on the edge and the second structure 7320 is placed in contact with the first microstructured structure 7300 such that the flow channel 7326 contacts the via 7312. FIG. 6 shows an assembly of a microfabricated elastomeric structure 7340 of a compound by doing so. By employing the compound structure 7340, fluid can be removed from the flow channel 7306 or introduced into the flow channel 7306 via the via 7312.

(Appropriate elastomeric material)
Allcock, et al, Contemporary Polymer Chemistry, 2nd edition, describes elastomers as polymers that generally exist at temperatures between their glass transition temperature and liquefaction temperature. Elastomeric materials allow the polymer chains to twist easily and react to forces to allow the unwinding of the backbone chains, and this skeleton chain recoiling takes on the previous shape in the absence of forces. Shows elastic properties. Generally, an elastomer deforms when a force is applied, but then returns to its original shape when the force is removed. This elasticity exhibited by the elastomeric material can be characterized by Young's modulus. Between about 1 Pa and 1 TPa, more preferably between about 10 Pa and 100 GPa, more preferably between about 20 Pa and 1 GPa, more preferably between about 50 Pa and 10 MPa, and more preferably between about 100 Pa and 1 MPa. While elastomeric materials having a Young's modulus between are useful in accordance with the present invention, elastomeric materials having a Young's modulus outside these ranges may also be utilized depending on the needs of a particular application.

  The system of the present invention can be made from a wide range of elastomers. In a specific aspect, it is preferred that the elastomer layers 20, 22, 42, 46 and 50 can be made from silicone rubber. However, other suitable elastomers can be utilized.

In a specific aspect of the invention, the system comprises GE RTV 615 (formulation), vinyl-
Manufactured from an elastomeric polymer such as a silane cross-linked (type) silicone elastomer (family). However, the system is not limited to this one formulation polymer, this one type of polymer, or even this family of polymers, but rather is suitable for almost any elastomeric polymer. An important requirement for the preferred method of manufacturing this microvalve is the ability to bond multiple layers of elastomer together. In multilayer soft lithography, each layer of elastomer is cured separately and then bonded together. This design requires that the cured layers have sufficient reactivity to adhere to each other. Either each layer is of the same type and capable of bonding to each other, or each layer is of two different types and capable of bonding to each other. Another possibility includes using an adhesive between each layer and using a thermoset elastomer.

  Given the vast range of polymer chemistry, precursors, synthesis methods, reaction conditions, and potential additives, a vast number of possible elastomers are needed to create monolithic elastomeric microvalves and pumps. The system can be used. The variation of materials used is most often determined by the need for specific material properties, ie, solvent resistance, hardness, gas permeability, or temperature stability.

  There are many types of elastomeric polymers. A brief description of the most common class of elastomers is presented here, but there are many possibilities for bonding, even with relatively “standard” polymers. Common elastomeric polymers include polyisoprene, polybutadiene, polychloroprene, polyisobutylene, poly (styrene-butadiene-styrene), polyurethane, and silicone.

(Polyisoprene, polybutadiene, polychloroprene :)
Polyisoprene, prebutadiene, and polychloroprene are all polymerized from diene monomers and, therefore, have one double bond per monomer when polymerized. This double bond allows the polymer to be converted to an elastomer by a vulcanization process (essentially sulfur is used to form crosslinks between the double bonds by heat treatment). This facilitates homogeneous multilayer soft lithography with incomplete vulcanization of the layers to be joined. Photoresist encapsulation is possible by a similar mechanism.

(Polyisobutylene :)
Pure polyisobutylene does not have a double bond, but it is crosslinked for use as an elastomer by including a small amount (about 1%) of isoprene in the polymerization. The isoprene monomer provides a double bond depending on the backbone of the polyisobutylene, which can be sulfided as described above.

(Poly (styrene-butadiene-styrene) :)
Poly (styrene-butadiene-styrene) is produced by living anionic polymerization (ie, there is no natural chain termination step in the middle of the reaction), so the ends of the “living” polymer are in the cured polymer. Can exist. This makes this polymer a natural candidate for the present photoresist encapsulation system (in this case, unreacted monomers will be present in the liquid layer poured onto the top surface of the cured layer). Incomplete curing allows homogeneous multilayer soft lithography (A vs. A bond). This chemical property also facilitates creating one layer with excess butadiene ("A") and a binder and creating the other layer ("B") without butadiene ( As heterogeneous multi-layer soft lithography). SBS is a “thermoset elastomer” and means that when a certain temperature is exceeded, this elastomer melts and becomes plastic (as opposed to becoming elastic), which reduces the temperature. And again yields an elastomer. Thus, the layers can be bonded together by heat treatment.

(Polyurethane :)
Polyurethanes are made from diisocyanates (AA) and dialcohols or diamines (BB), and because there are a wide variety of diisocyanates and dialcohols / amines, the number of dissimilar polyurethanes is huge. . However, due to the A-to-B nature of the polymer, these are heterogeneous just like RTV 615 by utilizing excess A-A in one layer and excess B-B in the other layer. Useful for multilayer soft lithography.

(silicone:)
Although silicone polymers appear to have the greatest structural diversity, there is almost no doubt that there is a maximum number of formulations available on the market. RTV 615
Cross-linking of vinyl to (Si-H), which enables both heterogeneous multilayer soft lithography and photoresist encapsulation, has already been discussed, but it is used in the chemical properties of silicone polymers. It is only one of several crosslinking methods.

(Crosslinking agent :)
In addition to the use of the simple “pure” polymer described above, a crosslinking agent can also be added. Some reagents (such as monomers with pendant double bonds for sulfurization) are suitable to allow homogeneous (A vs. A) multilayer soft lithography or photoresist encapsulation and complementary These reagents (ie, one monomer having a pendant double bond and another monomer having a pendant Si-H group) are suitable for heterogeneous (A vs. B) multilayer soft lithography. In this approach, complementary reagents are added to adjacent layers.

(Other materials :)
In addition, polymers incorporating materials such as chlorosilane or methylsilane, ethylsilane, and phenylsilane, and polydimethylsiloxane (PDMS) such as Dow Chemical's Sylgard 182, 184, 186, or Aliphatic urethane diacrylates such as (but not limited to) Ebecryl 270 or Irr245 sold by UBC Chemical may also be used.

  The following is a non-limiting list of elastomeric materials that can be utilized in connection with the present invention: polyisoprene, polybutadiene, polychloroprene, polyisobutylene, poly (styrene-butadiene-styrene), polyurethane, and silicone polymers. Or poly (bis (fluoroalkoxy) phosphazene (PNF, Eypel-F), poly (carborane-siloxane) (Dexsil), poly (acrylonitrile-butadiene) (nitrile rubber), poly (1-butene), Poly (chlorotrifluoroethylene-vinylidene fluoride) copolymer (Kel-F), poly (ethyl vinyl ether), poly (vinylidene fluoride), poly (vinylidene fluoride-hexafluoropropylene) copolymer (Vit n), elastomeric compositions of polyvinylchloride (PVC), polysulfone, polycarbonate, polymethyl methacrylate (PMMA), and polytetrafluoroethylene (Teflon).

(Doping and dilution :)
Elastomers can be “doping” with the same class of non-crosslinkable polymer chains. For example, RTV 615 may be diluted with GE SF 96-50 silicone fluid. This serves to reduce the viscosity of the uncured elastomer and reduces the Young's modulus of the cured elastomer. In essence, the crosslinkable polymer chain is branched in a more discrete manner by the addition of an “inert” polymer chain, which is referred to as “dilution”. As the Young's modulus decreases dramatically, RTV
615 cures at dilutions up to 90%.

  FIG. 49 plots the Young's modulus vs. percent dilution for the GE RTV 615 elastomer GE SF 96-50 diluent having a ratio of 30: 1 A: B. FIG. 49 shows that the flexibility of the elastomeric material, and thus the responsiveness of the valve membrane to the applied actuation force, can be controlled during the fabrication of this device.

  Other examples of elastomeric material doping may include the introduction of electrical conduction or magnetic species, as detailed below in connection with alternative methods of operation of the membrane of this device. If desired, doping with fine particles of a material having a refractive index different from that of the elastomeric material (ie, silica, diamond, sapphire) is also considered as a system for changing the refractive index of the material. Strong absorbing or opaque particles can be added to color the elastomer or make it opaque to incidence. This can possibly be beneficial in an optically addressable system.

  Finally, by doping the elastomer with specific chemical species, these doped chemical species can be provided at the elastomeric surface, thus anchoring or starting for further chemical derivatization. Acts as a point.

(Pretreatment and surface coating)
Once the elastomeric material has been shaped or etched into the appropriate shape, it may be necessary to pretreat this material to facilitate operations associated with a particular application.

  For example, one possible application for an elastomeric device according to the present invention is to sort biological entities such as cells or DNA. In such applications, the hydrophobic nature of the biological entity can cause attachment of the channel walls to the hydrophobic elastomer. Thus, it may be useful to pretreat the elastomeric structure to convey hydrophilicity to the channel wall. In an embodiment of the present invention that utilizes a General Electric RTV 615 elastomer, this is accomplished by boiling the formed elastomer in acid (eg, 0.01% HCl in water, pH 2.7, 40 ° C. for 40 minutes). Can be achieved.

  Pretreatment of other types of elastomeric materials is also contemplated by this application. For example, certain portions of the elastomer can be pretreated to create anchors for surface chemical reactions (eg, in the formation of peptide chains), or binding sites for antibodies, which are beneficial in a given application. is there. Other examples of pretreatment of the elastomeric material may include the introduction of a reflective material onto the elastomeric surface, as detailed below in connection with the micromirror array application.

(Method of operating the present invention)
7B and 7H both show the closing operation of the first flow channel by pressurizing the second flow channel, and FIG. 7B (front sectional view with the flow channel 32 broken in the corresponding FIG. 7A) in the open state. FIG. 7H shows the first flow channel 30 closed by pressurization of the second flow channel 32.

  Referring to FIG. 7B, a first flow channel 30 and a second flow channel 32 are shown. The membrane 25 separates the flow channels and forms the top of the first flow channel 30 and the bottom of the second flow channel 32. As shown, the flow channel 30 is in the “open state”.

As can be seen in FIG. 7H, pressurization of the flow channel 32 (whether by gas introduced therein or by liquid) causes the membrane 25 to deflect downward, thereby passing through the flow channel 30. Squeeze Flow F to make it thinner. Thus, by varying the pressure in the channel 32, the flow channel 30 is provided with a linearly operable valve operating system that allows the flow channel 30 to be opened and closed as desired by moving the membrane 25. . (For illustrative purposes only, channel 30 in FIG. 7G is shown in a “nearly closed” position, not in a “fully closed” position).

It is understood that exactly the same valve opening and closing can be achieved using flow channels 60 and 62. Such a valve is actuated by moving the roof of the channel itself (ie by moving the membrane 25). Therefore, the valves and pumps manufactured by this technology have a truly zero dead volume, and switching the valve made by this technology is the operating volume of the valve (eg about 100 × 100 × 10 μm = 100 pL). ) Having a dead volume approximately equal to. The area consumed by the dead volume and the moving film is about two orders of magnitude and smaller than a known normal fine valve. Smaller and larger valves and repetitive valves are contemplated in the present invention and a non-limiting list of dead volume ranges is 1aL to 1 μL, 100aL to 100nL, 1fL to 10nL, 100fL to 1nL, and 1pL To 100 pL.

  Extremely small volumes can be delivered by the pumps and valves according to the present invention, providing substantial advantages. The smallest known volume that can be metered manually, in particular, is about 0.1 μl. The smallest known volume that can be weighed by an automated system is about 10 times larger (1 μl). Utilizing pumps and valves according to the present invention, a volume of liquid of 10 nl or less can be metered and dispensed as specified. The precise metering of this very small volume of fluid made possible by the present invention is extremely valuable in many biological applications, including diagnostic tests and assays.

Equation 1 provides a very simplified mathematical model of the deflection of a rectangular, linear, elastic, uniform thickness isotropic plate with applied pressure.
(1) w = (BPb ⁴ ) / (Eh ³ ), where:
w = plate deflection;
B = shape factor (depends on length vs. width and support of plate edges);
p = application pressure;
b = plate width
E = Young's modulus; and
h = plate thickness Thus, even in this extremely simplified representation, the deflection of the elastomeric membrane in response to pressure: length, width, and membrane thickness, membrane flexibility (Young's modulus), applied Is a function of the actuation force. Each of these parameters varies widely depending on the actual dimensions and physical composition of a particular elastomeric device according to the present invention, so that a wide range of film thickness and elasticity, channel width, and actuation force are Are contemplated by the present invention.

  Since in general the membrane does not have a uniform thickness, the formula provided above is only schematic, the thickness is not necessarily small compared to the length and width, and the deflection is the length of this membrane, It is understood that the width or thickness is not necessarily small. Nonetheless, this equation serves as a useful guide for adjusting parameters that can be varied to achieve the desired response of deflection to applied force.

FIGS. 21 a and 21 b illustrate valve opening versus applied pressure for a 100 μm wide first flow channel 30 and a 50 μm wide second flow channel 32. The membrane of this device is formed by a layer of General Electric Silicones RTV 615 having a thickness of about 30 μm and a Young's modulus of about 750 kPa. Figures 21a and 21b show the degree to which the valve opening is substantially linear over the range of most applied pressures.

  Through a piece of 10 cm long plastic tubing having an outer diameter of 0.025 inches connected to a 25 mm piece of stainless steel hypodermic tubing having an outer diameter of 0.025 inches and an inner diameter of 0.013 inches Air pressure was applied to actuate the device membrane. The tubing was placed in contact with the control channel by insertion into the elastomer block in a direction perpendicular to the control channel. Lee Co. Air pressure was applied by subcutaneous tissue tubing from an external LHDA miniature solenoid valve manufactured by the company.

  The connection of a normal microfluidic device to an external fluid flow presents a number of problems that are avoided by the external geometry as described above. One such problem is the vulnerability of connectivity with the external environment. In particular, a typical microfluidic device is composed of a hard, inflexible material (such as silicon), to which tubing or tubing that allows connection to external elements must be joined. The stiffness of the normal material creates considerable physical stress at the point of contact with small and delicate external tubing, and tends to crush and leak normal microfluidic devices at these points of contact.

  In contrast, the elastomers of the present invention are flexible and easily penetrated for external connection by a tube made of hard material. For example, in an elastomeric structure made using the method shown in FIGS. 1-7B, a hole extending from the outer surface of the structure to the control channel is shown after the upper elastomeric piece has been removed from the mold (shown in FIG. 3). ), And before the piece is bonded to the lower elastomeric piece (shown in FIG. 4), it can be made by piercing the elastomer with metal subcutaneous tissue tubing. During these steps, the control channel roof is exposed to the user's field of view, allowing access to insertion and proper placement of the holes. Following completion of fabrication of the device, a metal subcutaneous tissue tubing is inserted into the hole to complete the fluid connection.

  Furthermore, the elastomer of the present invention bends in response to physical strain at the point of contact with the external connection, making the external physical connection more robust. This flexibility substantially reduces the possibility of leakage or breakage of the device.

  Another drawback of a conventional microfluidic device is the difficulty of establishing an effective seal between the device and its external link. Due to the extremely narrow diameter of the channels of these devices, an appropriate rate of fluid flow may require extremely high pressure. Unnecessary leakage at the junction between this device and external connections can occur. However, the flexibility of the device's elastomer helps to overcome pressure leakage as well. In particular, the flexible elastomeric material bends around the inserted tubing to form a pressure resistant seal.

  Although control of the flow of material through this device has been described using applied gas pressure, other fluids can be used.

For example, air is compressible and thus experiences a finite delay between the time of application of pressure by the external solenoid valve and the time that this pressure is experienced by the membrane. In an alternative embodiment of the invention, pressure can be applied from an external source to an incompressible fluid, such as water or hydraulic oil, resulting in a quasi-instantaneous movement of the pressure applied to the membrane. However, if the displaced volume of the valve is large or the control channel is narrow, the higher viscosity of the control fluid can contribute to the delay in operation. The optimum medium for pressure transfer is therefore dependent on the specific application and device geometry, and both gaseous and liquid media are contemplated by the present invention.

  Externally applied pressure as described above is applied by the pump / tank system through a pressure regulator and an external miniature valve, but other methods of applying external pressure are also contemplated in the present invention and include gas tanks, compressors, piston systems, And a liquid column. It is also considered that naturally occurring pressures such as those that can be seen in vivo (eg, blood pressure, gastric pressure, cerebral spinal pressure, pressure present in the intraocular space, and pressure exerted by normal flexing muscles) Is the use of the source. Other methods for regulating external pressure such as miniature valves, pumps, micro peristaltic pumps, pinch valves, and other types of fluid regulating devices known to those skilled in the art are also contemplated.

  As can be seen, the response of a valve according to an embodiment of the invention has been shown experimentally with minimal hysteresis, almost perfectly linearly over most of its range of movement. Thus, the valve of the present invention is ideally suited for microfluidic metering and fluid control. This linearity of the valve response indicates that the individual valves are well modeled as springs following Hooke's law. Further, high pressure in the fluid channel (ie back pressure) can be countered by simply increasing the operating pressure. Experimentally, we achieved valve closure at a back pressure of 70 kPa, but higher pressures are also considered. The following is a non-limiting list of pressure ranges encompassed by the invention: 10 Pa to 25 MPa; 100 Pa to 10 MPa, 1 kPa to 1 MPa, 1 kPa to 300 kPa, 5 kPa to 200 kPa, and 15 kPa to 100 kPa.

  Valves and pumps do not require linear actuation to open and close, but the linear response allows the valve to be used more easily as a metering device. In one embodiment of the invention, the opening of the valve is used to control the flow rate by partially actuating to a known degree of closure. Linear valve actuation makes it easier to determine the amount of actuation force required to close the valve to the desired degree of closure. Another advantage of linear actuation is that the force required for valve actuation is easily determined from the pressure in the flow channel. If the actuation is linear, the increased pressure in the flow channel can be countered by applying the same pressure (force per unit area) to the actuation portion of the valve.

The linearity of the valve depends on the structure, composition, and method of operation of the valve structure. Furthermore, whether linearity is a desired characteristic in a valve depends on its application. Thus, both linearly actuable valves and non-linearly actuatable valves are contemplated in the present invention, and the pressure range over which the valves can be actuated linearly varies with the particular implementation.

  FIG. 22 shows the time response of a 100 μm × 100 μm × 10 μm RTV microvalve with a 10 cm long air tube connected from the tip to the pneumatic valve (valve closure as a function of time as a function of applied pressure) ).

The two-cycle digital control signal, the actual air pressure at the end of the tube, and the valve opening are shown here. The pressure applied to the control line is 100 kPa, which is substantially higher than about 40 kPa required to close the valve. Thus, during the closing operation, the valve is pressed closed with a pressure 60 kPa greater than required. However, when opening, the valve is returned to its rest position only with its own spring force (less than 40 kPa). Therefore, τ _close is predicted to be smaller than τ _open . There is also a delay between the control signal and the control pressure response due to the limitations of the miniature valve used to limit the pressure. When this delay is called t and the 1 / e time constant is called τ, each value is as follows. That is, t _open = 3.63 ms, τ _open = 1.88 ms, t _close = 2.15 ms, and τ _close = 0.51 ms. Assuming 3τ is assigned for each opening and closing, the valve operates comfortably at 75 Hz when filled with aqueous solution.

  The valve operates at about 375 Hz when another method of operation is employed that does not suffer from opening and closing delays. Note also that the spring constant can be adjusted by changing the thickness of the membrane, which allows optimization of either fast opening or fast closing. As it is possible to act as a membrane by introducing dopants into this membrane, or by utilizing different elastomeric materials (FIGS. 7C-7H), this spring constant determines the elasticity (Young's modulus) of the membrane. It is also adjusted by changing.

  When the valve characteristics as exemplified in FIGS. 21 and 22 were experimentally measured, the valve opening rate was measured by fluorescence. In these experiments, the flow channel was filled with a solution of fluorescein isothiocyanate (FITC) in a buffer (pH 8 or higher), and the fluorescence in the square area occupying about one third of the center of the channel was observed in the 10 kHz band It was monitored with an external fluorescence microscope equipped with a photomultiplier tube. The pressure was monitored using a Wheatstone bridge pressure sensor (SenSym SCC15GD2) that was pressurized simultaneously with the control line by a nearly identical pneumatic connection.

(Flow channel cross section :)
The flow channels of the present invention can be designed with different cross-sectional dimensions and cross-sectional shapes that provide different advantages, as needed, depending on the respective desired application. For example, the lower flow channel cross-sectional shape may have a curved upper surface along its entire length or in a region located below the upper transverse channel extending across it. Such a curved upper surface facilitates valve sealing as described below.

  Referring to FIG. 19, a cross-sectional view (similar to that of FIG. 7B) with flow channel 30 and flow channel 32 cut away is shown. As illustrated, the flow channel 30 has a rectangular cross-sectional shape. Instead, as shown in FIG. 20, in an alternative preferred aspect of the present invention, the cross section of the flow channel 30 has an upper curved surface.

