EP1195523A2 - Microfabricated elastomeric valve and pump systems - Google Patents

Abstract

A method of fabricating an elastomeric structure, comprising: forming a firstelastomeric layer on top of a first micromachined mold, the first micromachined mold havinga first raised protrusion which forms a first recess extending along a bottom surface of thefirst elastomeric layer; forming a second elastomeric layer on top of a second micromachinedmold, the second micromachined mold having a second raised protrusion which forms asecond recess extending along a bottom surface of the second elastomeric layer; bonding thebottom surface of the second elastomeric layer onto a top surface of the first elastomeric layersuch that a control channel forms in the second recess between the first and secondelastomeric layers; and positioning the first elastomeric layer on top of a planar substrate suchthat a flow channel forms in the first recess between the first elastomeric layer and the planarsubstrate.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
• This nonprovisional patent application claims the benefit of the followingpreviouslyfiled provisional patent applications: U.S. provisional patent application no.60/141,503 filed June 28, 1999, U.S. provisional patent application no. 60/147,199 filedAugust 3, 1999, and U.S. provisional patent application no. 60/186,856 filed March 3,2000. The text of these prior provisional patent applications is hereby incorporated byreference.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDERFEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
• The U.S. Government has a paid-up license in this invention and the rightin limited circumstances to require the patent owner to license others on reasonable termsas provided for by the terms of Grant No. HG-01642-02. awarded by the NationalInstitute of Health.
TECHNICAL FIELD
• The present invention relates to microfabricated structures and methods forproducing microfabricated structures, and to microfabricated systems for regulating fluid-flow.
BACKGROUND OF THE INVENTION
• Various approaches to designing micro-fluidic pumps and valves havebeen attempted. Unfortunately, each of these approaches suffers from its own limitations.
• The two most common methods of producing microelectromechanical(MEMS) structures such as pumps and valves are silicon-based bulk micro-machining(which is a subtractive fabrication method whereby single crystal silicon islithographically patterned and then etched to form three-dimensional structures), andsurface micro-machining (which is an additive method where layers of semiconductor-type materials such as polysilicon, silicon nitride, silicon dioxide, and various metals aresequentially added and patterned to make three-dimensional structures).
• A limitation of the first approach of silicon-based micro-machining is thatthe stiffness of the semiconductor materials used necessitates high actuation forces, whichin turn result in large and complex designs. In fact, both bulk and surface micro-machiningmethods are limited by the stiffness of the materials used. In addition,adhesion between various layers of the fabricated device is also a problem. For example,in bulk micro-machining, wafer bonding techniques must be employed to createmultilayer structures. On the other hand, when surface micro-machining, thermal stressesbetween the various layers of the device limits the total device thickness, often toapproximately 20 microns. Using either of the above methods, clean room fabricationand careful quality control are required.
SUMMARY OF THE INVENTION
• The present invention sets forth systems for fabricating and operatingmicrofabricated structures such as on/off valves, switching valves, and pumps e.g. madeout of various layers of elastomer bonded together. The present structures and methodsare ideally suited for controlling and channeling fluid movement, but are not so limited.
• In a preferred aspect, the present invention uses a multilayer softlithography process to build integrated (i.e.: monolithic) microfabricated elastomericstructures.
• Advantages of fabricating the present structures by binding together layersof soft elastomeric materials include the fact that the resulting devices are reduced bymore than two orders of magnitude in size as compared to silicon-based devices. Furtheradvantages of rapid prototyping, ease of fabrication, and biocompatability are alsoachieved.
• In preferred aspects of the invention, separate elastomeric layers arefabricated on top of micromachined molds such that recesses are formed in each of thevarious elastomeric layers. By bonding these various elastomeric layers together, therecesses extending along the various elastomeric layers form flow channels and controllines through the resulting monolithic, integral elastomeric structure. In various aspectsof the invention, these flow channels and control lines which are formed in theelastomeric structure can be actuated to function as micro-pumps and micro-valves, aswill be explained.
• In further optional aspects of the invention, the monolithic elastomericstructure is sealed onto the top of a planar substrate, with flow channels being formedbetween the surface of the planar substrate and the recesses which extend along thebottom surface of the elastomeric structure.
• In one preferred aspect, the present monolithic elastomeric structures areconstructed by bonding together two separate layers of elastomer with each layer firstbeing separately cast from a micromachined mold. Preferably, the elastomer used is atwo-component addition cure material in which the bottom elastomeric layer has anexcess of one component, while the top elastomeric layer has an excess of anothercomponent. In an exemplary embodiment, the elastomer used is silicone rubber. Twolayers of elastomer are cured separately. Each layer is separately cured before the toplayer is positioned on the bottom layer. The two layers are then bonded together. Eachlayer preferably has an excess of one of the two components, such that reactive moleculesremain at the interface between the layers. The top layer is assembled on top of thebottom layer and heated. The two layers bond irreversibly such that the strength of theinterface approaches or equals the strength of the bulk elastomer. This creates amonolithic three-dimensional patterned structure composed entirely of two layers ofbonded together elastomer. Additional layers may be added by simply repeating theprocess, wherein new layers, each having a layer of opposite "polarity" are cured, andthereby bonded together.
• In a second preferred aspect, a first photoresist layer is deposited on top ofa first elastomeric layer. The first photoresist layer is then patterned to leave a line orpattern of lines of photoresist on the top surface of the first elastomeric layer. Anotherlayer of elastomer is then added and cured, encapsulating the line or pattern of lines ofphotoresist. A second photoresist layer is added and patterned, and another layer ofelastomer added and cured, leaving line and patterns of lines of photoresist encapsulatedin a monolithic elastomer structure. This process may be repeated to add moreencapsulated patterns and elastomer layers. Thereafter, the photoresist is removedleaving flow channel(s) and control line(s) in the spaces which had been occupied by thephotoresist. This process may be repeated to create elastomer structures having amultitude of layers.
• An advantage of patterning moderate sized features (>/= 10 microns) usinga photoresist method is that a high resolution transparency film can be used as a contact mask. This allows a single researcher to design, print, pattern the mold, and create a newset of cast elastomer devices, typically all within 24 hours.
• A further advantage of either above embodiment of the present inventionis that due to its monolithic or integral nature, (i.e., all the layers are composed of thesame material) is that interlayer adhesion failures and thermal stress problems arecompletely avoided.
• Further advantages of the present invention's preferred use of a siliconerubber or elastomer such as RTV 615 manufactured by General Electric, is that it istransparent to visible light, making a multilayer optical trains possible, thereby allowingoptical interrogation of various channels or chambers in the microfluidic device. Asappropriately shaped elastomer layers can serve as lenses and optical elements, bondingof layers allows the creation of multilayer optical trains. In addition, GE RTV 615elastomer is biocompatible. Being soft, closed valves form a good seal even if there aresmall particulates in the flow channel. Silicone rubber is also bio-compatible andinexpensive, especially when compared with a single crystal silicon.
• Monolithic elastomeric valves and pumps also avoid many of the practicalproblems affecting flow systems based on electro-osmotic flow. Typically, electro-osmoticflow systems suffer from bubble formation around the electrodes and the flow isstrongly dependent on the composition of the flow medium. Bubble formation seriouslyrestricts the use of electro-osmotic flow in microfluidic devices, making it difficult toconstruct functioning integrated devices. The magnitude of flow and even its directiontypically depends in a complex fashion on ionic strength and type, the presence ofsurfactants and the charge on the walls of the flow channel. Moreover, since electrolysisis taking place continuously, the eventual capacity of buffer to resist pH changes may alsobe reached. Furthermore, electro-osmotic flow always occurs in competition withelectrophoresis. As different molecules may have different electrophoretic mobilities,unwanted electrophoretic separation may occur in the electro-osmotic flow. Finally,electro-osmotic flow can not easily be used to stop flow, halt diffusion, or to balancepressure differences.
• A further advantage of the present monolithic elastomeric valve and pumpstructures are that they can be actuated at very high speeds. For example, the presentinventors have achieved a response time for a valve with aqueous solution therein on theorder of one millisecond, such that the valve opens and closes at speeds approaching orexceeding 100 Hz. In particular, a non-exclusive list of ranges of cycling speeds for the opening and closing of the valve structure include between about 0.001 and 10000 ms,between about 0.01 and 1000 ms, between about 0.1and100 ms, and between about 1 and10 ms. The cycling speeds depend upon the composition and structure of a valve used fora particular application and the method of actuation, and thus cycling speeds outside ofthe listed ranges would fall within the scope of the present invention.
• Further advantages of the present pumps and valves are that their smallsize makes them fast and their softness contributes to making them durable. Moreover, asthey close linearly with differential applied pressure, this linear relationship allows fluidmetering and valve closing in spite of high back pressures.
• In various aspects of the invention, a plurality of flow channels passthrough the elastomeric structure with a second flow channel extending across and abovea first flow channel. In this aspect of the invention, a thin membrane of elastomerseparates the first and second flow channels. As will be explained, downward movementof this membrane (due to the second flow channel being pressurized or the membranebeing otherwise actuated) will cut off flow passing through the lower flow channel.
• In optional preferred aspects of the present systems, a plurality ofindividually addressable valves are formed connected together in an elastomeric structureand are then activated in sequence such that peristaltic pumping is achieved. Morecomplex systems including networked or multiplexed control systems, selectablyaddressable valves disposed in a grid of valves, networked or multiplexed reactionchamber systems and biopolymer synthesis systems are also described.
• One embodiment of a microfabricated elastomeric structure in accordancewith the present invention comprises an elastomeric block formed with first and secondmicrofabricated recesses therein, a portion of the elastomeric block deflectable when theportion is actuated.
• One embodiment of a method of microfabricating an elastomeric structurecomprises the steps of microfabricating a first elastomeric layer, microfabricating asecond elastomeric layer; positioning the second elastomeric layer on top of the firstelastomeric layer, and bonding a bottom surface of the second elastomeric layer onto atop surface of the first elastomeric layer.
• A first alternative embodiment of a method of microfabricating anelastomeric structure comprises the steps of forming a first elastomeric layer on top of afirst micromachined mold, the first micromachined mold having at least one first raisedprotrusion which forms at least one first channel in the bottom surface of the first elastomeric layer. A second elastomeric layer is formed on top of a secondmicromachined mold, the second micromachined mold having at least one second raisedprotrusion which forms at least one second channel in the bottom surface of the secondelastomeric layer. The bottom surface of the second elastomeric layer is bonded onto atop surface of the first elastomeric layer such that the at least one second channel isenclosed between the first and second elastomeric layers.
• A second alternative embodiment of a method of microfabricating anelastomeric structure in accordance with the present invention comprises the steps offorming a first elastomeric layer on top of a substrate, curing the first elastomeric layer,and depositing a first sacrificial layer on the top surface of the first elastomeric layer. Aportion of the first sacrificial layer is removed such that a first pattern of sacrificialmaterial remains on the top surface of the first elastomeric layer. A second elastomericlayer is formed over the first elastomeric layer thereby encapsulating the first pattern ofsacrificial material between the first and second elastomeric layers. The secondelastomeric layer is cured and then sacrificial material is removed thereby forming at leastone first recess between the first and second layers of elastomer.
• An embodiment of a method of actuating an elastomeric structure inaccordance with the present invention comprises providing an elastomeric block formedwith first and second microfabricated recesses therein, the first and secondmicrofabricated recesses being separated by a portion of the structure which is deflectableinto either of the first or second recesses when the other of the first and second recesses.One of the recesses is pressurized such that the portion of the elastomeric structureseparating the second recess from the first recess is deflected into the other of the tworecesses.
• In other optional preferred aspects, magnetic or conductive materials canbe added to make layers of the elastomer magnetic or electrically conducting, thusenabling the creation of all elastomer electromagnetic devices.
BRIEF DESCRIPTION OF THE DRAWINGSPart I - Figs. 1 to 7A illustrate successive steps of a first method of fabricating thepresent invention, as follows:
• Fig. 1 is an illustration of a first elastomeric layer formed on top of amicromachined mold.
• Fig. 2 is an illustration of a second elastomeric layer formed on top of amicromachined mold.
• Fig. 3 is an illustration of the elastomeric layer of Fig. 2 removed from themicromachined mold and positioned over the top of the elastomeric layer of Fig. 1
• Fig. 4 is an illustration corresponding to Fig. 3, but showing the secondelastomeric layer positioned on top of the first elastomeric layer.
• Fig. 5 is an illustration corresponding to Fig. 4, but showing the first andsecond elastomeric layers bonded together.
• Fig. 6 is an illustration corresponding to Fig. 5, but showing the firstmicromachine mold removed and a planar substrate positioned in its place.
• Fig. 7A is an illustration corresponding to Fig. 6, but showing theelastomeric structure sealed onto the planar substrate.