  Referring first to FIG. 19, when the flow channel 32 is pressurized, the thin film portion 25 of the elastomeric block 24 separating the flow channel 30 and the flow channel 32 faces downward, dotted lines 25A, 25B, 25C, 25D. , 25E to a continuous position. As shown, an incomplete seal may occur at the edge of the flow channel 30 adjacent to the flat substrate 14.

  In the alternative preferred embodiment of FIG. 20, flow channel 30 has a curved upper wall 25A. When flow channel 32 is pressurized, membrane portion 25 moves downward to a continuous position indicated by dotted lines 25A2, 25A3, 25A4, and 25A5, with the membrane edge moving to this flow channel, and then The top membrane moves. The advantage of having a curved upper surface in membrane 25A is that a more complete seal is provided when flow channel 32 is pressurized. In particular, the top wall of the flow channel 30 provides a continuous contact edge against the flat substrate 14 so that the “island” of contact seen between the wall 25 and the bottom of the flow channel 30 of FIG. Avoid occurrence.

Another advantage of having a curved upper flow channel surface in membrane 25A is that it can more easily follow the shape and volume of the flow channel in response to actuation. In particular, when a rectangular flow channel is employed, this entire periphery (2 × flow channel height + flow channel width) must be forced into this flow channel. However, if an arcuate channel is used, the periphery of the smaller material (only the semicircular arc) must enter this channel. In this manner, the membrane requires smaller changes in the periphery for actuation, and therefore becomes responsive to the applied actuation force and blocks this channel.

  In an alternative aspect (not shown), the bottom of the flow channel 30 is rounded so that its curved surface couples with the curved top wall 25A as seen in FIG. 20 described above.

  In a further alternative aspect, the control channel can be positioned below the flow channel with an arched ceiling, so that due to the deflection of the membrane, the membrane is bent upwards to match the arched ceiling of the flow channel; This ensures good encapsulation. FIG. 72 shows a cross-sectional view of such an alternative valve structure 7700 where the control channel is formed in the first elastomer layer 7704 in contact with the underlying substrate 7706. A second elastomeric layer 7708 containing a flow channel 7710 is positioned over the first elastomeric layer 7704 so that the flow channel 7710 is orthogonal to the underlying control channel.

  FIG. 72 shows that a membrane portion 7712 defined between the control channel 7702 and the flow channel 7710 can be deflected to the flow channel 7710 to conform to the arcuate shape of the ceiling 7710a of the flow channel 7710. An activated membrane 7712 coincidence with a flow channel ceiling shape prevents material leakage through the closed valve and helps ensure a linear response of the valve.

  The valve architecture shown in FIG. 72 is particularly useful when the flow channel is deep (ie,> 50 μm), and the large volume of elastomer present at the edge of the flow channel can cause the edge of the membrane to overlap the flow channel. Interfere with deflection. A valve architecture of the type shown in FIG. 72 is operated to achieve a 300 μm wide, 50 μm deep flow channel closure with an operating pressure in the control channel of less than 1 psi. Closure of a valve of the type shown in FIG. 72 having a 50 μm deep and 100 μm wide flow channel is achieved by an operating pressure in the 8 psi control channel.

  In short, the actual structural change experienced by the membrane in operation depends on the configuration of the particular elastomeric structure. In particular, the structural changes are due to the length, width, and thickness profile of the membrane, the adhesion to the rest of the membrane, and the height, width, and shape of the flow and control channels used and the use Depends on the material properties of the elastomer being made. This structural change may also depend on the method of operation, since the operation of the membrane in response to applied pressure will vary somewhat from that in response to magnetic or electrostatic forces.

  Furthermore, the desired structural change in the membrane also depends on the specific application for the elastomeric structure. In the simplest embodiment described above, the valve can be open or closed metered to control the degree of closure of the valve. However, in other embodiments, it may be desirable to change the shape of this membrane and / or flow channel to achieve more complex flow control. For example, the flow channel may include a raised ridge below the membrane, and in operation, the membrane may be configured to move the flow channel with a proportion of blocked flow that is insensitive to the applied actuation force. Block only the flow rate that passes.

Many film thickness profiles and flow channel cross-sections are contemplated by the present invention, including rectangular, trapezoidal, circular, elliptical, parabolic, hyperbolic, and polygonal shapes, and portions of the above shapes. More complex cross-sectional shapes are also contemplated by the present invention, such as the embodiment with the protrusions described immediately above, or the embodiment with a recess in the flow channel.

  Furthermore, although the present invention is primarily described above in connection with embodiments in which the flow channel walls and ceiling are formed from an elastomer and the channel floor is formed from an underlying substrate, the present invention is not limited to this. It is not limited to a specific orientation. The channel walls and floor may also be formed in the underlying substrate, and only the ceiling of the flow channel may be composed of elastomer. The ceiling of the elastomeric flow channel protrudes into the lower channel in response to an applied actuation force, thereby controlling the flow of material through the flow channel.

  Furthermore, isotropic etching of a non-elastomeric substrate such as single crystal silicon typically produces a recess having a concave profile. When flow channel walls and floors in a non-elastomeric substrate are produced by isotropic etching, the superimposed elastomeric membrane can easily conform to and seal against the concave shape of the flow channel floor.

  In general, monolithic elastomeric structures as described elsewhere in immediate applications are preferred for microfluidic applications. However, if such an arrangement provides advantages, it may be useful to employ channels formed in the substrate. For example, a substrate that includes an optical waveguide can be constructed such that the optical waveguide directs light particularly toward the microfluidic channel.

(Alternative valve actuation technology :)
In addition to the pressure based actuation system described above, electrostatic actuation and magnetic actuation systems are also contemplated as follows.

  Electrostatic actuation is achieved by forming directly oppositely charged electrodes (which tend to attract each other when a voltage difference is applied to each) on a monolithic elastomeric structure. can do. For example, referring to FIG. 7B, a first electrode 70 (shown in phantom) is placed on (or in) the membrane 25 as needed. If necessary, the second electrode 72 (also indicated by a virtual line) is disposed on (or inside) the flat substrate 14. When electrode 70 and electrode 72 are charged to opposite polarities, the attractive force between the two electrodes causes the membrane 25 to deflect downward, thereby closing this “valve” (ie, closing the flow channel 30).

  A sufficiently flexible electrode to ensure that the membrane electrode is sufficiently conductive to support electrostatic actuation, but not mechanically rigid to deter valve movement. Must be provided in or on the membrane 25. Such an electrode is provided by a thin metallized layer doped with a polymer with a conductive material or made a surface layer from a conductive material.

  In a specific aspect, the electrode present in the flexing thin film can be provided by a thin metallized layer, such as by sputtering a thin layer of metal such as 20 nm gold. In addition to forming metallized films by sputtering, other metallization methods such as chemical epitaxy, vapor deposition, electroplating, and non-electroplating can also be used. Physical transfer of the metal layer to the surface of the elastomer is also available, such as by evaporating the metal onto a weakly attached flat substrate, then placing the elastomer on the metal and peeling the metal from the substrate Is possible.

Conductive electrode 70 can be obtained by wiping over dry powder or by exposing the elastomer to a suspension of carbon black in a solvent that causes the elastomer to swell (such as a chlorinated solvent in the case of PDMS). It is also formed by deposition of carbon black (ie, Cabot Vulcan XC72R) on the elastomer surface. Alternatively, the electrode 70 can be formed by constructing the entire layer 20 from an elastomer doped with a conductive material (ie, carbon black or finely divided particles). Still further alternatively, the electrode may be formed by electrostatic deposition or by a chemical reaction that produces carbon. In experiments conducted according to the present invention, increasing the carbon black concentration from 5.6 × 10 ⁻¹⁶ to about 5 × 10 ⁻³ (Ω-cm) ⁻¹ showed conductivity. The lower electrode 72, which is not required to move, can be a flexible electrode as described above, or it can be a conventional electrode such as a deposited gold, metal plate, or doped semiconductor electrode.

  Pumps or valves according to embodiments of the present invention can also be activated by applying a potential to a material whose physical properties can also be changed in the electromagnetic field. An example of such a material is liquid mercury, whose surface tension changes in the applied electromagnetic field. In this method of operation, liquid mercury pockets are present in the control channel that covers the flow channel. The mercury fluid pocket is connected to the electrode. In response to a voltage applied across the electrodes, the adjacent membrane is changed from a relaxed state to an unrelaxed state. Depending on the particular structure of the valve, this altered state may correspond to either opening or closing the valve. Upon interruption of the applied voltage, the mercury in the control channel regains its original surface tension and the membrane regains its relaxed position.

  In a similar approach, the surface of the control channel can be coated with a material that changes shape in response to an applied potential. For example, polypyrrole is a conjugated polymer that changes shape within an electrolyte that produces an applied voltage. The control channel can be coated with polypyrrole or other organic conductors that change the macroscopic structure in response to an applied electric field. The coated control channel is then filled with an electrolyte, which is placed in contact with the electrode. When a potential difference is applied across the electrolyte, the coated channel is attached to the electrode. Thus, by designing an appropriate arrangement of the polypyrrole-coated channel in relation to the electrolyte, the flow channel can be selectively opened or closed by applying a current.

  Magnetic actuation of the flow channel can be achieved by making a film that separates this flow channel with a magnetic polarisable material such as iron or a permanent magnetic material such as polarized NdFeB. In experiments by the present inventors, magnetic silicones were made by adding iron powder (about 1 μm particle size) to 20 wt% iron.

  When a film is made using a magnetically polarizable material, the film is actuated by an attractive force in response to an applied magnetic field. If the film is made of a material capable of maintaining permanent magnetism, the material is first magnetized by exposure to a sufficiently strong magnetic field, and then by an attractive force depending on the polarity in the applied inhomogeneous magnetic field, Or actuated by repulsion.

  The magnetic field that causes the operation of this film can be generated in a variety of ways. In one embodiment, this magnetic field is generated by an extremely small inductive coil formed in or close to the elastomeric film. The actuation effect of such a magnetic coil can be localized and allows the actuation of individual pump and / or valve structures. Alternatively, the magnetic field can be generated by a larger, more powerful source, in which case the operation can be global, operating multiple pumps and / or structures at once.

  Furthermore, a combined pressure actuation of electrostatic actuation or magnetic actuation is possible. In particular, a bellows structure in fluid communication with the recess is actuated to change the pressure in the recess electrostatically or magnetically, thereby actuating the membrane structure adjacent to the recess.

  In addition to the electrical or magnetic actuation as described above, optional electrolyte and electrokinetic actuation systems are contemplated by the present invention.

  For example, the operating pressure on the membrane can result from an electrolytic reaction in a recess (control channel) that covers the membrane. In such an embodiment, the electrode in this recess applies a voltage through the electrolyte in this recess. This potential difference results in an electrochemical reaction at the electrode and results in gas evolution, which in turn creates a pressure difference in this recess. Depending on the type of elastomer and the precise device structure, the gas generated by such an electrolyte reaction can be allowed to escape mechanically or slowly diffuse out of the elastomeric polymer matrix, Release the pressure generated in step 1 to return the membrane to a relaxed state.

  Alternatively, rather than relying on reversible external diffusion of operation, the gas can recombine to form water, releasing the pressure and returning the membrane to its relaxed state. Water formation from hydrogen and water vapor can be achieved through the use of a catalyst or by providing sufficient energy to cause controlled combustion.

  One potential application of the electrolysis method of operation is the microsyringe structure shown in FIG. FIG. 56 is a schematic diagram of an elastomeric block that creates a flow channel 6100 in fluid communication with each of the first chamber 6102, the second chamber 6104, and the third chamber 6106. First chamber 6102 contains salt solution 6103 in contact with electrodes 6108 and 6110. The third chamber 6106 contains drug 6107 or other liquid material that is discharged from the fluidic device through the discharge chamber 6112. The second chamber 6104 contains an inert oil 6105 that is intended to physically insulate the drug 6107 from the salt solution 6103. Upon application of a potential difference across electrodes 6108 and 6110, salt solution 6103 undergoes electrolysis and generates gas, so that first chamber 6102 immediately experiences an increase in pressure. This pressure increase causes oil 6105 to flow from the second chamber 6104 to the third chamber 6106 to displace the drug 6107 and create a flow of drug 6107 from the third chamber 6106 to the drain channel 6112 and ultimately to the patient. .

  An embodiment of a method for actuating a microfabricated elastomeric structure provides a water soluble salt solution to a control recess formed in an elastomeric block, covering the surface of the flow channel and separated from the flow channel by an elastomeric membrane. And a step of applying a potential difference to the salt solution to generate gas and causing the membrane to conform to the flow channel by the pressure in the control recess.

  An embodiment of a microfabricated syringe structure according to the present invention includes a first chamber formed in an elastomeric block and containing a water soluble salt solution, a first electrode, and a second electrode. The second chamber is formed in the elastomeric block and contains an inert liquid, and the second chamber is in fluid communication with the first chamber through the first flow channel. A third chamber is formed in the elastomeric block and contains an evacuable material, the third chamber is in fluid communication with the second chamber through the second flow channel within the fluid and in fluid communication with the environment through the outlet. As a result, the application of a potential difference across the electrodes generates gas in the first chamber, which replaces the inert material with the third chamber, and the inert material replaces the injectable material with the environment. .

The operating pressure on the membrane of the device according to embodiments of the present invention can also arise from a dynamic current body in the control channel. In such an embodiment, the electrode at the opposite end of the control channel provides a potential difference through the electrolyte present in the control channel. The electrokinetic flow induced by the potential difference can cause a pressure difference.

  Finally, based on the application of thermal energy, the device can also be activated by creating a fluid flow in the control channel (either by thermal expansion or by production of gas from the liquid). It is also possible. For example, in one alternative embodiment according to the present invention, a pocket of fluid (eg, in a control channel filled with fluid) is disposed on the flow channel. The fluid in the pocket may communicate with a temperature variation system, such as a heater. Thermal expansion of the fluid, or conversion of material from the liquid to the gas phase, can cause an increase in pressure and close adjacent flow channels. Subsequent cooling of the fluid relieves the pressure and allows the flow channel to open. Alternatively, or in connection with simple cooling, the vapor heated from the fluid pocket can be diffused from the elastomeric material, thereby releasing the pressure and allowing the flow channel to open. The loss of fluid from the control channel due to such a process can be replenished from an internal or external reservoir.

  Similar to the temperature operation discussed above, a chemical reaction that generates a gaseous product may provide an increase in pressure sufficient for membrane operation.

(Networked system :)
23A and 23B show a diagram of a single on / off valve identical to the system previously specified (eg, in FIG. 7A). FIGS. 24A and 24B show a peristaltic pumping system composed of a single addressable multiple on / off valve as seen in FIG. 23, but networked together. FIG. 25 is a graph showing pumping flow versus frequency achieved in the experiment for the peristaltic pumping system of FIG. FIGS. 26A and 26B show schematic diagrams of multiple flow channels that can be controlled by a single control line. The system also includes a single addressable multiple on / off valve of FIG. 23 and is multiplexed together, but with a different configuration than that of FIG. FIG. 27 is an illustration of a multiplexing system comprised of the single addressable multiple on / off valves of FIG. 23, joined together or networked and adapted to allow fluid flow through selected channels. FIG.

  Referring first to FIGS. 23A and 23B, a schematic of flow channel 30 and flow channel 32 is shown. The flow channel 30 preferably has a fluid (or gas) flow F therethrough. The flow channel 32 (as traversing the flow channel 30 as previously described herein) is pressurized and the membrane 25 separating the flow channels is pressed into the flow channel 30 path. As described above, the passage of the flow F passing therethrough is blocked. Thus, the “flow channel” 32 may be referred to as a “control line” that operates one valve in the flow channel 30. In FIGS. 23-26, a plurality of such addressable valves can be connected in a variety of arrangements or networked together to create pumps and other fluid logic applications capable of peristaltic pumping. ing.

  Referring to FIGS. 24A and 24B, the system for peristaltic pumping is applied as follows. The flow channel 30 has a plurality of generally parallel flow channels (ie, control lines) 32A, 32B and 32C passing thereover. By pressurizing the control line 32A, the flow F through the flow channel 30 is blocked under the membrane 25A at the intersection of the control line 32A and the flow channel 30. Similarly (not shown), by pressurizing the control line 32B, the flow F through the flow channel 30 is blocked under the membrane 25B at the intersection of the control line 32B and the flow channel 30, and the like.

Each of the control lines 32A, 32B, 32C can be addressed separately. Hence,
Control lines 32A and 32C are actuated together, after which control line 32A is actuated, followed by actuating control lines 32A and 32B together, followed by actuation of control line 32B, after which control line 32B and The peristalsis may be activated by a pattern such as operating 32C together. This corresponds to a continuous pattern of “101, 100, 110, 010, 011, 001”, where “0” indicates “valve open” and “1” indicates “valve closed”. Yes. This peristaltic pattern is also known as a 120 degree pattern (meaning the phase angle of operation between the three valves). Other peristaltic patterns are equally possible, including a 60 degree pattern and a 90 degree pattern.

  In experiments conducted by the inventors, a pumping flow rate of 2.35 nL / s was measured by measuring the distance traveled by a water column in a thin (0.5 mm internal dimension) tube, A 100 × 100 × 10 μm valve was placed under 40 kPa working pressure. The pumping speed increased with operating frequency up to about 75 Hz and then remained almost constant until it exceeded 200 Hz. Valves and pumps were extremely tolerant and it was not observed that the elastomeric membrane, control channel, or bond worked. In experiments conducted by the inventors, none of the valves of the peristaltic pump described herein show signs of wear or fatigue even after more than 4 million actuations. . In addition to valve resistance, the valve is also gentle. A solution of E. coli pumped through the channel and tested for viability showed a 94% survival rate.

  FIG. 25 is a graph showing the pumping speed versus frequency achieved experimentally for the peristaltic pumping system of FIG.

  The embodiment of the pumping system shown in FIGS. 24A-24B utilizes multiple parallel flow channels, but this is not required by the present invention. FIG. 73A presents a plan view of an alternative embodiment of a pump structure according to the present invention, where the serpentine control channel 7800 crosses over the underlying flow channel 7802 at three different points, thereby Three valve structures 7804, 7806, and 7808 are generated. The three valve structures 7804, 7806, and 7808 have membranes 7804a, 7806a, and 7808a, respectively.

  Application of a high pressure signal to the first end 7800a of the control channel 7800 causes the high pressure signal to go to the first valve 7804, then to the second valve 7806, and finally to as shown in Table 1. Propagated to the third valve 7808.

結果として得られる膜７８０４ａ、７８０６ａ、および７８０８ａが一致する配列は、フローチャネル７８０２において方向Ｆにポンピング動作を生成する。さらに、時間Ｔ_３における制御チャネル７８００の第一の端部７８００ｄでの圧力の緩和により、低圧信号が第一のバルブ７８０４に、次いで、第二のバルブ７８０６に、そして最後に第三のバル
ブ７８０８に伝播され、チャネル７８０２を通じて以前にフローされた物質の方向の逆転を引き起こすことなく、別のポンピング配列のためのステージを設定する。

The resulting arrangement of matching membranes 7804a, 7806a, and 7808a produces a pumping motion in direction F in the flow channel 7802. Furthermore, the pressure relief in the first end 7800d of control channel 7800 at time _{T 3,} the low pressure signal is a first valve 7804, then to second valve 7806, and finally the third valve, 7808 Set up a stage for another pumping arrangement without causing a reversal of the direction of the material previously propagated through channel 7802.

  73B and 73C plot the flow rate against the frequency of the application of the high pressure signal to the control line of the pump structure of FIG. Have FIG. 73B shows the flow rate resulting from the working pressure oscillating between the elevated pressure and the ambient pressure. FIG. 73C shows the flow rate resulting from the working pressure oscillating between the increased pressure and the vacuum. Both FIGS. 73B and 73C show an efficient pumping operation, with a larger operating pressure in the range of FIG. 73C resulting in a faster flow rate.

  26A and 26B illustrate another method of assembling the addressable valves of FIG. In particular, a plurality of parallel flow channels 30A, 30B, 30C are provided. A flow channel (ie, control line) 32 passes across the flow channels 30A, 30B, 30C. The pressurization of the control line 32 simultaneously blocks the flows F1, F2, and F3 by pressing the membranes 25A, 25B, and 25C disposed at the intersections of the control line 32 and the flow channels 30A, 30B, and 30C.

  FIG. 27 is a schematic diagram of a multiplexing system adapted to selectively allow fluid to flow through selected channels, as described below. The downward deflection (eg, membranes 25A, 25B, 25C in FIGS. 26A and 26B) of the thin film that separates the respective flow channels from the control lines passing above them is strongly dependent on the size of the thin film. . Thus, by varying the width of the flow channel control line 32 of FIGS. 26A and 26B, it is possible to have the control line cross multiple flow channels, but only operate (ie, seal) the desired flow channel. It is. FIG. 27 illustrates an overview of such a system as follows.

  A plurality of parallel flow channels 30A, 30B, 30C, 30D, 30E, 30F are installed below the plurality of parallel control lines 32A, 32B, 32C, 32D, 32E, and 32F. Control channels 32A, 32B, 32C, 32D, 32E, and 32F utilize flow valve 30A, 30B, 30C, 30D, 30E, parallel to each other using any of the valve systems described above but including the following modifications. Adapted to block fluid flows F1, F2, F3, F4, F5 and F6 passing through 30F.