• Figs. 7B is a front sectional view corresponding to Fig. 7A, showing anopen flow channel.
• Figs. 7C-7G are illustrations showing steps of a method for forming anelastomeric structure having a membrane formed from a separate elastomeric layer.
Part II - Fig. 7H show the closing of a first flow channel by pressurizing a secondflow channel, as follows:
• Fig. 7H corresponds to Fig. 7A, but shows a first flow channel closed bypressurization in second flow channel.
Part III - Figs. 8 to 18 illustrate successive steps of a second method of fabricatingthe present invention, as follows:
• Fig. 8 is an illustration of a first elastomeric layer deposited on a planarsubstrate.
• Fig. 9 is an illustration showing a first photoresist layer deposited on top ofthe first elastomeric layer of Fig. 8.
• Fig. 10 is an illustration showing the system of Fig. 9, but with a portion ofthe first photoresist layer removed, leaving only a first line of photoresist.
• Fig. 11 is an illustration showing a second elastomeric layer applied on topof the first elastomeric layer over the first line of photoresist of Fig. 10, thereby encasingthe photoresist between the first and second elastomeric layers.
• Fig. 12 corresponds to Fig. 11, but shows the integrated monolithicstructure produced after the first and second elastomer layers have been bonded together.
• Fig. 13 is an illustration showing a second photoresist layer deposited ontop of the integral elastomeric structure of Fig. 12.
• Fig. 14 is an illustration showing the system of Fig. 13, but with a portionof the second photoresist layer removed, leaving only a second line of photoresist.
• Fig. 15 is an illustration showing a third elastomer layer applied on top ofthe second elastomeric layer and over the second line of photoresist of Fig. 14, therebyencapsulating the second line of photoresist between the elastomeric structure of Fig. 12and the third elastomeric layer.
• Fig. 16 corresponds to Fig. 15, but shows the third elastomeric layer curedso as to be bonded to the monolithic structure composed of the previously bonded firstand second elastomer layers.
• Fig. 17 corresponds to Fig. 16, but shows the first and second lines ofphotoresist removed so as to provide two perpendicular overlapping, but not intersecting,flow channels passing through the integrated elastomeric structure.
• Fig. 18 is an illustration showing the system of Fig. 17, but with the planarsubstrate thereunder removed.
Part IV - Figs. 19 and 20 show further details of different flow channel cross-sections,as follows:
• Fig. 19 shows a rectangular cross-section of a first flow channel.
• Fig. 20 shows the flow channel cross section having a curved uppersurface.
Part V - Figs. 21 to 24 show experimental results achieved by preferredembodiments of the present microfabricated valve:
• Fig. 21 illustrates valve opening vs. applied pressure for various flowchannels.
• Fig. 22 illustrates time response of a 100µm×100µm×10µm RTVmicrovalve.
Part VI - Figs. 23A to 33 show various microfabricated structures, networkedtogether according to aspects of the present invention:
• Fig. 23A is a top schematic view of an on/off valve.
• Fig. 23B is a sectional elevation view along line 23B-23B in Fig. 23A
• Fig. 24 is a top schematic view of a peristaltic pumping system.
• Fig. 24B is a sectional elevation view along line 24B-24B in Fig. 24A
• Fig. 25 is a graph showing experimentally achieved pumping rates vs.frequency for an embodiment of the peristaltic pumping system of Fig. 24.
• Fig. 26A is a top schematic view of one control line actuating multipleflow lines simultaneously.
• Fig. 26B is a sectional elevation view along line 26B-26B in Fig. 26A
• Fig. 27 is a schematic illustration of a multiplexed system adapted topermit flow through various channels.
• Fig. 28A is a plan view of a flow layer of an addressable reaction chamberstructure.
• Fig. 28B is a bottom plan view of a control channel layer of an addressablereaction chamber structure.
• Fig. 28C is an exploded perspective view of the addressable reactionchamber structure formed by bonding the control channel layer of Fig 28B to the top ofthe flow layer of Fig 28A.
• Fig. 28D is a sectional elevation view corresponding to Fig. 28C, takenalong line 28D-28D in Fig. 28C.
• Fig. 29 is a schematic of a system adapted to selectively direct fluid flowinto any of an array of reaction wells.
• Fig. 30 is a schematic of a system adapted for selectable lateral flowbetween parallel flow channels.
• Fig. 31A is a bottom plan view of first layer (i.e.: the flow channel layer)of elastomer of a switchable flow array.
• Fig. 31B is a bottom plan view of a control channel layer of a switchableflow array.
• Fig. 31C shows the alignment of the first layer of elastomer of Fig. 31Awith one set of control channels in the second layer of elastomer of Fig. 31B.
• Fig. 31D also shows the alignment of the first layer of elastomer of Fig.31A with the other set of control channels in the second layer of elastomer of Fig. 31B.
• Fig. 32 is a schematic of an integrated system for biopolymer synthesis.
• Fig. 33 is a schematic of a further integrated system for biopolymersynthesis.
• Fig. 34 is an optical micrograph of a section of a test structure havingseven layers of elastomer bonded together.
• Figs. 35A-35D show the steps of one embodiment of a method forfabricating an elastomer layer having a vertical via formed therein.
• Fig. 36 shows one embodiment of a sorting apparatus in accordance withthe present invention.
• Fig. 37 shows an embodiment of an apparatus for flowing process gasesover a semiconductor wafer in accordance with the present invention.
• Fig. 38 shows an exploded view of one embodiment of a micro-mirrorarray structure in accordance with the present invention.
• Fig. 39 shows a perspective view of a first embodiment of a refractivedevice in accordance with the present invention.
• Fig. 40 shows a perspective view of a second embodiment of a refractivedevice in accordance with the present invention.
• Fig. 41 shows a perspective view of a third embodiment of a refractivedevice in accordance with the present invention.
• Figs. 42A-42J show views of one embodiment of a normally-closed valvestructure in accordance with the present invention.
• Figs. 43 shows a plan view of one embodiment of a device for performingseparations in accordance with the present invention.
• Figs. 44A-44D show plan views illustrating operation of one embodimentof a cell pen structure in accordance with the present invention.
• Figs. 45A-45B show plan and cross-sectional views illustrating operationof one embodiment of a cell cage structure in accordance with the present invention.
• Figs. 46A-46B show cross-sectional views illustrating operation of oneembodiment of a cell grinder structure in accordance with the present invention.
• Fig. 47 shows a plan view of one embodiment of a pressure oscillatorstructure in accordance with the present invention.
• Figs. 48A and 48B show plan views illustrating operation of oneembodiment of a side-actuated valve structure in accordance with the present invention.
• Fig. 49 plots Young's modulus versus percentage dilution of GE RTV 615elastomer with GE SF96-50 silicone fluid.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
• The present invention comprises a variety of microfabricated elastomericstructures which may be used as pumps or valves. Methods of fabricating the preferredelastomeric structures are also set forth.
Methods of Fabricating the Present Invention:
• Two exemplary methods of fabricating the present invention are providedherein. It is to be understood that the present invention is not limited to fabrication byone or the other of these methods. Rather, other suitable methods of fabricating thepresent microstructures, including modifying the present methods, are also contemplated.
• Figs. 1 to 7B illustrate sequential steps of a first preferred method offabricating the present microstructure, (which may be used as a pump or valve). Figs. 8 to18 illustrate sequential steps of a second preferred method of fabricating the presentmicrostructure, (which also may be used as a pump or valve).
• As will be explained, the preferred method of Figs. 1 to 7B involves usingpre-cured elastomer layers which are assembled and bonded. Conversely, the preferredmethod of Figs. 8 to 18 involves curing each layer of elastomer "in place". In thefollowing description "channel" refers to a recess in the elastomeric structure which cancontain a flow of fluid or gas.
The First Exemplary Method:
• Referring to Fig. 1, a firstmicro-machined mold 10 is provided.Micro-machinedmold 10 may be fabricated by a number of conventional silicon processingmethods, including but not limited to photolithography, ion-milling, and electron beamlithography.
• As can be seen,micro-machined mold 10 has a raised line or protrusion 11extending therealong. A firstelastomeric layer 20 is cast on top ofmold 10 such that afirst recess 21 will be formed in the bottom surface ofelastomeric layer 20, (recess 21corresponding in dimension to protrusion 11), as shown.
• As can be seen in Fig. 2, a secondmicro-machined mold 12 having araisedprotrusion 13 extending therealong is also provided. A secondelastomeric layer 22 is cast on top ofmold 12, as shown, such that arecess 23 will be formed in its bottomsurface corresponding to the dimensions ofprotrusion 13.
• As can be seen in the sequential steps illustrated in Figs. 3 and 4, secondelastomeric layer 22 is then removed frommold 12 and placed on top of firstelastomericlayer 20. As can be seen, recess 23 extending along the bottom surface of secondelastomeric layer 22 will form aflow channel 32.
• Referring to Fig. 5, the separate first and secondelastomeric layers 20 and22 (Fig. 4) are then bonded together to form an integrated (i.e.: monolithic)elastomericstructure 24.
• As can been seen in the sequential step of Figs. 6 and 7A,elastomericstructure 24 is then removed frommold 10 and positioned on top of aplanar substrate 14.As can be seen in Fig. 7A and 7B, whenelastomeric structure 24 has been sealed at itsbottom surface toplanar substrate 14,recess 21 will form aflow channel 30.
• The present elastomeric structures form a reversible hermetic seal withnearly any smooth planar substrate. An advantage to forming a seal this way is that theelastomeric structures may be peeled up, washed, and re-used. In preferred aspects,planar substrate 14 is glass. A further advantage of using glass is that glass is transparent,allowing optical interrogation of elastomer channels and reservoirs: Alternatively, theelastomeric structure may be bonded onto a flat elastomer layer by the same method asdescribed above, forming a permanent and high-strength bond. This may proveadvantageous when higher back pressures are used.
• As can be seen in Fig. 7A and 7B,flow channels 30 and 32 are preferablydisposed at an angle to one another with asmall membrane 25 ofsubstrate 24 separatingthe top offlow channel 30 from the bottom offlow channel 32.
• In preferred aspects,planar substrate 14 is glass. An advantage of usingglass is that the present elastomeric structures may be peeled up, washed and reused. Afurther advantage of using glass is that optical sensing may be employed. Alternatively,planar substrate 14 may be an elastomer itself, which may prove advantageous whenhigher back pressures are used.
• The method of fabrication just described may be varied to form a structurehaving a membrane composed of an elastomeric material different than that forming thewalls of the channels of the device. This variant fabrication method is illustrated in Figs.7C-7G.
• Referring to Fig. 7C, a firstmicro-machined mold 10 is provided.Micro-machinedmold 10 has a raised line or protrusion 11 extending therealong. In Fig. 7D,firstelastomeric layer 20 is cast on top of firstmicro-machined mold 10 such that the topof the firstelastomeric layer 20 is flush with the top of raised line or protrusion 11. Thismay be accomplished by carefully controlling the volume of elastomeric material spunontomold 10 relative to the known height of raised line 11. Alternatively, the desiredshape could be formed by injection molding.
• In Fig. 7E, secondmicro-machined mold 12 having a raisedprotrusion 13extending therealong is also provided. Secondelastomeric layer 22 is cast on top ofsecond mold 12 as shown, such thatrecess 23 is formed in its bottom surfacecorresponding to the dimensions ofprotrusion 13.
• In Fig. 7F, secondelastomeric layer 22 is removed frommold 12 andplaced on top of thirdelastomeric layer 222. Secondelastomeric layer 22 is bonded tothirdelastomeric layer 20 to form integralelastomeric block 224 using techniquesdescribed in detail below. At this point in the process, recess 23 formerly occupied byraisedline 13 will form flowchannel 23.
• In Fig. 7G,elastomeric block 224 is placed on top of firstmicro-machinedmold 10 and firstelastomeric layer 20. Elastomeric block and firstelastomeric layer 20are then bonded together to form an integrated (i.e.: monolithic)elastomeric structure 24having a membrane composed of a separateelastomeric layer 222.
• Whenelastomeric structure 24 has been sealed at its bottom surface to aplanar substrate in the manner described above in connection with FIG. 7A, the recessformerly occupied by raised line 11 will form flowchannel 30.
• The variant fabrication method illustrated above in conjunction with FIGS.7C-7G offers the advantage of permitting the membrane portion to be composed of aseparate material than the elastomeric material of the remainder of the structure. This isimportant because the thickness and elastic properties of the membrane play a key role inoperation of the device. Moreover, this method allows the separate elastomer layer toreadily be subjected to conditioning prior to incorporation into the elastomer structure.As discussed in detail below, examples of potentially desirable condition include theintroduction of magnetic or electrically conducting species to permit actuation of themembrane, and/or the introduction of dopant into the membrane in order to alter itselasticity.