  Each of the control lines 32A, 32B, 32C, 32D, 32E, and 32F has both a wide portion and a narrow portion. For example, the control line 32A is wide at each location located over the flow channels 30A, 30C and 30E. Similarly, control line 32B is wide at each location located across flow channels 30B, 30D and 30F, and control line 32C is at each location located across flow channels 30A, 30B, 30E and 30F. It is wide.

  At each position where the respective control line is wide, the pressurization significantly pushes the membrane 25 separating the flow channel and the control line into the flow channel, thereby causing the flow through it. Block the route. On the contrary, in each place where each control line is narrow, the film 25 is also narrowed. Thus, as a result of the same degree of pressurization, the membrane (25) does not press into the flow channel (30). Therefore, the fluid path below it is not blocked.

For example, the control line 32A, when pressurized, blocks the flows F1, F3, F5 in the flow channels 30A, 30C and 30E. Similarly, control line 32C, when pressurized, blocks flows F1, F2, F5 and F6 in flow channels 30A, 30B, 30E and 30F. As will be appreciated, one or more control lines can be activated simultaneously. For example, control lines 32A and 32C can be pressurized simultaneously to block all flows of fluids except F4 (32A blocks F1, F3 and F5, 32C blocks F1, F2, F5 and F6) ).

By selectively pressurizing the different control lines 32 both together and in various orders, a significant degree of fluid flow control can be achieved. Furthermore, by extending the system to more than 6 parallel flow channels 30 and more than 4 parallel control lines 32, and by changing the positioning of the wide and narrow areas of the control lines, Complex fluid flow control systems can be manufactured. A characteristic of such a system is that any one flow channel can be turned on from n flow channels using only 2 (log ₂ n) control lines.

The inventors have succeeded in producing a microfluidic structure with a density of 30 devices / mm ² , but higher densities can be achieved. For example, FIG. 60 shows a plan view of the multiplexer device 6500. This multiplexer device 6500 includes 64 parallel flow channels 6502 controlled by 12 superposition control channels 6504. Fluid is introduced into multiplexer structure 6500 through input 6506 and is distributed to flow channel 6502 through peristaltic pumping action of pumping control lines 6508a-c.

  Control channels 6504a-l may be understood as six pairs of control lines 6504a-b, 6504c-d, 6504e-f, 6504i-j, and 6504k-l with complementary wide and narrow channel region functions. For example, application of control pressure to line 6504a closes the first 32 flow channels 6502, while application of control pressure to line 6504b closes the other 32 flow channels 6502. Similarly, application of control pressure to line 6504k closes one set of alternating flow channels 6502, while application of control pressure to line 6504l closes another set of alternating flow channels 6502. Thus, by selectively applying a control pressure to one line of each control line pair 6504a-b, 6504c-d, 6504e-f, 6504g-h, 6504kl, the output from the output 6510 of the multiplexer structure 6500. Fluid flow may be limited to a single control channel.

  Although the above description shows a multiplexer with 64 flow channels, this is just one particular embodiment. The multiplexer structure according to the present invention is not limited to any particular number of flow channels. A non-limiting list of the number of flow channels for a multiplexer structure according to the present invention is as follows: 4, 8, 16, 32, 64, 96, 128, 256, 384, 512, 1024, and 1536.

Multiplexer structures that include a number of flow channels other than the number listed are also contemplated so long as the 2 (log ₂ n) relationship governing the minimum number of control lines for a given number of flow channels is satisfied. Multiplexer structures having less than 2 (log 2n) control lines for n flow lines are also contemplated by the present invention. Such a multiplexer structure can produce an operational pattern useful in the flow line (ie, 1111000011110000...).

The multiplexer embodiment of FIG. 60 illustrates the use of a valve structure in combination with a separate pumping system, but this is not required by the present invention. Specifically, control channel / flow channel overlap regions that are not otherwise utilized for control flow through a given flow channel may be activated to pump fluid through the flow channel. This aspect of the invention is shown below in connection with FIG.

  FIG. 74 shows a plan view of a multiplexer structure 7900 that includes at least three parallel flow channels 7902a-c overlapped by at least three control channels 7904a-c. The wide overlap of the first control channel 7904a with the first channel 7902a creates a multiplexer valve 7906 that controls the flow of material F1 through the first flow channel 7902a.

  The second control channel 7904b and the third control channel 7904c simply cross over the first flow channel 7902a before spreading to the control flows F2 and F3 through the second flow channel 7902b and the third flow channel 7902c, respectively. is there. However, by applying an array of high pressure signals to the control channels 7904b and 7904c coordinated with the operation of the multiplexer valve 7906, fluid pumping can cause the first flow channel 7902a to descend.

  On the other hand, the high pressure present in the control channels 7904b and 7904c during pumping of the first flow channel 7902a further activates the multiplexer valves 7908 and 7810 of the second flow channel 7902b and third flow channel 7902c, respectively. However, the upstream or downward stream of other multiplexer valve closures (not shown) of multiplexer valves 7908 and 7910 blocks undesired movement of fluid through flow channels 7902b and 7902c. As shown in FIG. 60, such additional upstream or downstream stream multiplexer valves are present in multiplexers that control even a moderate number of flow channels.

  The networked structure described herein utilizes two layers of elastomeric material to control fluid movement in a single plane. Greater degrees of mobility in controlling fluid flow through the channels and chambers can be achieved through the use of an elastomer layer greater than two. This is shown in connection with FIG.

  FIG. 75 presents a cross-sectional view of a microfluidic structure in accordance with one embodiment of the present invention. This microfluidic structure is formed from three elastomeric layers on the top of the substrate. Specifically, the elastomeric device 8000 includes a first elastomeric layer 8002 that overlays a flat substrate 8004 resulting in a first concave control channel 8006. The second elastomer layer 8008 overlays the first elastomer layer 8002 and the concave flow channel 8010 of the second elastomer layer 8008 is separated from the first control channel 8006 by the first membrane 8010.

  The third elastomeric layer 8012 overlays the second elastomeric layer 8008, resulting in a second concave control channel 8014 separated from the underlying flow channel 8010 by the second membrane 8016. The elastomeric layer arrangement shown here allows control channels 8006 and 8014 to be operated independently to control the flow of material through flow channel 8010. The use of both control channels above and below the flow channel gives the designer greater mobility in routine control signals.

The usefulness of the three-layer structure of FIG. 75 is further illustrated in connection with FIG. FIG. 76 shows a cross-sectional view of a pinch-off valve according to an embodiment of the present invention. First control channel 8100 is defined between a recess in the bottom surface of first elastomer layer 8102 and underlying substrate 8104. A flow channel 8106 is defined between the recess in the bottom surface of the second elastomer layer 8108 and the underlying first elastomer layer 8102. A second control channel 8110 aligned on the first control channel 8100 is defined between the recess in the bottom surface of the third elastomer layer 8112 and the underlying second elastomer layer 8108.

  During operation, pressure is simultaneously applied to the first control channel 8100 and the second control channel 8110 so that the first membrane 8114 and the second membrane 8116 are aligned from opposite sides to match the flow channel 8106. The By reducing the degree of coincidence required to close the flow channel, the pinch-off valve structure of FIG. 76 allows a reduced actuation force to be employed to close the flow channel, or A film with less mobility can be employed.

  The valve embodiment of FIG. 76 can be employed to create a multiplexer structure having a reduced number of control lines. FIG. 79 shows a simplified plan view of an alternative embodiment of a multiplexer structure according to the present invention.

  Multiplexer 8400 includes a first set of parallel control channels 8402 formed in a first elastomer layer overlaying a substrate. The flow channel 8494 is formed in a second elastomer layer that overlays the first elastomer layer. A second set of parallel control channels 8406 is formed in a third elastomer layer overlying the second elastomer layer, and the second set of control channels 8406 is the first set of underlying control channels 8402. Orientated orthogonally.

  The point of overlap of the first control channel 8402, the flow channel 8404, and the second control channel 8406 creates a pinch-off valve 8408 in the flow channel 8404. Only during operation of both control channels 8402 and 8406, pinch-off valve 8408 closes flow channel 8404.

  FIG. 80A shows a plan view of an alternate embodiment of a valve structure according to the present invention, utilizing a control layer disposed on the opposite side of the layer containing the flow channel. FIG. 80B shows a cross-sectional view of the valve structure of FIG. 80A along line 80B-80B '.

  The valve 8500 includes a lower control channel 8502 defined between a recess in the first elastomer layer 8504 and an underlying flat substrate 8506. A flow channel 8508 is defined between the recess in the second elastomer layer 8510 and the top surface of the underlying first elastomer layer 8504. Upper control channel 8512 is defined between a recess in third elastomer layer 8514 and the top surface of underlying second elastomer layer 8510.

  At the first T-junction 8516, the flow channel 8508 is split into branches 8508a and 8508b, each having the same capacity as the main flow channel portion 8508. Branches 8508a and 8508b recombine at a second T-junction 8518 to reform the main flow channel portion 8508. Only the first flow channel branch 8518 a overlays the lower control channel 8502. The upper control channel 8512 overlays only the second flow channel branch 8508b. As a result of the architecture described herein, valve 8500 is closed only when both lower control channel 8502 and upper control channel 8512 are activated. Under any other condition, the substance continues to flow through at least one of the branches 8508a and 8508b of the flow channel 8508.

The branched valve structure of FIGS. 80A-B can be utilized to create an embodiment of a multiplexer structure that requires only two elastomer layers. FIG. 81 presents a simplified schematic diagram of such an alternative embodiment of a multiplexer structure. Multiplexer 8600
Includes a lower elastomeric layer defining a plurality of flow channels 8602, each flow channel 8602 being divided into M parallel branches 8602a. In the particular multiplexer embodiment shown in FIG. 81, M = 2.

The upper elastomer layer overlying the lower elastomer layer defines N control channels 8604 that are orthogonal to the flow channel 8602a. The particular multiplexer embodiment shown in FIG. 81 has N = 6. The control channel 8604 includes an expanded portion that produces a membrane 8604a that can be matched to the underlying flow channel branch 8602a. Selective activation of control channel 8604 allows control over (N / M) ^M flow channels.

  Although FIGS. 75 and 79-80B show an embodiment of an elastomeric structure of a multiplexer that utilizes a control channel disposed on the opposite side of the flow channel, the present invention is not limited to this particular configuration. FIG. 77 shows an embodiment of a multilayer microfabricated elastomeric structure according to the present invention where two control channel layers are disposed on the same side of the flow channel.

  Specifically, the microfabricated elastomeric structure 8200 includes a plurality of parallel flow channels 8202 defined by a lower elastomer layer and recesses in the bottom surface of the underlying substrate. Flow channel 8202 encounters successive functional blocks 8204, 8206, and 8208 that include complex flow networks. An example of the function performed by blocks 8204, 8206, and 8208 may be the crushing, separation, and analysis of cells that are flowing down the flow line 8202.

  Fluid movement between functional blocks 8204, 8206, and 8208 is a first set of control lines 8210 defined between the top surface of the underlying elastomer layer and the recess in the bottom surface of the intermediate elastomer layer. Controlled by. The overlap of control line 8210 and flow channel 8202 defines a plurality of control valves 8212.

  A second set of control lines 8214 interacts with each functional block 8204, 8206, and 8208 to control material flow and performance of specific functions. A second set of control lines 8214 is also defined between the recesses in the top surface of the underlying elastomer layer and the bottom surface of the intermediate elastomer layer.

  Functional blocks 8204, 8206, and 8208 communicate with a second set of control lines 8214 to simplify the number of control lines and thereby reduce the complexity of the microfabricated elastomeric device. In order to ensure the independent operation of blocks 8204, 8206, and 8208 and maximum mobility of functionality for device 8200, the second set of control lines 8214 is then controlled by the third set of control lines 8216. Be controlled. A third set of control lines 8216 is defined between the top surface of the intermediate elastomer layer and the recess in the bottom surface of the top elastomer layer.

If activation of the second set of control lines 8214 is intended to dominate the functionality of the first functionality block 8204, lines 8216b and 8216c of the third control line set 8216 are activated and the second Block communication of signal by control line set 8214 to second functionality block 8206 and third functionality block 8208. Conversely, if the operation of the second set of control lines 8214 is intended to dominate the functionality of the second functionality block 8206, the control lines 8216a and 8216c of the third control line set 8216 are activated. Block communication of signals by the second control line set 8214 to the first functionality block 8206 and the third functionality block 8208. Similarly, if the operation of the second set of control lines 8214 is intended to dominate the functionality of the third functionality block 8208, the control lines 8216a and 8216b of the third control line set 8214 are activated. Block communication of signals by the second control line set 8214 to the first functional block 8204 and the second functional block 8206.

  The use of one set of control lines to control another set of control lines common to multiple functional blocks reduces the total number of control lines and control inputs. The overall architecture of the device is thereby simplified and reduces costs.

(Selectively addressable reaction chamber along the flow line)
In a further embodiment of the invention illustrated in FIGS. 28A, 28B, 28C, and 28D, fluid flow is selected for another one of the plurality of reaction chambers disposed along the flow line. A system for directing direction is presented.

  FIG. 28A shows a top view of a flow channel 30 along which a plurality of reaction chambers 80A and 80B are disposed. The flow channel 30 and the reaction chambers 80A and 80B are formed together as a recess into the bottom surface of the first layer 100 of elastomer. preferable.

  FIG. 28B shows a bottom view of another elastomeric layer 110 in which each of the two control lines 32A and 32B is generally narrow, but the widened portions 33A and 33B are formed as recesses.

  As can be seen in the exploded view of FIG. 28C, and as can be seen in the assembled view of FIG. 28D, the elastomeric layer 110 is placed over the elastomeric layer 100. Layer 100 and layer 110 are coupled together and this integrated system selectively directs fluid flow F (through flow channel 30) to either or both of reaction chambers 80A and 80B as follows: Operate. By pressurization of the control line 32A, the membrane 25 (that is, a thin portion of the elastomer layer 100 disposed below the extension 33A and above each region 82A of the reaction chamber 80A) is pressed, thereby causing the region The fluid flow path at 82A is blocked and the reaction chamber 80 is effectively sealed from the flow channel 30. As shown in the figure, the extension 33A is wider than the remaining part of the control line 32A. Thus, the control line 32A does not seal the flow channel 30 as a result of pressurization of the control line 32A.

  As will be appreciated, either or both of control lines 32A and 32B can be activated at a time. When both control lines 32A and 32B are pressurized together, the sample flow in the flow channel 30 does not enter either reaction chamber 80A or 80B.

  The concept of selectively controlling fluid introduction into various addressable reaction chambers arranged along a flow line (FIG. 28) selectively directs fluid flow through one or more of a plurality of parallel flow lines. Combined with the concept of controlling (FIG. 27), a system can be created in which one or more samples of fluid can be delivered to any particular reaction chamber in an array of any reaction chamber. One specific example of such a system is presented in FIG. 29, in which control channels 32A, 32B, 32C that are parallel to each other, along with the extension 34 (all shown in phantom), are , Selectively directing fluid flows F1, F2 to either array of reaction wells 80A, 80B, 80C, or 80D, while simultaneously pressurizing control lines 32C and 32D causes flows F2 and F1 to flow. Each block selectively.

In another novel embodiment, fluid paths between parallel flow channels are possible. Referring to FIG. 30, either or both of the control lines 32A or 32D are depressurized to allow fluid flow through the side passageway 35 (between the flow channels 30A and 30B parallel to each other). In this aspect of the invention, pressurization of the control lines 32C and 32D blocks the flow channel 30A between 35A and 35B and also blocks the lateral passage 35B. Thus, the flow that entered as flow F1 moves continuously through flow channels 30A and 35A and exits flow channel 30B as flow F4.

(Switchable flow array)
In yet another novel embodiment, the fluid passage may flow selectively directed in one of two vertical directions. One example of such a “switchable flow array” system is given in FIGS. FIG. 31A shows a bottom view of a first layer 90 of elastomer (or any other suitable substrate), the bottom surface of this first layer forming a flow channel grid defined by an array of solid posts 92. A flow channel passes around each of the posts having a pattern of recesses.

  In a preferred aspect, an additional layer of elastomer is bonded to the top surface of layer 90 so that fluid flow can be selectively directed in either direction F1 or vertical direction F2. FIG. 31 is a bottom view of the bottom surface of the second layer 95 of elastomer, showing recesses formed in the form of alternating “vertical” control lines 96 and “horizontal” control lines 94. The “vertical” control line 96 has the same width along it, while the “horizontal” control line 94 has alternating wide and narrow portions as shown.

  The elastomer layer 95 is located on top of the elastomer layer 90 so that the “vertical” control line 96 is located on the post 92 and the “horizontal” control line 94 is shown in FIG. 31C. As shown in FIG. 31D, the wide portion is located between the posts 92.

  As seen in FIG. 31C, when the “vertical” control line 96 is pressurized, it is a monolithic membrane formed by an elastomeric layer (this is initially located in the region 98 between the layers 90 and 95). Is biased downward beyond the array of flow channels so that the flow can simply pass in the flow direction F2 (ie, vertical) as shown.

  As seen in FIG. 31D, when the “horizontal” control line 94 is pressurized, it is a monolithic membrane formed by an elastomeric layer (this is initially located in the region 99 between layers 90 and 95). Is biased down across the array of flow channels (but only in the widest area of this line), so that the flow simply passes in the flow direction F1 (ie, horizontal) as shown. Can do.

  The design shown in FIG. 31 allows a switchable flow array to be composed of only two elastomer layers, where the vertical bias does not need to pass between the control lines of the different elastomer layers. If all vertical flow control lines 94 are connected, they can be pressurized from one input. The same is true for all vertical flow control lines 96.

(Biopolymer synthesis)
The elastomeric valve structure of the present invention can also be used for biopolymer synthesis (eg, synthesis of oligonucleotides, proteins, peptides, DNA, etc.). In a preferred aspect, such a biopolymer synthesis system may include an integrated system that includes an array of containers, fluid logic for selecting a flow from a particular container (according to the invention), It includes an array of channels or containers in which the synthesis is performed, and fluid logic (also according to the invention) for determining the channels into which the selected reagent flows. An example of such a system 200 is shown in FIG. 32 as follows.

  The four containers 150A, 150B, 150C, and 150D have bases A, C, T, and G, respectively, placed therein as shown. Four flow channels 30A, 30B, 30C and 30D are connected to containers 150A, 150B, 150C and 150D. Four control lines 32A, 32B, 32C, and 32D (shown in phantom) allow flow through only flow channel 30A when control line 32A is pressurized (ie, flow channels 30B, 30C, and 30D). A control line 32A is placed across these channels to seal. Similarly, control line 32B, when pressurized, allows flow through only flow channel 30B. As such, selective pressurization of control lines 32A, 32B, 32C, and 32D results in selecting the desired bases A, C, T, and G from the desired vessel 150A, 150B, 150C, or 150D. When fluid then passes through the flow channel 120 and enters the multi-channel flow controller 125 (eg, including any of the systems shown in FIGS. 26A-31D), this then directs the fluid flow to a plurality of synthesis channels or Directed to one or more of chambers 122A, 122B, 122C, 122D or 122E, where solid phase synthesis can occur.

  FIG. 33 shows the further scope of this system, in which a plurality of vessels R1-R13 (which are bases A, C, T and G, or other reactants (such as those used in combinatorial chemistry). Are connected to the system 200 as shown in FIG. The system 200 is connected to a multi-channel flow controller 125 (eg, including any system as shown in FIGS. 26A-31D), which is then switchable flow array (eg, as shown in FIG. 31). Connected). The advantage of this system is that a multi-channel flow controller 125 is assumed, provided that a “closed horizontal” control line is provided and a “closed vertical” control line (imaginary lines 160 and 162) is also provided. And the fluid selection system 200 can be controlled by the same pressure inputs 170 and 172.

  In a further alternative aspect of the present invention, a plurality of multi-channel flow control devices (eg, 125) are placed, with each flow control device initially layered on top of each other on a different elastomer layer. With vertical bias or interconnects (this can be done by lithographically patterning the etch resistant layer on top of the elastomer layer, then etching the elastomer, and finally adding the last elastomer layer) And can be used by removing.

  For example, a vertical groove through the elastomer layer etches a hole down on a raised line on a microfabricated mold and bonds the adjacent layers so that the channel passes through the hole. Can be made. In this aspect of the invention, multiple combining with multiple multi-channel flow controllers 125 is possible.

  The process of joining successive layers of molded elastomer to form a multilayer structure is shown in FIG. This is an optical micrograph of a section of a test structure consisting of seven layers of elastomer. The scale bar in FIG. 34 is 200 μm.

  One method of producing an elastomeric layer with vertical grooves according to the features utilized in the multilayer structure is shown in FIGS. FIG. 35A shows a process of forming an elastomer layer 3500 on a microfabricated mold 3502 having raised lines 3502a.

FIG. 35B shows the step of forming a metal etch blocking layer 3504 on the elastomer layer 3500, followed by the photoresist mask 3 on the etch blocking layer 3504.
Patterning 506 shows covering masked area 3508, leaving exposed unmasked area 3510. FIG. 35C shows the exposure to a solvent that removes the etch blocking layer 3504 in the unmasked region 3510.