• While the above method is illustrated in connection with forming variousshaped elastomeric layers formed by replication molding on top of a micromachinedmold, the present invention is not limited to this technique. Other techniques could beemployed to form the individual layers of shaped elastomeric material that are to bebonded together. For example, a shaped layer of elastomeric material could be formed bylaser cutting or injection molding, or by methods utilizing chemical etching and/orsacrificial materials as discussed below in conjunction with the second exemplarymethod.
The Second Exemplary Method:
• A second exemplary method of fabricating an elastomeric structure whichmay be used as a pump or valve is set forth in the sequential steps shown in Figs. 8-18.
• In this aspect of the invention, flow and control channels are defined byfirst patterning photoresist on the surface of an elastomeric layer (or other substrate,which may include glass) leaving a raised line photoresist where a channel is desired.Next, a second layer of elastomer is added thereover and a second photoresist is patternedon the second layer of elastomer leaving a raised line photoresist where a channel isdesired. A third layer of elastomer is deposited thereover. Finally, the photoresist isremoved by dissolving it out of the elastomer with an appropriate solvent, with the voidsformed by removal of the photoresist becoming the flow channels passing through thesubstrate.
• Referring first to Fig. 8, aplanar substrate 40 is provided. A firstelastomeric layer 42 is then deposited and cured on top ofplanar substrate 40. Referringto Fig. 9, afirst photoresist layer 44A is then deposited over the top ofelastomeric layer42. Referring to Fig. 10, a portion ofphotoresist layer 44A is removed such that only afirst line ofphotoresist 44B remains as shown. Referring to Fig. 11, a secondelastomericlayer 46 is then deposited over the top of firstelastomeric layer 42 and over the first lineofphotoresist 44B as shown, thereby encasing first line ofphotoresist 44B between firstelastomeric layer 42 and secondelastomeric layer 46. Referring to Fig. 12,elastomericlayers 46 is then cured onlayer 42 to bond the layers together to form a monolithicelastomeric substrate 45.
• Referring to Fig. 13, asecond photoresist layer 48A is then deposited overelastomeric structure 45. Referring to Fig. 14, a portion ofsecond photoresist layer 48A isremoved, leaving only asecond photoresist line 48B on top ofelastomeric structure 45 as shown. Referring to Fig. 15, a thirdelastomeric layer 50 is then deposited over the top ofelastomeric structure 45 (comprised of secondelastomeric layer 42 and first line ofphotoresist 44B) andsecond photoresist line 48B as shown, thereby encasing the secondline ofphotoresist 48B betweenelastomeric structure 45 and thirdelastomeric layer 50.
• Referring to Fig. 16, thirdelastomeric layer 50 and elastomeric structure45 (comprising firstelastomeric layer 42 and secondelastomeric layer 46 bondedtogether) is then bonded together forming a monolithicelastomeric structure 47 havingphotoresist lines 44B and 48B passing therethrough as shown. Referring to Fig. 17,photoresist lines 44B, 48B are then removed (for example, by an solvent ) such that afirstflow channel 60 and asecond flow channel 62 are provided in their place, passingthroughelastomeric structure 47 as shown. Lastly, referring to Fig. 18,planar substrate40 can be removed from the bottom of the integrated monolithic structure.
• The method described in Figs. 8-18 fabricates a patterned elastomerstructure utilizing development of photoresist encapsulated within elastomer material.However, the methods in accordance with the present invention are not limited toutilizing photoresist. Other materials such as metals could also serve as sacrificialmaterials to be removed selective to the surrounding elastomer material, and the methodwould remain within the scope of the present invention. For example, as described indetail below in connection with Figs. 35A-35D, gold metal may be etched selective toRTV 615 elastomer utilizing the appropriate chemical mixture.
Preferred Layer and Channel Dimensions:
• Microfabricated refers to the size of features of an elastomeric structurefabricated in accordance with an embodiment of the present invention. In general,variation in at least one dimension of microfabricated structures is controlled to themicron level, with at least one dimension being microscopic (i.e. below 1000 µm).Microfabrication typically involves semiconductor or MEMS fabrication techniques suchas photolithography and spincoating that are designed for to produce feature dimensionson the microscopic level, with at least some of the dimension of the microfabricatedstructure requiring a microscope to reasonably resolve/image the structure.
• In preferred aspects,flow channels 30, 32, 60 and 62 preferably havewidth-to-depth ratios of about 10:1. A non-exclusive list of other ranges of width-to-depthratios in accordance with embodiments of the present invention is 0.1:1 to 100:1, more preferably 1:1 to 50:1, more preferably 2:1 to 20:1, and most preferably 3:1 to 15:1.In an exemplary aspect, flowchannels 30, 32, 60 and 62 have widths of about 1 to 1000microns. A non-exclusive list of other ranges of widths of flow channels in accordancewith embodiments of the present invention is 0.01 to 1000 microns, more preferably 0.05to 1000 microns, more preferably 0.2 to 500 microns, more preferably 1 to 250 microns,and most preferably 10 to 200 microns. Exemplary channel widths include 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, 100µm, 110 µm, 120 µm, 130 µm, 140 µm, 150 µm, 160 µm, 170 µm, 180 µm, 190 µm, 200µm, 210 µm, 220 µm, 230 µm, 240 µm, and 250 µm.
• Flow channels 30, 32, 60, and 62 have depths of about 1 to 100 microns.A non-exclusive list of other ranges of depths of flow channels in accordance withembodiments of the present invention is 0.01 to 1000 microns, more preferably 0.05 to500 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. Exemplarychannel depths include including 0.01 µm, 0.02 µm, 0.05 µm, 0.1 µm, 0.2 µm, 0.5 µm, 1µm, 2 µm, 3 µm, 4 µm, 5 µm, 7.5 µm, 10 µm, 12.5 µm, 15 µm, 17.5 µm, 20 µm, 22.5µm, 25 µm, 30 µm, 40 µm, 50 µm, 75 µm, 100 µm, 150 µm, 200 µm, and 250 µm.
• The flow channels are not limited to these specific dimension ranges andexamples given above, and may vary in width in order to affect the magnitude of forcerequired to deflect the membrane as discussed at length below in conjunction with Fig.27. For example, extremely narrow flow channels having a width on the order of 0.01µm may be useful in optical and other applications, as discussed in detail below.Elastomeric structures which include portions having channels of even greater width thandescribed above are also contemplated by the present invention, and examples ofapplications of utilizing such wider flow channels include fluid reservoir and mixingchannel structures.