  FIG. 35D shows the removal of the patterned photoresist, followed by the etching of the underlying elastomer 3500 in the unmasked area 3510 to form vertical grooves via 3512. Subsequent exposure to a solvent selectively removes the remainder of the etch blocking layer 3504 in the masked region 3508 so as to surround the elastomer 3500 and the mold 3502. This elastomeric layer can then be incorporated into the elastomeric structure by multilayer flexible lithography.

  This series of steps can be repeated as necessary to form a multilayer structure having the desired number and orientation of vertical bias between the channels of successive elastomer layers.

The inventors of the present invention have successfully etched the bias through a GE RTV 615 layer using a solution of tetrabutylammonium fluoride in an organic solvent. Gold acts as an etch blocking material, where gold is selectively transferred to GE RTV 615 utilizing a KI / I ₂ / H ₂ O mixture.

  Alternatively, the vertical bias between the channels of successive elastomer layers can be formed utilizing negative masking techniques. In this approach, the negative mask of the metal foil is patterned, and subsequently the formation of the etching blocking layer is suppressed where this metal foil is present. Once the etch blocking material is patterned, the negative metal foil mask is removed, allowing selective etching of the elastomer as described above.

  In yet another aspect, the vertical bias can be formed in the elastomeric layer using ablation of the elastomeric material by application of radiation from the applied laser beam.

  In yet another approach, a vertical bias can be formed by physically punching out holes in the elastomeric material. For example, FIG. 82A shows a cross-sectional view of a two-layer microfabricated elastomer device 8700. The elastomeric device 8700 has a flow channel 8702 formed in the lower elastomeric layer 8704 and a control channel 8706 in the upper elastomeric layer 8708. The first vertical via 8710 enables fluid communication between the control channel 8706 and the upper surface 8708a of the upper elastomeric layer 8708. The second vertical via 8712 allows fluid communication between the flow channel 8702 and the upper surface 8708 a of the upper elastomeric layer 8708.

  82B and 82C show perspective views of steps in the fabrication of the microfabricated elastomeric device of FIG. 82A. Specifically, in FIG. 82B, the first via 8710 may be formed by coreing a molded elastomeric layer 8708 having a rigid hollow member 8714, such as a steel capillary tube, prior to assembly of the structure. To ensure correct alignment between the first via 8710 and the control channel 8706, the upper elastomeric layer 8708 can be pierced by a rigid hollow member 8714 from the control channel side 8708b.

A vertical via that communicates with the flow channel of the underlying flow channel may then be formed once the molded and cored upper elastomer layer is placed over the lower elastomer layer. Specifically, as shown in FIG. 82C, the second via that allows fluid communication between the flow channel 8702 and the top surface 8708a of the upper elastomeric layer 8708 is
It can be formed by punching a rigid hollow member 8714 through both the lower elastomer layer 8704 and the upper elastomer layer 8708, respectively. Again, starting this core formation process from the flow channel side 8704a of the lower elastomer layer 8704 ensures the correct alignment of the second via with the flow channel 8702.

  Via formation by physical core formation or punching of elastomeric material presents numerous advantages. One is simplification, and no complicated lithography / etching process is required when via placement is controlled by physical manipulation of the core forming device. Another advantage of the core forming method is that the mobility of the elastomer allows for a stiff tube having slightly larger dimensions than the core forming device to be inserted into the via. The cored elastomer grips the larger sized tubing and secures it in place inside the via, producing a tight seal.

  Although the above approach is described with respect to biopolymer synthesis, the invention is not limited to this application. The present invention can also function in a wide range of combinatorial chemical synthesis approaches.

(Other applications)
The advantageous applications of the monolithic microfabricated elastomeric valve and pump of the present invention are numerous. Accordingly, the present invention is not limited to any particular application or use thereof. In preferred aspects, the following uses and applications of the present invention are contemplated.

(1. Cell / DNA selection)
The microfabricated pumps and valves of the present invention can also be used in flow cytometers for cell sorting and DNA sizing. Sorting objects based on size is very useful in many technical fields.

  For example, many assays in biology require the determination of the size of a molecular size entity. Of particular importance is the measurement of the length distribution of DNA molecules in a heterogeneous solution. This is usually done using gel electrophoresis, where these molecules are detected by their different mobilities in their gel matrix in an applied electric field and by absorption or emission of radiation. Are separated by the position of The length of the DNA molecules is then determined from their mobility.

  Although powerful, electrophoresis has drawbacks. For medium to large DNA molecules, the resolution, ie the minimum length difference at which different molecular lengths can be distinguished, is limited to about 10% of the total length. For extremely large DNA molecules, conventional sorting procedures are useless. Furthermore, gel electrophoresis is a relatively time consuming procedure and may require about several hours or days to perform.

  The selection of cell size entities is also an important task. Conventional flow cell sorters are designed to have a flow chamber with nozzles and are based on hydrodynamic principles concentrated on sheath flow. Most conventional cell sorters combine piezoelectric droplet generation and electrostatic bending techniques to achieve droplet generation and high sorting rates. However, this approach presents some serious drawbacks. One disadvantage is that the complexity, size, and cost of the sorting device requires that the device be reusable in order to be cost effective. Reuse can then lead to the problem that the remaining material causes sample contamination and fluid flow disturbance.

Thus, in the art, a sorting device that is simple, inexpensive, and easily made and relies on mechanical control of fluid flow rather than electrical interaction between particles and solutes. A device is needed.

  FIG. 36 shows one embodiment of a sorting device according to the present invention. Sorting device 3600 is formed from a switchable valve structure made from channels present in an elastomer block. Specifically, the flow channel 3602 is T-shaped and the stem 3602a of the flow channel 3602 is in fluid communication with a sample container 3604, which is represented by shape (square, circular, triangular, etc.). Different types of selectable entities 3606. The left branch 3602b of the flow channel 3602 is in fluid communication with the waste container 3608. The right branch 3602c of the flow channel 3602 is in fluid communication with the collection vessel 3610.

  The control channels 3612a, 3612b, and 3612c overlap the stem 3602a of the flow channel 3602, and are separated from the stem 3602a by elastomer membrane portions 3614a, 3614b, and 3614c, respectively. The stem 3602a of the flow channel 3602 and the control channels 3612a, 3612b, and 3612c together form a peristaltic pump structure 3616. This pump is similar to the pump long described above with respect to FIG. 24a.

  Control channel 3612d overlaps right branch 3602c of flow channel 3602 and is separated from right branch 3602c by elastomeric membrane portion 3614d. Together, the right branch 3602c of the flow channel 3602 and the control channel 3612d form a first valve structure 3618a. Control channel 3612e overlaps left branch 3602c of flow channel 3602 and is separated from left branch 3602c by elastomeric membrane portion 3614e. Together, the left branch 3602c of the flow channel 3602 and the control channel 3612e form a second valve structure 3618b.

  As shown in FIG. 36, the stem 3602a of the flow channel 3602 becomes significantly narrower as it approaches the detection window 3620 adjacent to the connection of the stem 3602a, the right branch 3602b, and the left branch 3602c. The detection window 3620 has a width sufficient to allow uniform illumination of this region. In one embodiment, the width of the stem is reduced by 100 μm to 5 μm in the detection window. The width of the stem in this detection window depends on the nature and size of the actual material that can be precisely formed and screened using flexible lithography or photoresist encapsulation fabrication techniques as broadly described above.

  The operation of the sorting device according to one embodiment of the present invention is as follows.

  Dilute the sample to a level such that only a single selectable entity is expected to be present in the detection window at any given time. Peristaltic pump 3616 is actuated by flowing fluid through control channels 3612a-c, as broadly described above. Further, the second valve structure 3618b is closed by flowing fluid through the control channel 3612e. As a result of the pumping action of peristaltic pump 3616 and the blocking action of second valve 3618 b, fluid flows from sample container 3604 through detection window 3620 to waste container 3608. Because the stem 3604 is narrowed, the selectable entities present in the sample container 3604 are carried through the detection window 3620 at a time by this normal flow or other flow.

Radiation 3640 from source 3642 is introduced into detection window 3620. This is possible because of the permeable nature of the elastomeric material. Absorption or emission of radiation 3640 by sortable entity 3606 is then detected by detector 3644.

  If the sortable entity 3606a in the detection window 3620 is intended to be separated and collected by the sorting device 3600, the first valve 3618a is activated and the second valve 3618b is deactivated. This has the effect of drawing the selectable entity 3606a into the collection container 3610 and at the same time allowing the second selectable entity 3606b to pass through the detection window 3620. If the second selectable entity 3602b is also intended to be collected, the peristaltic pump 3616 continues to extend the fluid through the right branch 3602c of the fluid channel 3602 to the collection container 3610. However, if the second entity 3606b is not collected, the first valve 3618a is opened and the second valve 3618b is closed, and the first peristaltic pump 3616 passes through the left branch 3602b of the liquid flow channel 3602 to the waste container 3608. Continue pumping to.

  One particular embodiment of the sorting device and the method of operating it is described in connection with FIG. 36, but the invention is not limited to this embodiment. For example, fluid need not be flowed through a flow channel using a peristaltic pump structure, but instead can be flowed under pressure using an elastomeric valve that only controls the direction of flow. In yet another embodiment, multiple sorting structures can be assembled in series to perform a continuous sorting operation, in which case the waste container of FIG. It only replaces the stem.

  In addition, a higher throughput method of sorting can be implemented, where the continuous flow of fluid from the sample container, through the window and connections, into the waste container, is the entity intended for collection. It is maintained until it is detected in the window. Upon detection of the entity to be collected, the direction of fluid flow through the pump structure is temporarily reversed to transfer the desired particles back through the junction to the collection vessel. In this manner, the sorting device can use higher flow rates and has the ability to go back once the desired entity is detected. Such alternative high throughput sorting techniques can be used when the entities to be collected are scarce and need to be turned back occasionally.

  Sorting according to the present invention has the disadvantages of sorting using conventional interfacial conduction flows (eg, bubble formation, strong dependence of flow size and direction on solution composition and surface chemistry, different migration of different species) Degree, as well as reduced viability of organisms that survive in the transfer medium).

(2. Semiconductor processing)
Systems for semiconductor gas flow control (especially for epitaxial applications where small amounts of gas are accurately measured) are also contemplated by the present invention. For example, during the manufacture of semiconductor devices, a solid material is deposited on top of a semiconductor substrate using chemical vapor deposition (CVD). This is accomplished by exposing the substrate to a mixture of gas precursor materials, thereby causing these gases to react and crystallize the product on top of the substrate.

  During such a CVD process, the conditions must be carefully controlled to ensure that the material is deposited uniformly and that there are no defects that can degrade the operation of the electrical device. One possible cause of non-uniformity is fluctuations in the flow rate of reactant gas into the region on the substrate. Poor control of gas flow rates can also result in layer thickness variations from run to run, which is another source of error. Unfortunately, there are significant problems in the control of the amount of gas entering the processing chamber and in maintaining a stable flow rate in conventional gas delivery systems.

  Accordingly, FIG. 37A shows one embodiment of the present invention adapted to carry process gas at a precisely controlled flow rate over the surface of a semiconductor wafer during CVD processing. Specifically, the semiconductor wafer 3700 is placed on a wafer support 3702 that is placed in a CVD chamber. An elastomeric structure 3704 having a number of equally distributed orifices 3706 is disposed directly above the surface of the wafer 3700.

  Various process gases are flowed from containers 3708a and 3708b through the flow channel of elastomer block 3704 and out of orifice 3706 at carefully controlled rates. As a result of the precisely controlled process gas flow over the wafer 3700, a solid material 3710 having a very uniform structure is deposited.

  Accurate measurement of reactant gas flow rates utilizing the valve and / or pump structure of the present invention is possible for several reasons. First, gas can be flowed through a valve that responds in a linear fashion to applied operating pressure, as described above with respect to FIGS. 21A and 21B. As an alternative or in addition to measuring the gas flow using a valve, the predictable behavior of the pump structure according to the invention can be used for an accurate measurement of the process gas flow.

  In addition to the chemical vapor deposition process described above, the techniques of the present invention are also useful for gas flow control in techniques such as molecular beam epitaxy and reactive ion etching.

(3. Fine mirror array)
While the embodiments of the invention described so far relate to the operation of structures entirely composed of elastomeric materials, the invention is not limited to this type of structure. Specifically, it is within the scope of the present invention to combine an elastomeric structure with a conventional semiconductor structure based on silicon.

  For example, a further intended use of the microfabricated pumps and valves of the present invention is that the elastomeric structure membrane may be a flat planar surface, depending on whether the membrane is activated, Or reflect the light, either as a curved surface. As such, the membrane acts as a switchable pixel. Such an array of switchable pixels can be utilized as a digital or analog fine mirror array with appropriate control circuitry.

  Accordingly, FIG. 38 shows an enlarged view of a portion of one embodiment of a micromirror array according to the present invention.

  The micromirror array 3800 includes a first elastomeric layer 3802 that overlies an underlying semiconductor structure 3804 and is separated from the semiconductor structure by a second elastomeric layer 3806. The surface 3804 a of the semiconductor structure 3804 has a plurality of electrodes 3810. The electrodes 3810 are separately addressable by conducting row and column lines as is known to those skilled in the art.

  The first elastomeric layer 3802 includes a plurality of intersecting channels 3822 and underlies a conductive, reflective elastomeric membrane portion 3802a. The first elastomeric layer 3802 is aligned over the second elastomeric layer 3806 and is under the semiconductor device 3804 so that the intersection of the channels 3822 overlies the electrode 3810.

In one embodiment of the manufacturing method according to the present invention, the first elastomer layer 3822 is formed by spin coating an elastomeric material onto a mold having cross channel characteristics, curing the elastomer, and forming the formed elastomer from the mold. It can be formed by removing and introducing a conductive dopant into the surface area of the formed elastomer. Alternatively, as described above with respect to FIGS. 7C-7G, the first elastomeric layer 3822 may be inserted into a mold having intersecting channels such that the elastomeric material is level with the height of the channel walls, and then It can be formed from two layers of elastomer by combining a separate doped elastomeric layer with an existing elastomeric material to form a film on the top surface.

  Alternatively, the first elastomer layer 3802 can be made from a conductive elastomer, where the electrical conductivity depends on either doping or the intrinsic properties of the elastomeric material.

  During operation of reflective structure 3800, an electrical signal is transmitted to electrode 3810a along selected row and column lines. By applying a voltage to the electrode 3810a, an attractive force is generated between the electrode 3810a and the overlying film 3802a. This attraction actuates a portion of the membrane 3802a and deflects that portion of the membrane downward into the cavity resulting from the intersection of the channels 3822. As a result of the deflection of the membrane 3802a from flat to concave, light is reflected at this point of the surface of the elastomeric structure 3802 differently from the surrounding flat membrane surface. In this way, a pixel image is created.

  The appearance of this pixel image is variable and can be controlled by changing the magnitude of the voltage applied to the electrodes. When a higher voltage is applied to this electrode, the attractive force of the membrane portion increases, further distorting its shape. When a lower voltage is applied to the electrode, the attractive force in the membrane is reduced, reducing the distortion of the shape from the plane. Any of these changes will affect the appearance of the resulting pixel image.

  The variable micromirror array structure as described can be used in a variety of applications including image display. Another application of the variable fine mirror array structure according to embodiments of the present invention is a high-capacitance switch for optical fiber communication systems, where each pixel affects the reflection and movement of components of the incident optical signal. obtain.

  Although the above embodiments describe a composite, elastomer / semiconductor structure that is utilized as a microarray, the invention is not limited to this particular embodiment.

For example, another optical application for embodiments of the present invention relates to a switchable Bragg mirror. Bragg mirrors reflect incident light in a specific range of wavelengths and allow all other wavelengths to pass through. A Bragg mirror according to an embodiment of the present invention is made by sputter depositing 30 alternating 1 μm thick layered SiO ₂ and Si ₃ N ₄ mirrors onto a 30 μm thick RTV elastomer film. This RTV elastomer membrane in turn overlays a control channel having a depth of 10 μm and a width of 100 μm. Following passivation of the mirror surface with additional RTV elastomers, application of a control pressure of 15 psi to the control channel deforms the membrane and allows certain wavelengths to pass. The result is shown in FIG. FIG. 65 plots the intensity of light at 490 nm passing through the mirror against the switching cycle. Bragg mirrors according to embodiments of the present invention can be utilized for a variety of purposes, including optical filtering.

(4. Refractive structure)
The fine mirror array structure just described controls the reflection of incident light. However, the present invention is not limited to the control of reflection. Yet another embodiment of the present invention allows for the implementation of precise control of the refraction of incident light in order to create lens and filter structures.

  FIG. 39 shows one embodiment of a refractive structure according to the present invention. Refractive structure 3900 includes a first elastomer layer 3902 and a second elastomer layer 3904, which are made of an elastomeric material that can transmit incident light 3906.

  The first elastomer layer 3902 includes a protrusion 3902a, which can be made by curing an elastomeric material formed on a microfabricated mold having a recess. The second elastomer layer 3904 has a flow channel 3905 and can be made from a microfabricated mold having raised lines, as described broadly above.

  The first elastomer layer 3902 is bonded to the second elastomer layer 3904 such that the protrusions 3902a are located on the flow channel 3905. This structure can serve a variety of purposes.

  For example, light incident on the elastomeric structure 3900 is collected in the underlying flow channel, allowing for possible transmission of light through the flow channel. Alternatively, in one embodiment of the elastomeric device according to the present invention, a fluorescent or phosphorescent liquid can be flowed through the flow channel so that light from the fluid is refracted by the curved surface to form a display. .

  FIG. 40 shows another embodiment of a refractive structure according to the present invention. The refractive structure 4000 is a multilayer optical train based on a Fresnel lens design. Specifically, refractive structure 4000 consists of four successive elastomer layers 4002, 4004, 4006, and 4008 bonded together. The upper surface of each first, second, and third elastomer layer 4002, 4004, and 4006 is a uniform sawtooth that is regularly spaced by a distance X (which is much greater than the wavelength of the incident light). The product 4010 is included. The serrations 4010 act to collect incident light and can be formed using a microfabricated mold as broadly described above. The first, second, and third elastomer layers 4002, 4004, and 4006 function as Fresnel lenses, as will be appreciated by those skilled in the art.

  The fourth elastomer layer 4008 has a uniform serration 4012 having a much smaller size than the overlying elastomer layer serration. The serrations 4012 are also spaced by a distance Y (which is much smaller than the sawtooth of the overlying elastomer layer), where Y is on the order of the wavelength of the incident light, so that the elastomer layer Reference numeral 4008 functions as a diffraction grating.

  FIG. 41 shows an embodiment of a refractive structure according to the present invention. This structure takes advantage of the difference in the refractive index of the materials, mainly to achieve refraction. The refractive structure 4100 includes a lower elastomer portion 4102 that is coated on the upper elastomer portion 4104. Both the lower elastomer portion 4102 and the upper elastomer portion 4104 are made of a material that transmits incident light 4106. The lower elastomeric portion 4102 has a plurality of specimen flow channels 4108 separated by elastomeric lands 4110. The flow channel 4108 includes a fluid 4112 having a different refractive index than the elastomeric material that forms the lands 4110. The fluid 4112 is pumped through the serpentine flow channel 4108 by actuation of the pump structure 4114. This pump structure is made by parallel control channels 4116a and 4116b that overlap the inlet portion 4108a of the flow channel 4108 and are separated from the inlet portion 4108a by a movable membrane 4118.

Light 4106 incident on refractive structure 4100 encounters a non-uniformly spaced, fluid-filled series of flow channels 4108 separated by elastomeric land 4110. As a result of the different optical properties of the materials present in these respective fluid / elastomeric regions, the portions of incident light are not uniformly refracted and interact to form an interference pattern. A stack of refractive structures in the manner just described can achieve even more complex and specialized refraction of incident light.

  The refractive elastomer structure just described can achieve a variety of purposes. For example, the elastomeric structure can act as a filter or optical switch to block incident light of selected wavelengths. Furthermore, the refractive properties of this structure can be easily adjusted depending on the needs of the particular application.

  For example, the composition of the fluid flowing through the flow channel (and hence the refractive index) can be varied to affect diffraction. Alternatively, or in combination with changing the properties of the flowing fluid, the distance separating adjacent flow channels can be accurately controlled during fabrication of the structure to produce an optical interference pattern having the desired characteristics.

  Yet another application involving reflection according to embodiments according to the present invention is a tunable microlens structure. As shown in FIG. 66, the adjustable microlens structure 7100 includes a chamber 7102 connected to an aeration control line 7104. The chamber 7102 can be formed by flexible lithography of a transparent substrate such as RTV. This transparent substrate is bonded to the elastomeric film 7106. Chamber 7102 is then filled with fluid 7103 selected for its refractive index. When the control line 7104 is pressurized, the membrane 7106 expands beyond the chamber 7102 within the valve, creating a lens. The radius of curvature R of the membrane 7106, and thus the focal length of the lens, can be controlled by changing the pressure in the control line 7104 and thus adjusting the lens. Possible applications of such lenses can be separate interrogation of different channel layers or scanning of bulk samples. Since defining the lens structure is accomplished using photolithography, such lenses can be made inexpensively and can be densely integrated onto a fluidics device. Lenses can be made in a wide range of sizes with dimensions varying from 1 μm to 1 cm. Alignment problems are significantly reduced because lateral alignment is achieved by lithography and vertical alignment is achieved by adjusting.

(5. Normally closed valve structure)
FIGS. 7B and 7H above show a valve structure in which the elastomeric membrane is movable from a first relaxed position to a second operating position where the flow channel is blocked. However, the present invention is not limited to this particular valve configuration.

  42A-42J, the elastomeric membrane can be moved using a negative control pressure from a first relaxed position blocking the flow channel to a second operating position where the flow channel is open. Fig. 4 shows various views of a normally closed valve structure.

  FIG. 42A shows a top view and FIG. 42B shows a cross-sectional view along line 42B-42B 'of valve 4200 that is normally closed in a non-actuated state. The flow channel 4202 and control channel 4204 are formed in an elastomeric block 4206 that overlies the substrate 4205. The flow channel 4202 includes a first part 4202 a and a second part 4202 b that are separated by a separation part 4208. The control channel 4204 overlaps the separation unit 4208. As shown in FIG. 42B, in its relaxed inoperative position, the separator 4008 remains in a position between the flow channel portions 4202a and 4202b that obstructs the flow channel 4202.

  FIG. 42C shows a cross-sectional view of valve 4200 (where separator 4208 is in the activated position). If the pressure in the control channel 4204 is reduced below the pressure in the flow channel (eg, by a vacuum pump), the separator 4208 receives an actuation force that pulls it into the control channel 4204. As a result of this actuation force, the membrane 4208 protrudes into the control channel 4204, thereby removing the obstruction to the flow of material through the flow channel 4202 and creating a passage 4203. Upon pressure increase in the control channel 4204, the separator 4208 assumes its original position, loosely returns, and obstructs the flow channel 4202.

  The behavior of this membrane in response to actuation force can be altered by changing the width of the overlapping control channels. Accordingly, FIGS. 42D-42H show top and cross-sectional views of another embodiment of a normally closed valve 4201 in which the control channel 4207 is substantially wider than the separator 4208. As shown in cross-sectional views 42E-F along line 42E-42E ′ in FIG. 42D, a larger area of elastomeric material is required to be moved during operation, so that the necessary work to be applied is applied. Power is reduced.

  42G and H show cross-sectional views along line 40G-40G 'in FIG. 40D. In comparison with the non-actuated valve configuration shown in FIG. 42G, FIG. 42H shows that the pressure drop in the wider control channel 4207 may cause the underlying elastomer 4206 to pull away from the substrate 4205 under certain circumstances. It shows that it has an effect that is not, thereby creating an undesired void 4212.

  Accordingly, FIG. 42I shows a plan view of a valve structure 4220 that avoids this problem by featuring a control line 4204 with a minimum width excluding the segment 4204a that overlaps the separator 4208, and FIG. 42D shows a cross-sectional view of the valve structure 4220 of FIG. 42I along line 42J-42J ′. As shown in FIG. 42J, even under operating conditions, the narrower cross section of the control channel 4204 reduces the attractive force on the underlying elastomeric material 4206, thereby pulling the elastomeric material away from the substrate 4205, And prevents the creation of undesired voids.

  A normally closed valve structure that operates in response to pressure is shown in FIGS. 42A-42J, but a normally closed valve in accordance with the present invention is not limited to this configuration. For example, the separator that obstructs the flow channel can alternatively be manipulated by an electric or magnetic field, as described extensively above.

(6. Separation of substances)
In further applications of the present invention, the elastomeric structure can be utilized to perform material separation. FIG. 43 shows one embodiment of such a device.

  Separation device 4300 features an elastomeric block 4301 comprising a fluid container 4302 in communication with a flow channel 4304. Fluid is pumped from the fluid container 4306 through the flow channel 4308 by a peristaltic pump structure 4310 formed by a control channel 4312 that overlies the flow channel 4304, as described fully above. Alternatively, if the peristaltic pump structure according to the present invention cannot provide sufficient back pressure, fluid from a container located outside the elastomeric structure can be pumped into the elastomeric device utilizing an external pump.

The flow channel 4304 leads to a separation column 4314 in channel form packed with a separation matrix 4316 behind a porous frit 4318. As is well known in the chromatographic arts, the composition of the separation matrix 4316 depends on the nature of the material to be separated and the particular chromatographic technique used. Elastomer separation structures are suitable for use with a variety of chromatographic techniques, including gel exclusion, gel permeation, ion exchange, reverse phase, hydrophobic interaction, affinity chromatography, fast protein liquids. All forms of chromatography (FPLC) and high performance liquid chromatography (HPLC) are included, but are not limited to these. The high pressure utilized for HPLC may require the use of urethane, dicyclopentadiene or other elastomer combinations.

  The sample is introduced into the fluid flow into separation column 4314 utilizing load channel 4319. Load channel 4319 receives fluid pumped from sample container 4320 by pump 4321. Upon opening of valve 4322 and actuation of pump 4321, sample flows from load channel 4319 to flow channel 4304. This sample then flows through the separation column 4314 by the action of the pump structure 4312. As a result of the different mobilities of the various sample components in the separation matrix 4316, these sample components are separated and eluted from the column 4314 at different times.

  Upon elution from the separation column 4314, various sample components pass into the detection region 4324. As is well known in the chromatographic arts, the identity of the substance eluted in the detection region 4324 can be determined using a variety of techniques including fluorescence, UV / visible / IR spectroscopy, radioactive labeling. , Amperometric detection, mass spectrometry, and nuclear magnetic resonance (NMR).

  The separation device according to the present invention offers the advantage of being extremely small in size so that only a small volume of fluid and sample is consumed during the separation. Furthermore, this device offers the advantage of increased sensitivity. In conventional separation devices, the size of the sample loop extends the injection of the sample onto the column, which can cause the elution peak widths to overlap each other. In general, the extremely small size and capacity of the load channel prevents this peak spreading behavior from becoming a problem.

  The separation structure shown in FIG. 43 represents only one embodiment of such a device, and other structures are contemplated by the present invention. For example, the separation device of FIG. 43 features a flow channel, a load loop, and a separation column oriented in a single plane, but this is not required by the present invention. One or more fluid containers, sample containers, flow channels, load loops, and separation columns are planes of elastomeric material that utilize each other and / or through the structure whose formation is fully described above in connection with FIGS. Can be oriented vertically.

(7. Cell pen / Cell cage / Cell grinder)
In further applications of the present invention, the elastomeric structure can be utilized to manipulate biological or other biological materials. 44A-44D show top views of one embodiment of a cell pen structure according to the present invention.

  Cell pen array 4400 features an array of orthogonally oriented flow channels 4402 with “pen” structures 4404 enlarged at alternating intersections of flow channels 4402. Valves 4406 are located at the entrance and exit of each pen structure 4404. A peristaltic pump structure 4408 is placed on each horizontal flow channel and on a vertical flow channel that lacks a cell pen structure.

The cell pen array 4400 of FIG. 44A is loaded with a sorting structure as described above, possibly related to FIG. 36, using pre-sorted cells AH. 44B-44C show: 1) opening valve 4406 on either side of adjacent pens 4404a and 4404b, 2) pumping horizontal flow channel 4402a to replace cells C and G, then 3) cell C To access and remove individually stored cells C by pumping the vertical flow channel 4402b. FIG. 44D shows that the second cell G is moved back into its previous position in the cell pen array 4400 by reversing the direction of liquid flow through the horizontal flow channel 4402a.

  The cell pen array 4404 described above can store material in selected addressable locations for quick access. However, living organisms (eg, cells) may require continuous food intake and waste output to maintain survival. Accordingly, FIGS. 45A and 45B show a plan view and a cross-sectional view (along line 45B-45B '), respectively, of one embodiment of a cell cage structure according to the present invention.

  The cell cage 4500 is formed as an enlarged portion 4500a of the flow channel 4501 in the elastomer block 4503 in contact with the substrate 4505. Cell cage 4500 is similar to individual cell pens as described above in FIGS. 44A-44D, except that ends 4500b and 4500c of cell cage 4500 do not completely seal interior region 4500a. Rather, the ends 4500a and 4500b of the cage 4500 are formed by a plurality of retractable pillars 4502. The pillar 4502 may be part of a membrane structure of a normally closed valve structure as described broadly above in connection with FIGS.

  Specifically, the control channel 4504 overlaps the pillar 4502. When the pressure in the control channel 4504 is reduced, the elastomeric pillar 4502 is pulled upward into the control channel 4504, thereby opening the end 4500b of the cell cage 4500 and allowing cell entry. Upon an increase in pressure in the control channel 4504, the pillar 4502 loosens downward relative to the substrate 4505 and prevents cells from exiting the cage 4500.

  Elastomeric pillar 4502 is sized and numbered to prevent migration of cells from cage 4500, but also includes gap 4508, which maintains the cells stored in cage interior 4500a. , Allowing nutrients to flow in it. A pillar 4502 on the opposite end 4500c is similarly configured under the second control channel 4506 to allow opening of the cage and removal of cells as desired.

  Under certain circumstances, it may be desirable to disrupt / disintegrate cells or other biological material to access component fragments.

  Accordingly, FIGS. 46A and 46B show a plan view and a cross-sectional view (along line 46B-46B '), respectively, of one embodiment of a cell grinder structure 4600 according to the present invention. The cell grinder 4600 includes a system of interlocking posts 4602 in the flow channel 4604 that close together upon actuation of the integral membrane 4606 by overlapping the control channels 4608. By closing together, the pillars 4602 break up the material present between them.

  The pillars 4602 are spaced at an appropriate interval to destroy a predetermined size entity (cell). For the destruction of the cellular material, it is appropriate to have the posts 4602 spaced about 2 μm apart. In another embodiment of the cell grinding structure according to the present invention, the posts 4602 can be disposed entirely on the overlying membrane or can be disposed generally on the floor of the control channel.

The cross-flow channel architecture shown and illustrated in FIGS. 44A-44D can be used to perform functions other than the cell pen described herein. For example, a crossflow channel architecture can be utilized in maximizing applications.

  This is shown in FIGS. 69A-B. FIGS. 69A-B show plan views of mixing steps performed by a microfabricated structure according to another embodiment of the present invention. Specifically, the microfabricated mixed structure portion 7400 includes a first flow channel 7402 that is orthogonal to and intersects the second flow channel 7404. Control channel 7406 lies over flow channels 7402 and 7404 and forms valve pairs 7408a-b and 7408c-d that surround each intersection 7412.

  As shown in FIG. 69A, valve pair 7408a-b is initially opened, valve pair 7408c-d is closed, and fluid sample 7410 is flowed to intersection 7412 through flow channel 7402. Valve pair 7408c-d is then actuated to trap fluid sample 7410 at intersection 7412.

  Next, as shown in FIG. 69B, the valve pair 7408a-b is opened so that the fluid sample 7410 is injected from the intersection 7412 into the flow channel 7404 resulting in a fluid cross-flow. The process shown in FIGS. 69A-B can be repeated to safely dispense any number of fluid samples below the crossflow channel 7404.

  The crossflow injection structure shown in FIGS. 69A-69B includes two sets of control lines. One is to control the valve pairs distributed along each axis. However, in certain applications, it can be valuable because it is possible to independently operate valves located along the flow channel.

  In order to achieve such independent valve actuation, it may be useful to form an elastomeric structure from three elastomer layers. This embodiment is shown in connection with FIG. FIG. 78 shows a top view of a row of flow channel arrays that function as independently controllable valves.

  Specifically, the flow channel array 8300 includes a first set of parallel flow channels 8304 and a second set of parallel flow channels 8306 formed in an intermediate elastomer layer (only one of which is shown in FIG. 77). including. The intersection of the first parallel flow channel 8304 with the second parallel flow channel 8306 defines an array of intersections 8308.

  Each flow channel junction 8308 is surrounded by a valve 8310 that governs the flow of material in and out of the junction. The first control channel 8312 and the second control channel 8314 exist below the intermediate elastomer layer and are defined by a recess in the first elastomer layer that overlays the substrate. The overlap of the flow channel 8304 on the first control channel 8312 defines the bottom valve 8310a. The overlap of the flow channel 8306 on the second control channel 8314 defines the left valve 8310b.

  Third control channel 8316 and fourth control channel 8318 are defined by a recess in the second elastomer layer overlaying the intermediate elastomer layer. The overlap of the third control channel 8316 and the flow channel 8304 defines the top valve 8310c. The overlap of the fourth control channel 8318 and the flow channel 8306 defines the right valve 8310d.

  During operation of structure 8300, first material 8320 can be flowed along flow channel 8306, while top valve 8310c and bottom valve 8310a remain closed. Next, the right valve 8310d and the left valve 8310b may be closed to trap the substance 8320 in the middle region 8306a of the flow channel 8306. In opening the top valve 8310 c and the bottom valve 8310 a, the second material 8324 can flow along the flow channel 8306.

  The fourth control channel 8318 can then be deactivated to selectively open the right valve 8310d, thereby contacting and bonding with the first material 8322 present in the internal bonding region 8306a of the flow channel 8306. A second substance 8324 present in the part 8308 is arranged. In the method described herein, a set of vertical intersections of parallel flow channels can be utilized to generate an array of separated chemical environments. One approach for such a structure is high-throughput material crystallization, as described below.

  Independent control (as described in FIG. 77) on each of the valves surrounding the flow channel junction cannot provide an independently operable, non-crossing control line in a single elastomer layer. It is difficult to achieve utilizing a structure formed from only two elastomer layers. The supply of control lines both above and below the flow channel thus allows the design and manufacture of flow structures that represent operational complexity and mobility that are not feasible using only a single control layer Can be.

(8. Pressure oscillator)
In still further applications of the present invention, the elastomeric structure can be utilized to create a pressure oscillator structure similar to the oscillator circuit often used in the electronics field. FIG. 47 shows a plan view of one embodiment of such a pressure oscillator structure.

  The pressure oscillator 4700 includes an elastomeric block 4702 that features a flow channel 4704 formed in the elastomeric block 4702. The flow channel 4704 includes a start 4704 a proximal to the pressure source 4706 and a serpentine 4704 b distal from the pressure source 4706. Initiator 4704a is in contact through 4708 in fluid communication with a control channel 4710 formed in elastomer block 4702 above the level of flow channel 4704. At a location more distal from the pressure source 4706 than through 4708, the control channel 4710 overlies the flow channel 4704 and is separated from the flow channel 4704 by an elastomeric membrane, thereby connecting the valve 4712 as described above. Form.

  The pressure oscillator structure 4700 operates as follows. Initially, pressure source 4706 provides pressure along flow channel 4704 and control channel 4710 through 4708. Due to the serpentine shape of the flow channel 4704b, the pressure is lower in the region 4704b when compared to the flow channel 4710. In valve 4712, the pressure difference between the serpentine flow channel portion 4704b and the overlapping control channel 4710 will eventually cause the membrane of the valve 4712 to protrude downward into the serpentine flow channel portion 4704b and close the valve 4712. However, due to the continuous operation of the pressure source 4706, the pressure begins to increase into the serpentine flow channel portion 4704b behind the closed valve 4712. Eventually, this pressure will be the same between the control channel 4710 and the serpentine flow channel portion 4704b, and the valve 4712 will open.

  Assuming continuous operation of the pressure source, the above increase and release of pressure lasts indefinitely, resulting in a regular oscillation of pressure. Such a pressure oscillating device may perform a number of possible functions, including but not limited to timing.

(9. Side operation valve)
While the above description focuses on a microfabricated elastomeric valve structure in which the control channel is positioned above and separated from the underlying flow channel by intervening in the elastomeric membrane, the present invention is directed to this configuration. It is not limited. 48A and 48B show plan views of one embodiment of a side actuated valve structure in accordance with one embodiment of the present invention.

  FIG. 48A shows the side-actuated valve structure 4800 in the inoperative position. A flow channel 4802 is formed in the elastomeric layer 4804. A control channel 4806 adjacent to the flow channel 4802 is also formed in the elastomeric layer 4804. Control channel 4806 is separated from flow channel 4802 by elastomeric membrane portion 4808. A second elastomer layer (not shown) is bonded to one side of the lower elastomer layer 4804 and seals the flow channel 4802 and the control channel 4806.

  FIG. 48B shows the side actuated valve structure 4800 in the actuated position. In response to an increase in pressure in the control channel 4806, the membrane 4808 deforms into the flow channel 4802 and blocks the flow channel 4802. Upon release of pressure in the control channel 4806, the membrane 4808 loosely returns into the control channel 4806 and opens the flow channel 4802.

  A side-actuated valve structure that operates in response to pressure is shown in FIGS. 48A and 48B, but a side-actuated valve according to the present invention is not limited to this configuration. For example, an elastomeric membrane portion located between adjacent flow channels and control channels can alternatively be manipulated by an electric or magnetic field, as described extensively above.

(10. Further application)
The following represent further aspects of the present invention: the valves and pumps of the present invention for drug delivery (eg, in an implantable drug delivery device); for biological fluid sampling (eg, spacer fluid plugs between samples) By continuously storing the sample in a column comprising: the sample can be flowed into different storage containers or passed directly through the appropriate sensor (s) . Such a fluid sampling device can also be implemented in the patient's body.

  The system of the present invention can also be used in devices that remove excess pressure in vivo using a fine valve or pump. For example, an implantable biocompatible microvalve can be used to remove excess pressure in the eye resulting from glaucoma. Other contemplated uses of the switchable microvalve of the present invention include vas deferens or fallopian tube implantation, which controls reversible long-term or short-term delivery without the use of drugs. Enable.

  Further uses of the present invention include DNA sequencing, whereby the DNA to be sequenced is provided with a polymerase and primers, and then a type of DNA base to rapidly assay for base incorporation. Simultaneous exposure to (A, C, T, or G). In such a system, these bases are flushed through the system and excess base must be quickly removed by washing. A pressure driven flow gated by an elastomeric microvalve according to the present invention is ideally suited to allow such rapid flow and reagent cleaning.

Other contemplated uses of the microvalve and micropump system of the present invention include use with DNA chips. For example, the sample can be flowed into a looped channel and pumped around a loop with scissors action so that the sample can create many passages for the probes of the DNA array. Such a device gives the sample an opportunity to bind to an alternative complementary probe, but is usually present and consumed on non-complementary probes. The advantage of such a looped flow system is that it reduces the sample volume required by the system, thereby increasing the sensitivity of the assay.

  A further application is in high-throughput screening where application can be beneficial by dispensing small volumes of liquid or by bead-based assays where sensitive detection substantially improves the sensitivity of the assay.

  Another contemplated application is the deposition of an array of various chemicals, particularly oligonucleotides, either through contact printing through fluid channel outlets in an elastomeric device proximate to the desired substrate, or inkjet printing. The process may or may not be chemically microfabricated in a preliminary operation of the device prior to deposition into a pattern or array on the substrate.

  The microfabricated elastomeric valves and pumps of the present invention can also be used to build systems for reagent dispensing, mixing and reaction for the synthesis of oligonucleotides, peptides or other biopolymers.

  A further application of the present invention comprises an ink jet print head, where a small opening is used to produce a pressure pulse sufficient to fire a droplet. A suitable actuating microvalve according to the invention can produce such a pressure pulse. The microvalves and pumps of the present invention can also be used to digitally dispense inks or dyes in quantities not necessarily as small as a single droplet. The droplets are not required to be fired into the air, but are brought into contact with the medium to be printed.

  Further use of the present invention takes advantage of the easy removal and reattachment of this structure from an underlying substrate (eg, glass) utilizing a glass substrate patterned with a bonding material or other material. . This allows separate construction of the patterned substrate and elastomeric structure. For example, a glass substrate can be patterned with a DNA microarray and the elastomeric valve and pump structure can be sealed onto the array in the next step.

(11. Further aspects of the present invention)
The following represents a further aspect of the present invention: the use of a bendable membrane to control the flow of fluid in a microfabricated channel of an elastomeric structure; making a microfabricated elastomer device with microfabricated moving parts The use of elastomeric layers; and the use of elastomeric materials to make microfabricated valves or pumps.

  A microfabricated elastomeric structure according to one embodiment of the invention comprises an elastomeric block formed with microfabricated recesses in an elastomeric block (wherein the part of the elastomeric block is when this part is actuated). Bendable). These recesses comprise a first microfabricated channel and a first microfabricated recess, and this portion curves into the first microfabricated channel when the elastomeric membrane is activated. With possible elastomeric membranes. These recesses have a width in the range of 10 μm to 200 μm, and this portion has a thickness between about 2 μm and 50 μm. The microfabricated elastomeric structure can be operated at speeds of 100 Hz and above and is substantially free of dead volume when this part is activated.

A method of actuating an elastomeric structure includes the steps of first and second microfabricated recesses in an elastomer block (a membrane portion of an elastomer block that can be bent into one of the first and second recesses in response to an actuation force. The first and second microfabricated recesses separated by the membrane and the membrane portion so that the membrane portion is curved into one of the first and second recesses Including applying an actuation force to the portion.