• Elastomeric layer 22 may be cast thick for mechanical stability. In anexemplary embodiment,layer 22 is 50 microns to several centimeters thick, and morepreferably approximately 4 mm thick. A non-exclusive list of ranges of thickness of theelastomer layer in accordance with other embodiments of the present invention isbetween about 0.1 micron to 10 cm, 1 micron to 5 cm, 10 microns to 2 cm, 100 micronsto 10 mm.
• Accordingly,membrane 25 of Fig. 7B separatingflow channels 30 and 32has a typical thickness of between about 0.01 and 1000 microns, more preferably 0.05 to500 microns, more preferably 0.2 to 250, more preferably 1 to 100 microns, morepreferably 2 to 50 microns, and most preferably 5 to 40 microns. As such, the thicknessofelastomeric layer 22 is about 100 times the thickness ofelastomeric layer 20.Exemplary membrane thicknesses include 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, 17.5µm, 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, firstelastomeric layer 42 may have a preferred thickness aboutequal to that ofelastomeric layer 20 or 22; secondelastomeric layer 46 may have apreferred thickness about equal to that ofelastomeric layer 20; and thirdelastomeric layer50 may have a preferred thickness about equal to that ofelastomeric layer 22.
Multilayer Soft Lithography Construction Techniques and Materials:Soft Lithographic Bonding:
• Preferably,elastomeric layers 20 and 22 (orelastomeric layers 42, 46 and50) are bonded together chemically, using chemistry that is intrinsic to the polymerscomprising the patterned elastomer layers. Most preferably, the bonding comprises twocomponent "addition cure" bonding.
• In a preferred aspect, the various layers of elastomer are bound together ina heterogenous bonding in which the layers have a different chemistry. Alternatively, ahomogenous bonding may be used in which all layers would be of the same chemistry.Thirdly, the respective elastomer layers may optionally be glued together by an adhesiveinstead. In a fourth aspect, the elastomeric layers may be thermoset elastomers bondedtogether by heating.
• In one aspect of homogeneous bonding, the elastomeric layers arecomposed of the same elastomer material, with the same chemical entity in one layerreacting with the same chemical entity in the other layer to bond the layers together. Inone embodiment, bonding between polymer chains of like elastomer layers may resultfrom activation of a crosslinking agent due to light, heat, or chemical reaction with aseparate chemical species.
• Alternatively in a heterogeneous aspect, the elastomeric layers arecomposed of different elastomeric materials, with a first chemical entity in one layerreacting with a second chemical entity in another layer. In one exemplary heterogenousaspect, the bonding process used to bind respective elastomeric layers together maycomprise bonding together two layers of RTV 615 silicone. RTV 615 silicone is a two-partaddition-cure silicone rubber. Part A contains vinyl groups and catalyst; part Bcontains silicon hydride (Si-H) groups. The conventional ratio for RTV 615 is 10A:1B.For bonding, one layer may be made with 30A:1B (i.e. excess vinyl groups) and the otherwith 3A:1B (i.e. excess Si-H groups). Each layer is cured separately. When the twolayers are brought into contact and heated at elevated temperature, they bond irreversiblyforming a monolithic elastomeric substrate.
• In an exemplary aspect of the present invention, elastomeric structures areformed utilizing Sylgard 182, 184 or 186, or aliphatic urethane diacrylates such as (butnot limited to) Ebecryl 270 or Irr 245 from UCB Chemical.
• In one embodiment in accordance with the present invention, two-layerelastomeric structures were fabricated from pure acrylated Urethane Ebe 270. A thinbottom layer was spin coated at 8000 rpm for 15 seconds at 170°C. The top and bottomlayers were initially cured under ultraviolet light for 10 minutes under nitrogen utilizing aModel ELC 500 device manufactured by Electrolite corporation. The assembled layerswere then cured for an additional 30 minutes. Reaction was catalyzed by a 0.5% vol/volmixture of Irgacure 500 manufactured by Ciba-Geigy Chemicals. The resultingelastomeric material exhibited moderate elasticity and adhesion to glass.
• In another embodiment in accordance with the present invention, two-layerelastomeric structures were fabricated from a combination of 25% Ebe 270 / 50% Irr245/ 25% isopropyl alcohol for a thin bottom layer, and pure acrylated Urethane Ebe 270 as atop layer. The thin bottom layer was initially cured for 5 min, and the top layer initiallycured for 10 minutes, under ultraviolet light under nitrogen utilizing a Model ELC 500device manufactured by Electrolite corporation. The assembled layers were then cured foran additional 30 minutes. Reaction was catalyzed by a 0.5% vol/vol mixture of Irgacure500 manufactured by Ciba-Geigy Chemicals. The resulting elastomeric materialexhibited moderate elasticity and adhered to glass.
• Alternatively, other bonding methods may be used, including activatingthe elastomer surface, for example by plasma exposure, so that the elastomerlayers/substrate will bond when placed in contact. For example, one possible approach to bonding together elastomer layers composed of the same material is set forth by Duffy etal, "Rapid Prototyping of Microfluidic Systems in Poly (dimethylsiloxane)",AnalyticalChemistry (1998), 70, 4974-4984, incorporated herein by reference. This paper discussesthat exposing polydimethylsiloxane (PDMS) layers to oxygen plasma causes oxidation ofthe surface, with irreversible bonding occurring when the two oxidized layers are placedinto contact.
• Yet another approach to bonding together successive layers of elastomer isto utilize the adhesive properties of uncured elastomer. Specifically, a thin layer ofuncured elastomer such as RTV 615 is applied on top of a first cured elastomeric layer.Next, a second cured elastomeric layer is placed on top of the uncured elastomeric layer.The thin middle layer of uncured elastomer is then cured to produce a monolithicelastomeric structure. Alternatively, uncured elastomer can be applied to the bottom of afirst cured elastomer layer, with the first cured elastomer layer placed on top of a secondcured elastomer layer. Curing the middle thin elastomer layer again results in formationof a monolithic elastomeric structure.
• Where encapsulation of sacrificial layers is employed to fabricate theelastomer structure as described above in Figs. 8-18, bonding of successive elastomericlayers may be accomplished by pouring uncured elastomer over a previously curedelastomeric layer and any sacrificial material patterned thereupon. Bonding betweenelastomer layers occurs due to interpenetration and reaction of the polymer chains of anuncured elastomer layer with the polymer chains of a cured elastomer layer. Subsequentcuring of the elastomeric layer will create a bond between the elastomeric layers andcreate a monolithic elastomeric structure.