  A method of microfabricating an elastomeric structure according to one embodiment of the present invention includes forming a first elastomer layer on a substrate, curing the first elastomer layer, and first on the first elastomer layer. Patterning the sacrificial layer. The second elastomer layer is formed on the first elastomer layer, thereby encapsulating the first patterned sacrificial layer between the first and second elastomer layers, and the second elastomer layer. Is cured and the first patterned sacrificial layer is selectively removed to the first elastomer layer and the second elastomer layer, thereby at least between the first and second layers of elastomer. One first recess is formed.

  Another embodiment of the method of processing further includes removing the second patterned sacrificial layer during removal of the first patterned sacrificial layer, at least along the bottom of the first elastomeric layer. Patterning a second sacrificial layer on the substrate prior to forming the first elastomeric layer to form one recess.

  A microfabricated elastomeric structure according to one embodiment of the present invention is microfabricated in an elastomeric block, first and second channels separated by a separator of the elastomeric structure, and an elastomeric block proximate to the separator. With a recess so that this separation can be actuated to be curved into the microfabricated recess 66. The curvature of the separation part opens a passage between the first channel and the second channel.

  A method for controlling fluid and gas through an elastomeric structure includes an elastomeric block, an elastomeric block having first, second, and third microfabricated recesses, and a first microfabricated channel through the block, first An elastomeric block having first, second, and third microfabricated recesses that are bendable in the first channel and separated from the first channel by first, second, and third membranes, respectively. , And repeatedly and continuously bending the first, second and third membranes into the first channel and pumping fluid flow through the first channel.

  A method of microfabricating an elastomeric structure includes microfabricating a first elastomer layer, microfabricating a second elastomer layer; disposing a second elastomer layer over the first elastomer layer; and Including bonding the lower surface of the second elastomer layer onto the upper surface of the first elastomer layer.

(Alternative device manufacturing method)
FIGS. 1-7 and 8-18 described above illustrate embodiments of multilayer soft lithography and encapsulation methods, respectively, for fabricating elastomeric structures according to the present invention. However, these fabrication methods are exemplary only and variations of these techniques can be used to produce elastomeric structures.

  For example, FIGS. 3 and 4 show an elastomeric structure that utilizes multilayer soft lithographic techniques, where the surface of the upper elastomer layer with the recesses is disposed over the surface of the lower elastomer layer without the recesses. However, the present invention is not limited to this configuration.

FIG. 50 shows an elastomeric structure 5410 that represents an alternative orientation of the elastomeric layer, where a surface 5400 having a recess in the first elastomeric layer 5404 and a second elastomer to produce a larger sized channel 5408. Layer 5406 with concave surface 5
402 is each arrange | positioned so that it may contact. Alternatively, FIG. 51 shows the orientation of the elastomer layer, where the recesses 5500 and 5502 are placed in contact so that the recesses are placed on both sides of the structure. Such an elastomeric structure 5512 can be sandwiched between the substrates 5508 and 5510 to create channels 5504 and 5506 that intersect each other.

  52A-52D show various views of the process of constructing a flow channel bridge structure utilizing an encapsulation method. Specifically, FIG. 52A shows a cross-sectional view of the formation of the lower elastomer portion 5600 of the crosslinked structure 5602. FIG. 52B shows a cross-sectional view of the configuration of the crosslinked elastomeric upper elastomer portion 5604. FIG. 52C shows the configuration of an upper elastomeric portion 5604 and a lower elastomeric portion 5600 that form a bridging structure 5602, where the fluid flowing in the channel 5606 passes through vias 5610 and 5612 and as well as the bridging portion. Bridge over crossing channel 5608 through 5614. FIG. 52D shows a top view of the cross-linked structure 5602, with the upper elastomeric cross-linked portion 5614 shown as a solid line and features in the underlying lower elastomer layer as outlined. This structure requires the formation of vias in the lower layer, but allows multiple liquid flows to flow in a single layer and across each other without mixing.

(13. Composite structure)
As already discussed in connection with the micromirror array structure of FIG. 38, the fabricated elastomeric structure of the present invention can be combined with a non-elastomeric material to produce a composite structure. The fabrication of such a composite structure will now be discussed in further detail.

  FIG. 53A shows a cross-sectional view of one embodiment of a composite structure according to the present invention. FIG. 53A shows a composite valve structure 5700 that includes a first thin elastomeric layer 5702 located over a semiconductor-type substrate 5704 having a channel 5706 formed therein. A second thicker elastomer layer 5708 is located on the first elastomer layer 5702. The first elastomer layer 5702 is driven to enter the channel 5706, causing the composite structure 5700 to act as a valve.

  Although FIG. 53A shows the flow channel walls and bottom formed in the substrate material, the invention is not limited to this particular configuration. Other features may also be defined in the substrate, including but not limited to wells or chambers containing fluids.

  53B shows a cross-sectional view of a variation of the subject matter of FIG. 53A, in which a thin elastomeric layer 5802 is sandwiched between two rigid semiconductor substrates 5804 and 5806, and the lower substrate 5804 comprises a channel 5808. FIG. Again, the thin elastomeric layer 5802 is driven to enter the channel 5808, causing the composite structure 5810 to act as a valve.

  The structure shown in FIGS. 53A-53B can be fabricated utilizing the multilayer soft lithography or encapsulation techniques described above. In multilayer soft lithography methods, an elastomeric layer or layers are formed and then placed on a semiconductor substrate having channels or other functions. In the encapsulation method, a channel is first formed in a semiconductor substrate, and then the channel is filled with a sacrificial material such as a photoresist. The elastomer is then formed in place on the substrate, the sacrificial material is removed, and the elastomeric film is placed on top to create a channel. As described below in connection with adhesion of elastomers to other types of materials, the encapsulation approach can provide a strong seal between the elastomeric membrane component and the underlying non-elastomeric substrate component.

As shown in FIGS. 53A-53B, a composite structure according to an embodiment of the present invention may include a rigid substrate having a passive feature, such as a channel or a chamber. However, the present invention is not limited to this approach, and the underlying rigid substrate may have an active feature that interacts with an elastomer component having a recess.

  This is shown in FIG. Here, the composite structure 5900 includes an elastomer component 5902 that includes a recess 5904 having a wall 5906 and a ceiling 5908. The ceiling 5908 forms a flexible membrane portion 5909. Elastomeric component 5902 is sealed against a substantially flat non-elastomeric component 5910 that includes active device 5912. The active device 5912 can interact with the material present in the recess 5904 and / or the flexible membrane portion 5909.

  In the embodiment of the micromirror array already described in connection with FIG. 38, the underlying substrate included an active structure in the form of an electrode array. However, other types of active structures may exist in the non-elastomeric substrate. Active structures that may be present in the underlying rigid substrate include resistors, capacitors, photodiodes, transistors, chemical field effect transistors (chemFETs), amperometric / coulometric electrochemical sensors, optical fibers, optical fiber mutual Connection, light emitting diode, laser diode, surface emitting semiconductor laser (VCSEL), micromirror, acceleration sensor, pressure sensor, flow sensor, CMOS imaging array, CCD camera, electronic logic, microprocessor, thermistor, peltier, waveguide , Resistance heater, chemical sensor, strain gauge, inductor, actuator (including electrostatic, magnetic, electromagnetic, bimetal, piezoelectric, shape memory alloy base, etc.), coil, magnet, electromagnet, magnetic sensor (hard drive, ultra Conductivity Interference devices (such as those used in SQUIDS and other types), radio frequency sources and receivers, microwave frequency sources and receivers, sources and receivers in other regions of the electromagnetic spectrum, radioactive particle counters and electrometers Including, but not limited to.

  As is well known in the art, a vast variety of technologies produce printed circuit board (PCB) technology, CMOS, surface micromachining, bulk micromachining, printable polymer electronics, and laptop and flat screen displays. Can be utilized to fabricate active functions in semiconductors and other types of rigid substrates, including but not limited to TFTs and other polycrystalline / single crystal technologies as used.

  A composite structure according to one embodiment of the present invention includes a non-elastomeric substrate having a surface with a first recess, a flexible elastomer film positioned on the non-elastomeric substrate, and embedded in the first recess. A membrane that can be actuated, and a layer overlying the flexible elastomeric membrane.

  Embodiments of a method for forming a composite structure include forming a recess in a first non-elastomeric substrate, filling the recess with a sacrificial material, and a thin coating of elastomeric material on the non-elastomeric substrate and the filled recess. Forming a thin film by curing the elastomer, and removing the sacrificial material.

  A composite structure according to an alternative embodiment of the present invention comprises an elastomer component defining a recess having a wall and a ceiling, a ceiling of the recess forming a flexible membrane portion, and a substantially flat sealed against the elastomer component. A non-elastomeric component, wherein the non-elastomeric component includes an active device that interacts with the material present in the at least one membrane portion and the recess.

A method of fabricating a composite structure includes forming a recess in an elastomer component having a wall and a ceiling that forms a flexible membrane portion, placing material in the recess, and substantially flat including an active device. Forming a non-elastomeric component, and sealing the elastomeric component to the non-elastomeric component to allow the active device to interact with at least one of the membrane portion and the material.

  A variety of approaches range from making van der Waals bonds between elastomeric and non-elastomeric components to making covalent or ionic bonds between composite and non-elastomeric components. Can be used to seal against non-elastomeric substrates. For example, an exemplary approach for sealing components to increase strength is described below.

  The first approach relies on a simple hermetic seal resulting from a van der Waals bond when the substantially flat elastomer layer is placed in contact with a substantially flat layer of a harder non-elastomeric material. It is to be. In one embodiment, the bonding of the RTV elastomer to the glass substrate produces a composite structure that can withstand pressures of about 3-4 psi. This may be sufficient for multiple potential applications.

The second approach is to use a liquid layer to assist the coupling. This one example involved bonding an elastomer to a hard glass substrate, where a weakly acidic solution (5 μl, HCl in H ₂ O, pH 2) was applied to the glass substrate. The elastomer component is then placed in contact with the glass substrate and the composite structure is baked at 37 ° C. to remove water. This provides a bond that can withstand pressures of about 20 psi between elastomers and non-elastomers. In this case, the acid can neutralize the silanol groups present on the glass substrate, allowing the elastomer and non-elastomer to make good van der Waals contact with each other.

  Exposure to ethanol may further cause device components to adhere to each other. In one embodiment, the RTV elastomer material and the glass substrate are cleaned with ethanol and then dried under nitrogen. The RTV elastomer is then placed in contact with the glass and the combination is baked at 80 ° C. for 3 hours. Optionally, the RTV can be further exposed to a vacuum to remove any bubbles trapped between the sliding surface and the RTV. The bond strength between elastomer and glass using this method withstands pressures in excess of 35 psi. The adhesion produced using this method is not permanent and the elastomer is peeled from the glass, cleaned and resealed against the glass. This ethanol wash approach can also be used to bond successive layers of elastomers together with sufficient strength to withstand a pressure of 30 psi. In alternative embodiments, chemicals such as alcohols or diols can be used to promote adhesion between layers.

  An embodiment of a method for promoting adhesion between microfabricated structure layers according to the present invention includes exposing a surface of a first component layer to a chemical, and exposing a surface of a second component layer to the chemical. And disposing the surface of the first component layer in contact with the surface of the second elastomer layer.

  A third approach is to create a covalent chemical bond between the elastomeric component and the functional groups introduced on the surface of the non-elastomeric component. Examples of non-elastomeric substrate surface applications that generate such functional groups include exposing a glass substrate to agents such as vinylsilane or aminopropyltriethoxysilane (APTES). This can be useful to allow glass to be bonded with silicone elastomer and polyurethane elastomer materials, respectively.

  A fourth approach is to create a covalent chemical bond between the elastomeric component and the functional group inherent to the surface of the non-elastomeric component. For example, an RTV elastomer can be produced with an excess of vinyl groups on its surface. These vinyl groups are, for example, the corresponding functional groups present outside the hard substrate material, such as Si—H bonds, that spread on the surface of a single crystalline silicon substrate after the native oxide has been removed by etching. Can be reacted. In this example, it is observed that the strength of the bond created between the elastomeric component and the non-elastomeric component exceeds the material strength of the elastomeric component.

  The previous discussion of composite structures has focused on bonding the elastomeric layer and the underlying non-elastomeric substrate. However, this is not required by the present invention.

  The already described microfabricated elastomeric structures can be sliced vertically, often along the channel cross section. According to embodiments of the present invention, the non-elastomeric component can be inserted into the elastomeric structure opened by such cutting, after which the elastomeric structure can be resealed. One example of such an approach is shown in FIGS. 57A-57C, which shows a cross-sectional view of a process for forming a flow channel having a membrane disposed thereon. Specifically, FIG. 57A shows a cross section of a portion of a device 6200 that includes an elastomeric membrane 6202 and an elastomeric substrate 6206 positioned over a flow channel 6204.

  FIG. 57B shows a device 6200 cut along a vertical line 6208 extending along the length of the flow channel 6204 to form shards 6200a and 6200b. FIG. 57C shows that the permeable membrane element 6210 is inserted between the splits 6200a and 6200b, and then the splits 6200a and 6200b are attached to the permeable membrane 6210. As a result of this configuration, the flow channel of the device actually includes channel portions 6204a and 6204b separated by a permeable membrane 6210.

  The structure of FIG. 57C can be utilized in a variety of applications. For example, the membrane is used to perform dialysis and alters the salt concentration of the sample in the flow channel. Yet another potential use for the structure of FIG. 57C is to separate the products of the reaction to suppress the product, for example, to remove the product from the enzymatic reaction. Depending on the composition of the membrane, the organic solvent can be present on one side of the membrane and the aqueous buffer is present on the other side of the membrane. Yet another possible function of the membrane is to bind specific chemical components, such as proteins, peptides or pieces of DNA, for purification, catalysis or analysis.

  An embodiment of a method of making an elastomeric structure includes cutting a first elastomeric structure along a vertical cross section to form a first elastomeric part and a second elastomeric part, and the first elastomeric structure comprises: Including coupling to another component.

(14. Priming)
A potentially useful property of the elastomeric structure is gas permeability. Specifically, the elastomeric material may allow diffusion of certain gas types while preventing liquid diffusion. This property can be very useful in manipulating small volumes of fluid.

For example, fluidic devices that generally have complex channel architectures must address the problem of priming channels. Since the fluid is first injected into the complex channel structure and then into the path with the least resistance, it can leave some area of the structure unfilled. It is usually difficult or impossible to fill the dead end area of the structure with liquid.

  Thus, one approach of the present invention takes advantage of the gas permeability of certain elastomeric materials to fill a channel structure including dead end channels and chambers. According to one embodiment of the method for priming a microfluidic structure, the channel inlets to all structures are first blocked except one. Neutral buffer is then injected into the remaining channels and maintained under pressure. Pressurized buffer fills the channel and compresses any gas present in the channel in its presence. Thus, pressurized gas confined within the channel is forced to diffuse out of the structure through the elastomer.

  In this way, the liquid sample can be introduced into the flow channel of the microfabricated device without creating undesired gas pockets. By injecting the liquid sample into the flow channel of the microfluidic device under pressure and then maintaining the injection pressure for a given time, the liquid sample filled the channel and created in the channel Any gas pockets diffuse out of the elastomeric material. By this method, the entire microfluidic structure can be quickly filled from a single via. Using this method, a liquid filled dead end chamber can be used in storage, metering, and mixing applications.

  The gas permeability of the elastomeric material can be introduced into the flow channel as a result. Here, a pneumatic (air driven) drive system is used. Such pneumatic valves can be operated at high control pressures to withstand high back pressures. Under such operating conditions, the gas can diffuse through the relatively thin membrane, which introduces bubbles into the flow channel. Such undesired air diffusion through the membrane can be avoided by utilizing a control medium that is hardly permeable to the elastomer, ie, a gas that diffuses much more slowly through the elastomer or liquid. As described above, the control line functions well and, when filled with water or oil, transmits control pressure and does not introduce bubbles into the flow channel. Furthermore, using the priming method described above, it is possible to fill the dead-end control channel with fluid, and thus no modification of the existing air driven control structure is required.

  An embodiment of a method for filling a microfabricated elastomeric structure with a fluid according to the present invention includes providing an elastomeric block having a flow channel, the elastomeric block comprising an elastomeric material known as gas permeable. . The flow channel is filled with a gas and fluid is injected into the flow channel under pressure, allowing the gas remaining in the flow channel to diffuse out of the elastomeric material.

(15. Weighing by volume exclusion)
Multiple high-throughput screening and diagnostic applications require an accurate combination of different reagents within the reaction chamber. Ensures that the mixed solution is not diluted or contaminated by the contents of the reaction chamber prior to sample introduction when it is required to prime the channels of the microfluidic device to ensure fluid flow It can be difficult to do.

  Volume exclusion is one technique that allows accurate metering of fluid into the reaction chamber. In this approach, the reaction chamber can be completely or partially evacuated prior to sample injection. This method can be used to reduce the contamination of the chamber contents by residual contents and accurately meter the introduction of the solution into the reaction chamber.

In particular, Figures 58A-58D show cross-sectional views of a reaction chamber in which volume exclusion is used to meter reactants. FIG. 58A shows a cross-sectional view of a portion 6300 of a microfluidic device that includes a first elastomeric layer 6302 overlying a second elastomeric layer 6304. The first elastomeric layer 6302 includes a control chamber 6306 in fluid communication with a control channel (not shown). Control chamber 6306 is located above and is separated from dead end reaction chamber 6308 of second elastomer layer 6304 by membrane 6310. The second elastomer layer 6304 further includes a flow channel 6312 that leads to a dead-end reaction chamber 6308. As described above, the first reactant X can be introduced into the dead-end reaction chamber 6308 under pressure. FIG. 58B shows the result of the increase in pressure in the control chamber 6306. Specifically, as the control chamber pressure increases, the membrane 6310 is bent downward into the reaction chamber 6308 and the effective volume of the reaction chamber 6308 is reduced by the volume V. This in turn eliminates the equivalent volume V of reactant from the reaction chamber 6308, and thus the volume of the first reactant X is output from the flow channel 6312. A complete correlation between the increasing pressure in the control chamber 6306 and the volume of material output from the flow channel 6312 can be accurately calibrated.

  As shown in FIG. 58C, increasing pressure is maintained in the control chamber 6306 while the volume V ′ of the second reactant Y is placed in contact with the flow channel 6312 and the reaction chamber 6308. .

  In the next step shown in FIG. 58D, the pressure in the control chamber 6306 is reduced to the original level. As a result, the membrane 6310 relaxes and the effective volume of the reaction chamber 6308 increases. The volume V of the second reactant Y is sucked into the device. By changing the relative sizes of the reaction chamber and the control chamber, it is possible to accurately mix the solution at a specific relative concentration. It is worth noting that the amount of second reactant Y sucked into the device depends solely on the excluded volume V and not on the Y volume V ′ made available at the opening of the flow channel. There is.

  58A-58D illustrate one embodiment of the present invention that includes a single reaction chamber, while in more complex embodiments, a parallel structure of hundreds or thousands of reaction chambers is a single control line. Can be driven by increasing pressure.

  Furthermore, while the above description shows two reactants combined at a relative concentration that is fixed by the size of the control chamber and reaction chamber, the volume exclusion technique can be used for several reactions at various concentrations in a single reaction chamber. Can be used to combine objects. One possible approach is to use several separately controllable control chambers on each reaction chamber. One example of this architecture is to have 10 separate control lines instead of a single control chamber, which allows a volume equivalent to 10 to be extruded or aspirated To do.

  Another possible approach utilizes a single control chamber located over the entire reaction chamber, and the effective volume of the reaction chamber is adjusted by changing the pressure in the control chamber. In this way, analog control over the effective volume of the reaction chamber is possible. Analog volume control in turn allows the combination of multiple solution reactants of any relative concentration.

  An embodiment of a method for metering a volume of fluid according to the present invention comprises providing a chamber having a volume in the form of an elastomer block separated from a control recess by an elastomeric membrane, and providing pressure to the control recess, Including deflecting into the chamber and reducing the volume by a calibrated amount, thereby eliminating the calibrated volume of fluid from the chamber.

(16. Protein crystallization)
As mentioned above, embodiments of microfabricated elastomeric devices according to the present invention allow fluids to be metered very accurately for mixing and reaction purposes. However, precise control over fluid volume metering can also be used to promote crystallization of molecules such as proteins.

  Protein recrystallization is an important technique utilized to identify protein structure and function. Recrystallization is usually performed by dissolving the protein in an aqueous solution, and then deliberately adding a countersolvent to change the polarity of the solution, thereby removing the protein from the solution and allowing it to individualize. Implemented by forcing you to enter. Forming high quality protein crystals is usually difficult and sometimes impossible, requiring many trials and errors in identifying and concentrating both the solvent and antisolvent used.

  Thus, FIG. 67 shows a plan view of a protein crystallization system that allows a large amount of recrystallization to be attempted. The protein crystallization system 7200 includes a control channel 7202 and flow channels 7204a, 7204b, 7204c and 7204d. Each of the flow channels 7204a, 7204b, 7204c, and 7204d represents a dead end chamber 7206 that is utilized as a recrystallization site. The control channel 7202 represents a network of control chambers 7205 of different widths that are separated from the chamber 7206 by a membrane 7208 that is located above and has the same width as the control chamber 7205. Although not shown for clarity of illustration, a second control characterizing the second network of membranes is used to create a stop valve that selectively opens and closes the opening to the dead-end chamber 7206. obtain. A complete discussion of the function and role of such stop valves is provided below in connection with FIG.

  The operation of the protein crystallization system 7200 is as follows. Initially, an aqueous solution containing the protein of interest is flowed through each of the flow channels 7204a, 7204b, 7204c, and 7204d, filling each dead-end chamber 7206. Next, high pressure is applied to the control channel 7202 such that the membrane 7208 flexes into the underlying chamber 7206 to exclude a given volume from the chamber 7206 and this excluded volume of the original protein solution to the chamber 7206. Pour out from.

  Next, pressure is maintained in the control channel 7202 while a different anti-solvent flows into each flow channel 7204a, 7204b, 7204c and 7204d. The pressure is then released at control line 7202, returning to its original position when membrane 7208 relaxes, and the volume of antisolvent previously eliminated enters chamber 7206 and is mixed with the original protein solution. Make it possible. Because the width of the control chamber 7205 and the underlying membrane 7208 are different, various volumes of antisolvent enter the chamber 7206 during this process.

  For example, chambers 7206a in the first two rows of system 7200 do not receive any antisolvent. This is because no volume is excluded by the overlying membrane. The second two rows of system 7200 receive an antisolvent volume of 1: 5 relative to the original protein solution. Chambers 7206c in the third two rows of system 7200 receive the volume of anti-solvent at a ratio of 1: 3 with the original protein solution. Chamber 7206d in the fourth two rows of system 7200 receives the volume of antisolvent at a ratio of 1: 2 with the original protein solution, and chamber 7206e in the fifth two rows of system 7200 Receive the protein solution and the volume of the antisolvent at a ratio of 4: 5.

Once the anti-solvent is introduced into the chamber 7206, these solvents can be resealed to the environment by re-applying high pressure to the control line 7202 to cause the membrane to flex and enter the chamber. Resealing may be necessary when recrystallization can be required to occur on the order of days or weeks. If visual inspection of the chamber reveals the presence of high quality crystals, the crystals can be physically removed from the chamber of the disposable elastomer system.

  Although the preceding description has described a protein crystal system that relies on volume exclusion to meter changes in the amount of antisolvent, the present invention is not limited to this particular embodiment. Accordingly, FIG. 70 shows a plan view of the protein crystallization system, where the different volume metrics of the antisolvent are determined by photolithography while the flow channel is formed.

  Protein crystallization system 7500 includes flow channels 7504a, 7504b, 7504c and 7504d. Each of the flow channels 7504a, 7504b, 7504c and 7504d characterizes a dead end chamber 7506 that is utilized as a recrystallization site.

  System 7500 further includes two sets of control channels. A first set of control channels 7502 is located above the opening of the chamber 7506 and defines a stop valve 7502 that, when activated, blocks access to the chamber 7506. A second control channel 7505 is located above the flow channels 7504a-d and defines a segment valve 7507 that, when activated, blocks flow between different segments 7514 of the flow channel 7404. .

  The operation of the protein crystallization system 7500 is as follows. Initially, an aqueous solution containing the protein of interest is flowed through each of the flow channels 7504a, 7504b, 7504c and 7504d to fill the dead end chamber 7506. High pressure is then applied to the control channel 7502 to drive the stop valve 7503, thereby preventing fluid from entering or leaving the chamber 7506.

  Each flow channel 7504a-d is then filled with a different anti-solvent while the stop valve 7503 is maintained closed. Second control line 7505 is then pressurized to isolate flow channels 7504a-d within segment 7514 and confine different volumes of antisolvent. Specifically, as shown in FIG. 70, the segments 7514 are not equal in volume. While protein crystallization structure 7500 is formed by soft lithography, photolithography techniques are used to define flow channels 7504a-d having segments 7514 of different widths 7514a and lengths 7514b.

  Thus, when pressure is released from the first control line 7502 and the stop valve 7503 is opened, a different volume of antisolvent from the various segments 7514 can diffuse into the chamber 7506. In this way, the exact dimensions defined by photolithography can be used to determine the volume of antisolvent trapped in the flow channel segment and then be introduced into the protein solution. This volume of antisolvent then sets the environment for protein crystallization.

  A protein crystallization system according to an embodiment of the present invention comprises an elastomeric block having a micromachined chamber having a volume and receiving a protein solution, and a micromachined flow channel in fluid communication with the chamber. The flow channel receives the antisolvent and introduces a fixed volume of antisolvent into the chamber.

(17. Pressure amplifier)
As mentioned above, certain embodiments of microfabricated elastomeric devices according to the present invention utilize pressure to control fluid flow. Thus, it may be useful to include structures in the device that allow amplification of the applied pressure to enhance these cures.

  FIGS. 59A and 59B show a cross-sectional view and a plan view, respectively, of an embodiment of a linear amplifier constructed using microfabrication techniques according to the present invention. The pressure amplifier 6400 includes a first (control) elastomer layer 6402 located over a second (amplification) elastomer layer 6404, the second elastomer layer overlying a third (flow) elastomer layer 6406. To position. The third elastomer layer 6406 is then positioned over the substrate 6409.

The third elastomer layer 6406 includes a flow channel 6408 separated by a membrane 6410 from an overlying amplification elastomer layer 6404. The conical amplifying element 6412 includes a lower surface 6414 that contacts the membrane 6410 and an upper surface 6416 that contacts the first elastomeric layer 6402. The region A _{1 on} the upper surface 6416 of the cone amplification element 6412 is larger than the region A ₂ on the lower surface 6414.

As a result of applying pressure p ₁ to the control channel 6415 of the first elastomer layer 6402, a force F ₁ is transmitted to the top surface 6416 of the cone structure 6402. The cone 6412 then transmits the force F ₁ to the lower surface 6414 having a smaller area. Since this force is equal to the pressure doubled by the region (F = pA), and the force applied to the top of the cone structure 6412 is equal to the force acting by the bottom of the cone structure 6412, p ₁ A ₁ = P ₂ A ₂ . Since A ₁ > A ₂ , the membrane 6410 has an amplified pressure p ₂ , p ₂ > p ₁ . The resulting amplification factor can be estimated by simply comparing the _two regions A ₁ and A ₂ .

₍₂₎ a _{p 2 / p 1 ~A 1 /} A 2, which is where p ₂ / _{p 1} = pressure amplifying factor.
Equation (2) is an approximation due to the elasticity of the amplification structure itself, which usually serves to reduce the amplification effect.

  Here, an example of a method of fabricating a pressure amplification structure is provided. A first control elastomer layer featuring a control channel of 200 μm width and 10 μm height is fabricated using 5A: 1B PDMS on a mold. A second flow elastomer layer characterized by a round flow channel with a width of 50 μm and a height of 10 μm is likewise a membrane having a thickness of 15 μm by rotating 5A: 1B PDMS over the mold at 4000 rpm for 60 seconds. Is produced.

  The third amplifying elastomer layer is formed by a lattice type <100> 3 ”silicon wafer (Silicon Quest International) with an oxide of 20,000 mm thick oxide layer. A pattern of photoresist 5740 is then formed that reflects the dimensions (in this case, a square having sides of 200 μm) Oxides of the wafer exposed by the photoresist pattern using the patterned photoresist as a mask. Is etched with HF.

  The patterned oxide layer is then used as a mask to remove the exposed underlying silicon to form a mold for the cone amplification structure. Specifically, the silicon exposed on the wafer is wet etched at 80 ° C. with 30% KOH (w / v), resulting in the formation of grooves with walls that are inclined at an angle of 54.7 °. Is done. The etch rate of silicon utilizing this chemistry is 1 μm / min, making it possible to precisely control the depth of the trench, and thus the height of the shaped amplification structure, and the resulting amplification factor. In this example, etching is used in which a depth of 20 μm is etched in 20 minutes.

  After the silicon etch is complete, the photoresist is removed and the acetone and oxide layers are removed by etching with HF. The silicon mold is then treated with trimethylchlorosilane (TMCS, Sigma) and the 20A: 1B RTV is spun and placed on the silicon mold containing the etched grooves at 2000 rpm for 60 seconds, then at 80 ° C. Baked for 60 minutes. Next, the control layer is allocated on the amplification layer. The two layers are baked together for an additional hour. The two layers are carefully peeled from the (amplification) mold and assigned onto the flow channel. After baking for another hour, the completed device is removed from the mold.

  FIG. 59C shows a photograph of the final assembled device. FIG. 59D shows a photograph of the final assembled device in the closed state in response to applying an 18 psi pressure to control the channel 6415 resulting in an amplification factor of about 1.3.

  An embodiment of a pressure amplifier according to the invention comprises an elastomer block in which first and second micromachined recesses are formed, and a first surface area in contact with the first recess and a contact with the second recess. An amplifier structure having a second surface region. The first surface region is larger than the second surface region, and the pressure in the first recess is transmitted to the second recess by the amplification structure as the amplification pressure.

  A method for amplifying pressure in a microfabricated elastomeric structure flow channel includes a first recess in contact with a first region of the amplification structure and a second recess in contact with a second region of the amplification structure. Providing an elastomeric block; applying pressure to the first region; and transmitting pressure to the second region, wherein the second region is larger than the first region, and therefore The pressure transmitted to the two recesses is amplified.

(18. Check valve)
One potentially useful structure in conventional fluid handling devices is a check valve that allows fluid through the conduit to flow in only one direction. 61A and 61B show a top view and a cross-sectional view, respectively, of a micromachined check valve structure according to an embodiment of the present invention. Microfabricated structure 6600 includes a flow channel 6602 formed in elastomer 6604. The left portion 6602 a and the right portion 6602 b of the flow channel 6602 exchange fluids with each other through the check valve 6606.

  Specifically, the microflow check valve 6606 allows fluid to flow in the M → direction through the flow channel 6602 and the movable flap 6608 but not in the reverse direction ← N. The flap 6608 is integral with the ceiling 6602c of the flow channel 6602 and does not contact the bottom 6602d or side 6602e, thus allowing the flap 6608 to swing freely. The flap 6608 can seal against the left portion 6602a of the flow channel 6602. This is because the flap is both larger in width and height than the cross section of the right channel portion. Alternatively, the right channel wall may have the function of a protrusion to prevent flap movement.

  Valve 6606 operates passively depending on the channel shape and elastomeric properties rather than external forces. Specifically, when the fluid flows from left to right in the direction of M →, the flap 6608 can swing to open to the right-hand side 6602b of the flow channel. However, if the direction of the flow channel is reverse ← N, the flap 6608 seals against the opening on the left hand side 6602 of the flow channel 6602.

62A-62E show cross-sectional views of a method of making a check valve according to the present invention. FIG.
In 2A, a first micromachined silicon mold 6620 is formed using a first patterned photoresist layer 6622 that defines a first recess 6624. The first recess in turn defines a bottom seal portion 6626 of the flow channel. In FIG. 62B, the elastomer is cast onto mold 6620 and solidified, so removal of first molded piece 6625 creates a raised bottom seal portion 6626. In FIG. 62C, a second micromachined silicon mold 6630 is formed using a second patterned photoresist layer 6632 defining a second recess 6634, which is then Defines the ceiling and flaps of the flow channel. In FIG. 62D, the elastomer is cast onto the second mold 6630 and cured, and thus removal of the second molded piece 6636 includes a protruding flap 6608. In FIG. 62E, a first molded piece 6625 and a second molded piece 6636 are bonded together to create an intervening flow channel 6602 and a check valve 6606.

  A check valve according to an embodiment of the present invention includes a micromachined channel formed of an elastomer block, a flap that is integral with and blocks the elastomer block protruding into the channel, and the fluid is only in the first direction. A flap is provided that can be deflected to allow it to flow.

(19. Fluid element)
The fluidic device relates to a technology that uses a flowing fluid as a signal having a medium, and utilizes a fluid dynamic characteristic of modification (switching, amplification) of these signals. Fluidic devices are similar to electronics, where the flow of electrons is used as a signal bearing medium and the electromagnetic properties are used for signal switching and amplification.

  Accordingly, another application of the microfabricated structure of the present invention is in fluid circuits. One embodiment of a fluidic logic device according to the present invention comprises an elastomeric block and a plurality of microfabricated channels formed of the elastomeric block, each channel including a pressure or flow representative of a signal to the first channel. Pressure or flow changes the pressure or fluid flow in the second channel consistent with the logic operation.

  The fluid logic structure according to embodiments of the present invention provides the advantage of compact size. Another advantage of the fluidic device structures of the present invention is that they have the potential to be used in radiation resistant applications. A further advantage of the fluid logic circuit is that it is non-electronic. Such a fluid logic circuit cannot be probed by an electromagnetic sensor and thus provides a safety benefit.

  Yet another advantage of fluid logic circuits is that these circuits can be easily integrated with microfluidic systems, allowing "onboard" control and reducing the need for external control means, Or erase. For example, fluid logic can be used to control the speed of a peristaltic pump based on downstream pressure, thus allowing the pressure to be directly regulated without the use of external means. Similar controls using external means are much more complex and difficult to implement, with separate pressure sensors and converters for pressure signals to electrical signals, software to control pump rates, and control signals for pneumatic control Requires external hardware to convert.

  One basic logic structure is a NOR gate. The truth table for the NOR logic structure is shown in TABLE 2 below.

本発明により製作されたＮＯＲゲート構造の１つの単純な実施形態は、入口部分および出口部分を含むフローチャネル、このフローチャネルに隣接し、かつ第１および第２のエラストマー膜によって、それぞれ第１のチャネルから分離されるので、制御チャネルへの圧力の付与が第１の膜および第２の膜の少なくとも１つを撓ませてフローチャネルに入れ、出口の圧力がＮＯＲ真理値表と整合して反映されるようにする少なくとも２つの制御チャネルを備える。

One simple embodiment of a NOR gate structure made in accordance with the present invention includes a flow channel that includes an inlet portion and an outlet portion, adjacent to the flow channel, and first and second elastomeric membranes, respectively, Since being separated from the channel, the application of pressure to the control channel deflects at least one of the first and second membranes into the flow channel and the outlet pressure reflects consistent with the NOR truth table At least two control channels to be

  FIG. 63 shows a plan view of an alternative embodiment of a NOR logic structure according to the present invention fabricated from a pressure amplifier structure. The NOR gate 6900 includes input flow channels 6902 and 6904 that contain a flow of pressurized fluid. Control channels 6906 and 6908 are orthogonal to the overlying flow channels 6902 and 6904 and form valves 6910a, 6910b, 6910c and 6910d. After passing through the lower control channels 6909 and 6908, flow channels 6902 and 6904 combine to form a single output flow channel 6912. The NOR gate 6900 operates as follows.

  When the input pressure signal to each of control lines 6906 and 6908 is low, valves 6910a-d open and fluid flows freely through flow channels 6902 and 6904, resulting in a high combined pressure in output flow channel 6912. ) Occurs. If a higher pressure is introduced into the first control line 6906 than is present in the flow channels 6902 and 6904, both valves 6910a and 6910b are closed and the pressure in the output flow channel 6912 is lowered. Similarly, if a pressure higher than that present in the flow channels 6902 and 6904 is introduced into the second control line 6908, the check valves 6910c and 6910d are closed and the output in the output flow channel 6912 is also low. . Of course, when a high pressure is applied to both control lines 6906 and 6908, the pressure at output 6912 is further reduced.

  The NOR gate 6900 can be linked with other logic devices to form more complex logic structures. For example, FIG. 63 shows the output of the first NOR gate 6900 used as one of the other logic devices (control lines) of the second NOR gate 6950. This gate is probably formed in an elastomeric layer located under the first NOR gate 6900. It may be necessary to amplify the pressure output from the first NOR gate 6900 to achieve the necessary control.

  Furthermore, signal amplification according to embodiments of the present invention can be utilized to maintain the control pressure signal and the information carrying (flow) pressure at approximately the same magnitude. Such approximate parity between information and control signals is one hallmark of conventional digital electronic control systems.

Without using amplified control pressure, application of fluidic elements according to embodiments of the present invention typically requires controlling pressure greater than fluid pressure to control the fluid flowing through the device. . However, with the pressure amplifier according to the present invention, the pressure in the control channel and the flow channel of the fluid circuit can be approximately the same magnitude.

  Another basic component of logic structures such as AND and OR gates are diodes. Accordingly, FIG. 64 shows a plan view of one embodiment of an AND gate fabricated using the fluid check valve according to the present invention as a diode. The truth table for the AND logic structure is shown in TABLE 3 below.

この真理値表による演算は、図６４の構造７０００を利用して可能である。具体的には、ＡＮＤゲート構造７０００は、フローレジスタ７００４を通ってフローチャネル７００２ｂの出口部分と流体をやり取りする入口部分７００２ａフローチャネル７００２を含む。第１の制御チャネル７００６および第２の制御チャネル７００８は、第１の逆流防止弁７０１０および第２の逆流防止弁７０１２それぞれを通ってフローレジスタ７００４のすぐ上流側にある接合部７００２ｃでフローチャネル７００２とつながる。

The calculation based on this truth table is possible using the structure 7000 in FIG. Specifically, AND gate structure 7000 includes an inlet portion 7002a flow channel 7002 that communicates fluid through flow register 7004 with the outlet portion of flow channel 7002b. The first control channel 7006 and the second control channel 7008 are flow channel 7002 at a junction 7002c immediately upstream of the flow register 7004 through the first check valve 7010 and the second check valve 7012, respectively. Connect with.

  Only when the first control channel 7006 and the second control channel 7008 are pressurized (each corresponding to a high logic state), high pressure flow results from the flow channel output portion 7002b. If the pressure in the first control channel 7006 is low, the pressure in the second control channel 7008 is low, or the pressure in both the first control channel 7006 and the second control channel 7008 is low, it passes through the inlet 7002a. Fluid flowing into device 7000 faces back pressure from flow register 7004 at junction 7002c, and in response, one or both of check valve 7010 and 7012 and respective control channel 7006 and It starts from 7008. More complex logic structures can be generated by connecting AND gates and other logic structures in various combinations.

  An embodiment of a microfluidic device structure according to the present invention comprises a substrate located below and a first elastomer layer located on the substrate, the first elastomer layer having a first recess on the bottom surface. . The second elastomer layer is located on the first elastomer layer, and the second elastomer layer has a second recess having an arched ceiling on the bottom surface. The membrane portion of the first elastomer layer is defined between the first recess and the second recess, the membrane portion can be deflected upward and enter the second recess, and the arch Along the ceiling and seal against this ceiling.

An embodiment of a microfluidic device according to the present invention comprises a substrate located below and a first elastomer layer located on the substrate, the first elastomer layer having a first recess on its bottom surface. . The second elastomer layer is located on the first elastomer layer, and the second elastomer has a second recess on its bottom surface. The third elastomer layer is located on the second elastomer layer, and the third elastomer layer has a third recess on its bottom surface, so the first deflectable membrane is , Defined from the portion of the first elastomer layer between the first recess and the second recess, the second deflectable membrane is between the second recess and the third recess It is defined from the portion of the second elastomer layer.

  Embodiments of a method of fabricating a microfabricated elastomeric device according to the present invention include forming a non-elastomeric mold having a plurality of features of different heights and providing an uncured elastomeric material on the non-elastomeric mold. Including. The elastomeric material is cured and removed from the mold so that the cured elastomeric material has recesses of different depths corresponding to the height of the mold features. A cured elastomeric material is disposed on the substrate to define a channel between the recess and the substrate, and a molded elastomeric layer is disposed on the cured elastomeric material.

  An embodiment of the structure of the microfluidic device according to the invention comprises an underlying substrate and a first elastomer layer located on the substrate, the first elastomer layer having a flow channel on the bottom surface. The second elastomer layer is located on the first elastomer layer, and the second elastomer has a serpentine control channel on the bottom surface. The serpentine channel overlaps the flow channel at at least three locations and defines at least three deflectable membranes between the flow channel and the control channel, and thus the application of a high pressure signal to the control channel Squeeze the membrane in turn downward into the flow channel to allow the material present in the flow channel to flow.

  An alternative embodiment of a microfluidic device according to the present invention comprises an underlying substrate and a first elastomeric layer overlying the first elastomeric layer, the first elastomeric layer having a serpentine control channel on the bottom surface. Have. The second elastomer layer is located on the first elastomer layer, and the second elastomer layer has a flow channel on the bottom surface. This flow channel overlaps the tortuous control channel in at least three locations and defines at least three deflectable membranes between the control channel and the flow channel, and thus the high pressure signal to the control channel. The application deflects the membrane in turn upward into the flow channel, allowing the material present in the flow channel to flow.

  An embodiment of a method for causing material to flow through a microfluidic device structure includes disposing a flow channel in a first elastomer layer. A serpentine control channel is disposed in a second elastomeric layer adjacent to the first elastomeric layer, the control channel overlapping the flow channel at at least three locations and the first, second and third flexures. A possible membrane is defined between the flow channel and the serpentine control channel. A high pressure signal is applied to the flow channel, causing the first, second and third membranes to deflect and enter the flow channel in a peristaltic pumping sequence.