• Referring to the first method of Figs. 1 to 7B, firstelastomeric layer 20may be created by spin-coating an RTV mixture onmicrofabricated mold 12 at 2000rpm's for 30 seconds yielding a thickness of approximately 40 microns. Secondelastomeric layer 22 may be created by spin-coating an RTV mixture on microfabricatedmold 11. Both layers 20 and 22 may be separately baked or cured at about 80°C for 1.5hours. The secondelastomeric layer 22 may be bonded onto firstelastomeric layer 20 atabout 80°C for about 1.5 hours.
• Micromachined molds 10 and 12 may be patterned photoresist on siliconwafers. In an exemplary aspect, a Shipley SJR 5740 photoresist was spun at 2000 rpmpatterned with a high resolution transparency film as a mask and then developed yielding an inverse channel of approximately 10 microns in height. When baked at approximately200°C for about 30 minutes, the photoresist reflows and the inverse channels becomerounded. In preferred aspects, the molds may be treated with trimethylchlorosilane(TMCS) vapor for about a minute before each use in order to prevent adhesion of siliconerubber.
• Using the various multilayer soft lithography construction techniques andmaterials set forth herein, the present inventors have experimentally succeeded in creatingchannel networks comprises of up to seven separate elastomeric layers thick, with eachlayer being about 40 µm thick. It is foreseeable that devices comprising more than sevenseparate elastomeric layers bonded together could be developed.
Suitable Elastomeric Materials:
• Allcock et al, ContemporaryPolymer Chemistry, 2^nd Ed. describeselastomers in general as polymers existing at a temperature between their glass transistiontemperature and liquefaction temperature. Elastomeric materials exhibit elastic propertiesbecause the polymer chains readily undergo torsional motion to permit uncoiling of thebackbone chains in response to a force, with the backbone chains recoiling to assume theprior shape in the absence of the force. In general, elastomers deform when force isapplied, but then return to their original shape when the force is removed. The elasticityexhibited by elastomeric materials may be characterized by a Young's modulus.Elastomeric materials having a Young's modulus of between about 1 Pa - 1 TPa, morepreferably between about 10 Pa - 100 GPa, more preferably between about 20 Pa - 1GPa, more preferably between about 50 Pa - 10 MPa, and more preferably between about100 Pa - 1 MPa are useful in accordance with the present invention, although elastomericmaterials having a Young's modulus outside of these ranges could also be utilizeddepending upon the needs of a particular application.
• The systems of the present invention may be fabricated from a widevariety of elastomers. In an exemplary aspect,elastomeric layers 20, 22, 42, 46 and 50may preferably be fabricated from silicone rubber. However, other suitable elastomersmay also be used.
• In an exemplary aspect of the present invention, the present systems arefabricated from an elastomeric polymer such as GE RTV 615 (formulation), a vinylsilanecrosslinked (type) silicone elastomer (family). However, the present systems are not limited to this one formulation, type or even this family of polymer; rather, nearly anyelastomeric polymer is suitable. An important requirement for the preferred method offabrication of the present microvalves is the ability to bond multiple layers of elastomerstogether. In the case of multilayer soft lithography, layers of elastomer are curedseparately and then bonded together. This scheme requires that cured layers possesssufficient reactivity to bond together. Either the layers may be of the same type, and arecapable of bonding to themselves, or they may be of two different types, and are capableof bonding to each other. Other possibilities include the use an adhesive between layersand the use of thermoset elastomers.
• Given the tremendous diversity of polymer chemistries, precursors,synthetic methods, reaction conditions, and potential additives, there are a huge numberof possible elastomer systems that could be used to make monolithic elastomericmicrovalves and pumps. Variations in the materials used will most likely be driven bythe need for particular material properties, i.e. solvent resistance, stiffness, gaspermeability, or temperature stability.
• There are many, many types of elastomeric polymers. A brief descriptionof the most common classes of elastomers is presented here, with the intent of showingthat even with relatively "standard" polymers, many possibilities for bonding exist.Common elastomeric polymers include polyisoprene, polybutadiene, polychloroprene,polyisobutylene, poly(styrene-butadiene-styrene), the polyurethanes, and silicones.
Polyisoprene, polybutadiene, polychloroprene:
• Polyisoprene, polybutadiene, and polychloroprene are all polymerized from dienemonomers, and therefore have one double bond per monomer when polymerized.This double bond allows the polymers to be converted to elastomers byvulcanization (essentially, sulfur is used to form crosslinks between the doublebonds by heating). This would easily allow homogeneous multilayer softlithography by incomplete vulcanization of the layers to be bonded; photoresistencapsulation would be possible by a similar mechanism.
Polyisobutylene:
• Pure polyisobutylene has no double bonds, but is crosslinked to use as anelastomer by including a small amount (∼1%) of isoprene in the polymerization. The isoprene monomers give pendant double bonds on the polyisobutylenebackbone, which may then be vulcanized as above.
Poly(styrene-butadiene-styrene):
• Poly(styrene-butadiene-styrene) is produced by living anionic polymerization(that is, there is no natural chain-terminating step in the reaction), so "live"polymer ends can exist in the cured polymer. This makes it a natural candidate forthe present photoresist encapsulation system (where there will be plenty ofunreacted monomer in the liquid layer poured on top of the cured layer).Incomplete curing would allow homogeneous multilayer soft lithography (A to Abonding). The chemistry also facilitates making one layer with extra butadiene("A") and coupling agent and the other layer ("B") with a butadiene deficit (forheterogeneous multilayer soft lithography). SBS is a "thermoset elastomer",meaning that above a certain temperature it melts and becomes plastic (as opposedto elastic); reducing the temperature yields the elastomer again. Thus, layers canbe bonded together by heating.
Polyurethanes:
• Polyurethanes are produced from di-isocyanates (A-A) and di-alcohols or diamines(B-B); since there are a large variety of di-isocyanates and dialcohols/amines,the number of different types of polyurethanes is huge. The Avs. B nature of the polymers, however, would make them useful for heterogeneousmultilayer soft lithography just as RTV 615 is: by using excess A-A in one layerand excess B-B in the other layer.