  An embodiment of a method for forming a via in a microfabricated elastomeric structure according to the present invention includes placing the elastomeric material in contact with a mold that includes raised features of the elastomeric material and curing the elastomeric material. . The cured elastomeric material is removed from the mold. The cured elastomeric material is pierced by the rigid hollow component and the rigid hollow component is removed from the cured elastomeric material to reveal a first via opening that communicates fluid with the first recess. To.

An embodiment of a microfluidic device structure according to the present invention comprises a substrate located below and a first elastomer layer located on the substrate, the first elastomer layer having a first recess on the bottom surface. The first recess is then patterned into a plurality of channels that separate into a plurality of parallel branches, and the parallel branches are reintegrated. The second elastomer layer is located on the first elastomer layer, the second elastomer layer has a second recess on the bottom surface, and the second recess is oriented perpendicular to the parallel branches. Patterned into a plurality of parallel channels. The membrane portion of the first elastomer layer is defined between an enlarged portion of parallel channels and an underlying parallel branch, the membrane portion controlling the fluid flowing through the parallel branches, It is possible to bend so that it may become a parallel branch.

  Although the invention has been described herein with reference to these specific embodiments, modifications, various changes and substitutions are contemplated in the foregoing disclosure, and in some examples, the invention It is understood that some of the characteristics can be used without corresponding use of other characteristics without departing from the scope of the invention described above. Accordingly, many modifications may be made to adapt a particular situation and material to the teachings of the present invention without departing from the essential scope and intent of the present invention.

  For example, other researchers have presented an alternative approach to microfabrication of microfluidic device devices using elastomeric materials. US Patent Applications Nos. 5,705,018 and 6,007,309 by Hartley generally describe a microfluidic device having microfabricated flow channels in a non-elastomeric substrate. The elastomeric membrane located above the flow channel is driven by static electricity and is deflected into the flow channel to flow fluid therethrough.

US Patent Application No. 5,376,252 by Ekstrom generally describes a microfluidic device structure featuring a base layer that is typically modified using a patterned elastomeric spacer layer. “Rapid Prototyping of by Duffy et al.
Microfluidic Systems in Poly (dimethylsiloxane), Analytical Chemistry, 70 (23): 4974-4984 (1998), for rapidly creating a template of an elastomeric layer having a channel and a reservoir with a molded non-elastomeric layer. A microfluidic device system used as a prototype is presented.

“A Pneumatically Actuated Micro Valve with a Silicon Rubber Membrane” by Vieider et al.
for Integration with Fluid-Handling Systems, "Proceedings of Transducers '95, the 8th International Conference on Solid-State Sensors and Actors, 1995. Pages 2,284-286 describe a microfluidic device pump structure comprising a movable elastomeric portion that supports a silicon plunger structure that can be pneumatically driven to close the flow channel. "A Microvalve System Fabricated by Thermoplastic Molding" by Fahrenberg et al., Journal of Micromechanics and Microengineering, vol. 5, no. 2 (June 1995) pages 169-171 describe the thermopneumatic drive of valves containing polyimide membranes.

Yang et al., “A MEMS Thermonematic Silicone Membrane Valve”, Proceedings of the IEEE.
10th Annual Workshop of Micro Electro Mechanical Systems (Japan, January 1997) pages 114-118 cure cured silicone film against non-elastomeric (Si / SiN) cross-links substantially removed by etching. The fabrication of the microfluidic valve structure according to is described. Shoji et al., “Smallest Dead Volume Microvalves for Integrated Chemical Analyzing Systems”, Proceedings of Transducers '91, the 1
991 International Conference on Solid-State Sensors and Actuators (San Francisco, June 1991) pages 1052-1055 are microfluidic device valve structures having a film of polymerized negative photoresist material driven by driven piezoelectric Is described.

"A Titanium-Nickel Shape-Memory Alloy Actuated Micropump" by Bernard et al., Proceedings
of Transducers '97, the 1997 International conference on Solid-State Sensors and Actuators (Chicago, 1997), vol. 1, pages 361-364 describe the use of polyimide check valves in connection with microfabricated valve structures that utilize non-elastomeric membrane actuation. Olsson et al., "Simulation Studios of Diffuser and Nozzle Elements for Valve-less Micropumps", Processeds of Transducers'97, the 1997 International Confences'97, the 1997 International Conferences. Pages 2,1039-1042 describe the use of a silicon mold to form an electroplated nickel mold that is later utilized to fabricate injection molded plastic pumps and valve structures.

Furthermore, much earlier attempts have been made to explore microfluidic device structures that use movable components composed of non-elastomeric materials, such as a thin layer of micromachined silicon. One example of this approach is Jerman's “Electrically-activated, Normally-Closed Diaphragm Valve”, Proceedings of Transducers '91 in the 1991 International Conference on Sent. It is a normally closed valve structure. Jerman's structure is linked around the material by a thinner SiO ₂ hinge that allows a thick non-elastomeric membrane to deflect the membrane.

  Accordingly, the various microfluidic device structure, method, application, and architecture approaches described herein are generally applicable to all types of microfluidic devices that handle devices, and are described herein. It is not limited to use with the multilayer elastomeric structure described in.

  The invention is not limited to the specific embodiments disclosed as the best mode contemplated for carrying out the invention, but the invention includes all embodiments and equivalents within the scope of the claims. .

  The following pending patent applications contain subject matter related to the present application and are incorporated herein by reference. These are pending US Patent Application No. 09 /,,, (Atoney Docket No. 020174-002510 US, 2001), dated “apparatus and methods for Conducting Cell Assays and High Throughput Screening” And a non-pending US patent application 09 / 724,548 (Atonie Docket number 0G638-US2, filed Nov. 28, 2000), referred to as "Integrated Active Flux Microfluidic Devices and Methods". .

Part I--FIGS. 1-7A are diagrams illustrating the continuous steps of a first method of making the present invention.

FIG. 1 is a diagram showing a first elastomer layer formed on the top surface of a micromachined mold.
FIG. 2 is a diagram showing that a second elastomer layer is formed on the top surface of the microfabricated mold. FIG. 3 is a diagram showing the elastomer layer of FIG. 2 removed from the microfabricated mold and placed on the top surface of the elastomer layer of FIG. FIG. 4 corresponds to FIG. 3, but shows a second elastomer layer placed on the top surface of the first elastomer layer. FIG. 5 corresponds to FIG. 4 but shows the first elastomer layer and the second elastomer layer being bonded together. FIG. 6 corresponds to FIG. 5 but shows that the first microfabricated mold has been removed and the flat substrate is in place. FIG. 7A corresponds to FIG. 6, but shows the elastomeric structure sealed on a flat substrate. FIG. 7B is a front cross-sectional view corresponding to FIG. 7A showing an open flow channel. FIG. 7C shows the steps of a method for forming an elastomeric structure having a membrane formed from another elastomeric layer. FIG. 7D shows the steps of a method for forming an elastomeric structure having a membrane formed from another elastomeric layer. FIG. 7E illustrates a method step for forming an elastomeric structure having a membrane formed from another elastomeric layer. FIG. 7F shows the steps of a method for forming an elastomeric structure having a membrane formed from another elastomeric layer. FIG. 7G illustrates the steps of a method for forming an elastomeric structure having a membrane formed from another elastomeric layer. Part II --- FIG. 7H illustrates closing the first flow channel by pressurizing the second flow channel.

FIG. 7H corresponds to FIG. 7A but shows the first flow channel closed by pressurization in the second flow channel.
Part III--FIGS. 8-18 show the sequential steps of the second method of making the present invention. FIG. 8 is a diagram illustrating a first elastomer layer deposited on a flat substrate. FIG. 9 is a diagram showing the first photoresist deposited on the top surface of the first elastomer layer of FIG. FIG. 10 is an illustration showing the system of FIG. 9, but only a portion of the first photoresist layer has been removed, leaving only the first line of photoresist. 11 provides a second elastomer layer over the first line of the first elastomer layer over the first line of the photoresist of FIG. 10, thereby providing the first elastomer layer and the second elastomer layer. FIG. 6 shows encapsulating photoresist between layers. FIG. 12 corresponds to FIG. 11 but shows that the monolithic monolithic structure has been created after the first and second elastomer layers are bonded together. FIG. 13 is a diagram showing a second photoresist layer deposited on the top surface of the integral elastomeric structure of FIG. FIG. 14 is a diagram illustrating the system of FIG. 13, except that a portion of the second photoresist layer has been removed, leaving only the second line of photoresist. FIG. 15 shows a third elastomer layer applied over the second line of the photoresist of FIG. 14 on the top surface of the second elastomer layer, whereby the elastomer structure of FIG. FIG. 6 encapsulates a second line of photoresist with an elastomer layer. FIG. 16 corresponds to FIG. 15 but with the third elastomer layer cured and bonded to a monolithic structure composed of the first and second elastomer layers previously bonded. It is a figure which shows becoming. FIG. 17 corresponds to FIG. 16, but removes the first and second lines of photoresist and overlaps in two orthogonal directions but does not intersect but is an integral elastomer. FIG. 4 shows a flow channel penetrating the structure. FIG. 18 shows the system of FIG. 17 with the flat substrate removed at the bottom. Part IV—FIGS. 19 and 20 show further details of different flow channel cross sections. FIG. 19 is a diagram showing a rectangular cross section of the first flow channel. FIG. 20 is a diagram illustrating a cross section of a flow channel having a curved upper surface. Part V --- FIGS. 21 to 24 show that experimental results have been achieved with the preferred embodiment of the microfabricated valve. FIG. 21 is a diagram showing applied pressure with respect to valve opening for various flow channels. FIG. 22 is a diagram showing a time response of a 100 μm × 100 μm × 10 μm RTV fine valve. Part VI --- FIGS. 23A-33 illustrate various microfabricated structures networked together in accordance with aspects of the present invention. FIG. 23A is a top schematic view of an on / off valve. FIG. 23B is a sectional elevation view taken along line 23B-23B in FIG. 23A. FIG. 24A is a top schematic view of a peristaltic pumping system. 24B is a sectional elevation view taken along line 24B-24B in FIG. 24A. FIG. 25 is a graph showing frequency versus experimentally achieved pumping speed for the embodiment of the peristaltic pumping system of FIG. FIG. 26A is a top schematic view showing a single control line operating multiple flow lines simultaneously. 26B is a cross-sectional elevation view taken along line 26B-26B in FIG. 26A. FIG. 27 is a schematic diagram illustrating a multiplexing system adapted to allow flow through various channels. FIG. 28A is a plan view showing the flow layers of an addressable reaction chamber structure. FIG. 28B is a bottom plan view showing the control channel layer of the addressable reaction chamber structure. 28C is a exploded perspective view of an addressable reaction chamber structure formed by coupling the control channel layer of FIG. 28B to the top surface of the flow layer of FIG. 28A. 28D is a cross-sectional elevation view corresponding to FIG. 28C, taken along line 28D-28D in FIG. 28C. FIG. 29 is a schematic diagram of a system adapted to selectively direct fluid flow into any of the array of reaction wells. FIG. 30 is a schematic diagram of a system adapted for selectable lateral flow between mutually parallel flow channels. FIG. 31A is a bottom plan view of a first layer of elastomer (ie, a layer of a flow channel) in a switchable flow arrangement. FIG. 31B is a bottom plan view of a layer of control channels in a switchable flow arrangement. FIG. 31C shows the first layer of elastomer of FIG. 31A in alignment with a set of control channels in the second layer of elastomer of FIG. 31B. FIG. 31D also shows the first layer of elastomer of FIG. 31A in alignment with another set of control channels in the second layer of elastomer of FIG. 31B. FIG. 32 is a schematic diagram of an integrated system for biopolymer synthesis. FIG. 33 is a schematic diagram of another integrated system for biopolymer synthesis. FIG. 34 is an optical micrograph of a portion of a test structure having seven elastomer layers bonded together. FIG. 35A shows the steps of one embodiment of a method for producing an elastomeric layer having vertical vias formed therein. FIG. 35B shows the steps of one embodiment of a method for producing an elastomeric layer having vertical vias formed therein. FIG. 35C shows the steps of one embodiment of a method for producing an elastomeric layer having vertical vias formed therein. FIG. 35D shows the steps of one embodiment of a method for producing an elastomer layer having vertical vias formed therein. FIG. 36 shows one embodiment of a classification device according to the present invention. FIG. 37 shows an embodiment of an apparatus for flowing process gas across a semiconductor wafer according to the present invention. FIG. 38 shows an exploded view of one embodiment of a fine mirror array structure according to the present invention. FIG. 39 shows a perspective view of a first embodiment of a refractive device according to the invention. FIG. 40 shows a perspective view of a second embodiment of a refractive device according to the invention. FIG. 41 shows a perspective view of a third embodiment of a refractive device according to the invention. FIG. 42A shows a diagram of one embodiment of a normally closed valve structure according to the present invention. FIG. 42B shows a diagram of one embodiment of a normally closed valve structure in accordance with the present invention. FIG. 42C shows a view of one embodiment of a normally closed valve structure in accordance with the present invention. FIG. 42D shows a diagram of one embodiment of a normally closed valve structure in accordance with the present invention. FIG. 42E shows a diagram of one embodiment of a normally closed valve structure in accordance with the present invention. FIG. 42F shows a diagram of one embodiment of a normally closed valve structure according to the present invention. FIG. 42G shows a diagram of one embodiment of a normally closed valve structure in accordance with the present invention. FIG. 42H shows a diagram of one embodiment of a normally closed valve structure in accordance with the present invention. FIG. 42I shows a diagram of one embodiment of a normally closed valve structure in accordance with the present invention. FIG. 42J shows a diagram of one embodiment of a normally closed valve structure in accordance with the present invention. FIG. 43 is a plan view of one embodiment of a device for performing separation according to the present invention. FIG. 44A shows a plan view illustrating the operation of one embodiment of a cell pen structure according to the present invention. FIG. 44B shows a plan view illustrating the operation of one embodiment of a cell pen structure according to the present invention. FIG. 44C shows a plan view illustrating the operation of one embodiment of a cell pen structure according to the present invention. FIG. 44D shows a plan view illustrating the operation of one embodiment of a cell pen structure according to the present invention. FIG. 45A shows a plan view illustrating the operation of one embodiment of a cell cage structure according to the present invention. FIG. 45B shows a cross-sectional view illustrating the operation of one embodiment of a cell cage structure according to the present invention. FIG. 46A shows a cross-sectional view illustrating the operation of one embodiment of a cell grinder structure according to the present invention. FIG. 46B shows a cross-sectional view illustrating the operation of one embodiment of a cell grinder structure according to the present invention. FIG. 47 shows a plan view of one embodiment of a pressure oscillator structure in accordance with the present invention. FIG. 48A shows a plan view illustrating the operation of one embodiment of a side-actuated valve structure according to the present invention. FIG. 48B shows a plan view illustrating the operation of one embodiment of a side-actuated valve structure according to the present invention. FIG. 49 plots Young's modulus versus percentage dilution of GE RTV 615 elastomer in GE SF96-50 silicon fluid. FIG. 50 shows a cross-sectional view of a structure in which the channel orientation plane is disposed on the contact to form a large size channel. FIG. 51 shows a cross-sectional view of a structure in which a non-channel orientation plane is disposed on a contact and is switched between two substrates. FIG. 52A shows a cross-sectional view of a process for constructing a bridge structure. FIG. 52B shows a cross-sectional view of a process for constructing a bridge structure. FIG. 52C shows a cross-sectional view of a process for constructing the bridge structure. FIG. 52D shows a plan view of the bridge structure. FIG. 53A shows a cross-sectional view of an embodiment of a composite structure in accordance with the present invention. FIG. 53B shows a cross-sectional view of an embodiment of a composite structure in accordance with the present invention. FIG. 54 shows a cross-sectional view of one embodiment of a composite structure in accordance with the present invention. FIG. 55A shows a cross-sectional view of a process for forming an elastomeric structure by bonding along a vertical line. FIG. 55B shows a cross-sectional view of a process for forming an elastomeric structure by bonding along a vertical line. FIG. 55C shows a cross-sectional view of a process for forming an elastomeric structure by bonding along a vertical line. FIG. 56 shows a schematic diagram of an electrolytically actuated syringe structure according to one embodiment of the present invention. FIG. 57A shows a cross-sectional view of a process for forming a flow channel having a film disposed therein. FIG. 57B shows a cross-sectional view of a process for forming a flow channel having a film disposed therein. FIG. 57C shows a cross-sectional view of a process for forming a flow channel having a film disposed therein. FIG. 58A shows a cross-sectional view of flow measurement with volume exclusion according to an embodiment of the present invention. FIG. 58B shows a cross-sectional view of flow measurement with volume exclusion according to an embodiment of the present invention. FIG. 58C shows a cross-sectional view of flow measurement with volume exclusion according to an embodiment of the present invention. FIG. 58D shows a cross-sectional view of flow measurement with volume exclusion according to an embodiment of the present invention. FIG. 59A shows a cross-sectional view of an embodiment of a linear amplifier constructed using a microfabrication technique according to the present invention. FIG. 59B shows a plan view of an embodiment of a linear amplifier constructed utilizing a microfabrication technique according to the present invention. FIG. 59C shows a photograph of the linear amplifier in the open position. FIG. 59D shows a photograph of the linear amplifier in the closed position. FIG. 60 shows a plan view of an embodiment of a large multiplexer structure according to the present invention. FIG. 61A shows a plan view of an embodiment of a one-way valve structure according to the present invention. FIG. 61B shows a cross-sectional view of an embodiment of a one-way valve structure according to the present invention. FIG. 62A shows a cross-sectional view of the steps of an embodiment of a process for forming a one-way valve according to the present invention. FIG. 62B shows a cross-sectional view of the steps of an embodiment of a process for forming a one-way valve according to the present invention. FIG. 62C shows a cross-sectional view of the steps of an embodiment of a process for forming a one-way valve according to the present invention. FIG. 62D shows a cross-sectional view of the steps of an embodiment of a process for forming a one-way valve according to the present invention. FIG. 62E shows a cross-sectional view of the steps of an embodiment of a process for forming a one-way valve according to the present invention. FIG. 63 is an embodiment of a NOR gate logic structure in accordance with the present invention. FIG. 64 is an embodiment of an AND gate logic structure according to the present invention that utilizes a one-way valve structure. FIG. 65 plots light intensity versus cycle for an embodiment of a Bragg mirror structure according to the present invention. FIG. 66 is a cross-sectional view of an embodiment of a tunable microlens structure in accordance with an embodiment of the present invention. FIG. 67 is a plan view of a protein crystallization system according to an embodiment of the present invention. FIG. 68A is a cross-sectional view of a method of bonding a vertically oriented microfabricated elastomeric structure to a horizontally oriented microfabricated elastomeric structure. FIG. 68B is a cross-sectional view of a method of joining a vertically oriented microfabricated elastomeric structure to a horizontally oriented microfabricated elastomeric structure. FIG. 69A shows a top view of a mixing process performed by a microfabricated structure according to another embodiment of the present invention. FIG. 69B shows a plan view of a mixing process performed by a microfabricated structure according to another embodiment of the present invention. FIG. 70 is a plan view of a protein crystallization system according to an alternative embodiment of the present invention. FIG. 71A shows a cross-sectional view of the mold functionalized topography feature at different heights. 71B shows a cross-sectional view of an elastomer layer patterned using the mold of FIG. 71A. FIG. 72 shows a cross-sectional view of an alternative embodiment of a valve structure. FIG. 73A presents a plan view of an alternative embodiment of a pump structure according to the present invention. FIG. 73B plots the flow rate against the frequency of application of the high pressure signal to the control line of the pump structure of FIG. 73A. FIG. 73C plots the flow rate against the frequency of application of the high pressure signal to the control line of the pump structure of FIG. 73A. FIG. 74 shows a plan view of the multiplexer structure. FIG. 75 presents a cross-sectional view of a microfluidic structure according to one embodiment of the present invention, the microfluidic structure being formed from three elastomer layers on the top of the substrate. FIG. 76 shows a cross-sectional view of a pinch-off valve according to an embodiment of the present invention. FIG. 77 shows an embodiment of a multilayer microfabricated elastomeric structure having two layers of control channels located on the same side as the flow channel. FIG. 78 shows a top view of a row of flow channel arrays that functionalize independent controllable valves. FIG. 79 shows a plan view of an alternative embodiment of a multiplexer structure according to the present invention. FIG. 80A shows a plan view of an alternative embodiment of a valve structure in accordance with the present invention, utilizing a control layer disposed on the opposite side of the layer containing the flow channel. FIG. 80B shows a cross-sectional view of an alternative embodiment of a valve structure in accordance with the present invention, utilizing a control layer disposed on the opposite side of the layer containing the flow channel. FIG. 81 shows a simplified schematic diagram of an alternative embodiment of a multiplexer structure. FIG. 82A is a cross-sectional view of a microfabricated structure that includes a vertical bias. FIG. 82B is a perspective view of a process for fabricating the structure shown in FIG. 82A. FIG. 82C is a perspective view of a process for fabricating the structure shown in FIG. 82A.

Claims (1)

  A microfluidic structure as described herein.

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