Silicones:
• Silicone polymers probably have the greatest structural variety, and almostcertainly have the greatest number of commercially available formulations. Thevinyl-to-(Si-H) crosslinking of RTV 615 (which allows both heterogeneousmultilayer soft lithography and photoresist encapsulation) has already beendiscussed, but this is only one of several crosslinking methods used in siliconepolymer chemistry.
Cross Linking Agents:
• In addition to the use of the simple "pure" polymers discussed above,crosslinking agents may be added. Some agents (like the monomers bearing pendantdouble bonds for vulcanization) are suitable for allowing homogeneous (A to A)multilayer soft lithography or photoresist encapsulation; in such an approach the sameagent is incorporated into both elastomer layers. Complementary agents (i.e. onemonomer bearing a pendant double bond, and another bearing a pendant Si-H group) aresuitable for heterogeneous (A to B) multilayer soft lithography. In this approachcomplementary agents are added to adjacent layers.
Other Materials:
• In addition, polymers incorporating materials such as chlorosilanes ormethyl-, ethyl-, and phenylsilanes, and polydimethylsiloxane (PDMS) such as DowChemical Corp. Sylgard 182, 184 or 186, or aliphatic urethane diacrylates such as (butnot limited to) Ebecryl 270 or Irr 245 from UCB Chemical may also be used.
• The following is a non-exclusive list of elastomeric materials which maybe utilized in connection with the present invention: polyisoprene, polybutadiene,polychloroprene, polyisobutylene, poly(styrene-butadiene-styrene), the polyurethanes,and silicone polymers; or poly(bis(fluoroalkoxy)phosphazene) (PNF, Eypel-F),poly(carborane-siloxanes) (Dexsil), poly(acrylonitrile-butadiene) (nitrile rubber), poly(1-butene),poly(chlorotrifluoroethylene-vinylidene fluoride) copolymers (Kel-F), poly(ethylvinyl ether), poly(vinylidene fluoride), poly(vinylidene fluoride - hexafluoropropylene)copolymer (Viton), elastomeric compositions of polyvinylchloride (PVC), polysulfone,polycarbonate, polymethylmethacrylate (PMMA), and polytertrafluoroethylene (Teflon).
Doping and Dilution:
• Elastomers may also be "doped" with uncrosslinkable polymer chains ofthe same class. For instance RTV 615 may be diluted with GE SF96-50 Silicone Fluid.This serves to reduce the viscosity of the uncured elastomer and reduces the Young'smodulus of the cured elastomer. Essentially, the crosslink-capable polymer chains arespread further apart by the addition of "inert" polymer chains, so this is called "dilution".RTV 615 cures at up to 90% dilution, with a dramatic reduction in Young's modulus.
• Fig. 49 plots Young's modulus versus percentage dilution with GE SF96-50diluent of GE RTV 615 elastomer having a ratio of 30:1 A:B. FIG. 49 shows that the flexibility of the elastomer material, and hence the responsiveness of the valve membraneto an applied actuation force, can be controlled during fabrication of the device.
• Other examples of doping of elastomer material may include theintroduction of electrically conducting or magnetic species, as described in detail belowin conjunction with alternative methods of actuating the membrane of the device. Shouldit be desired, doping with fine particles of material having an index of refraction differentthan the elastomeric material (i.e. silica, diamond, sapphire) is also contemplated as asystem for altering the refractive index of the material. Strongly absorbing or opaqueparticles may be added to render the elastomer colored or opaque to incident radiation.This may conceivably be beneficial in an optically addressable system.
• Finally, by doping the elastomer with specific chemical species, thesedoped chemical species may be presented at the elastomer surface, thus serving asanchors or starting points for further chemical derivitization.
Pre-Treatment and Surface Coating
• Once the elastomeric material has been molded or etched into theappropriate shape, it may be necessary to pre-treat the material in order to facilitateoperation in connection with a particular application.
• For example, one possible application for an elastomeric device inaccordance with the present invention is to sort biological entities such as cells or DNA.In such an application, the hydrophobic nature of the biological entity may cause it toadhere to the hydrophobic elastomer of the walls of the channel. Therefore, it may beuseful to pre-treat the elastomeric structure order to impart a hydrophilic character to thechannel walls. In an embodiment of the present invention utilizing the General ElectricRTV 615 elastomer, this can be accomplished by boiling the shaped elastomer in acid(e.g. 0.01% HCl in water, pH 2.7, at 60°C for 40 min).
• Other types of pre-treatment of elastomer material are also contemplatedby the present application. For example, certain portions of elastomer may be pre-treatedto create anchors for surface chemistry reactions (for example in the formation of peptidechains), or binding sites for antibodies, as would be advantageous in a given application.Other examples of pre-treatment of elastomer material may include the introduction ofreflective material on the elastomer surface, as described in detail below in conjunctionwith the micro-mirror array application.
Methods of Operating the Present Invention:
• Figs. 7B and 7H together show the closing of a first flow channel bypressurizing a second flow channel, with Fig. 7B (a front sectional view cutting throughflow channel 32 in corresponding Fig. 7A), showing an openfirst flow channel 30; withFig. 7H showingfirst flow channel 30 closed by pressurization of thesecond flowchannel 32.
• Referring to Fig. 7B,first flow channel 30 andsecond flow channel 32 areshown.Membrane 25 separates the flow channels, forming the top offirst flow channel30 and the bottom ofsecond flow channel 32. As can be seen, flowchannel 30 is "open".
• As can be seen in Fig. 7H, pressurization of flow channel 32 (either by gasor liquid introduced therein) causesmembrane 25 to deflect downward, thereby pinchingoff flow F passing throughflow channel 30. Accordingly, by varying the pressure inchannel 32, a linearly actuable valving system is provided such thatflow channel 30 canbe opened or closed by movingmembrane 25 as desired. (For illustration purposes only,channel 30 in Fig. 7G is shown in a "mostly closed" position, rather than a "fully closed"position).
• It is to be understood that exactly the same valve opening and closingmethods can be achieved withflow channels 60 and 62.
  Since such valves are actuated by moving the roof of the channels themselves (i.e.:moving membrane 25) valves and pumps produced by this technique have a truly zerodead volume, and switching valves made by this technique have a dead volumeapproximately equal to the active volume of the valve, for example about 100 x 100 x 10µm = 100pL. Such dead volumes and areas consumed by the moving membrane areapproximately two orders of magnitude smaller than known conventional microvalves.Smaller and larger valves and switching valves are contemplated in the present invention,and a non-exclusive list of ranges of dead volume includes 1 aL to 1 uL, 100 aL to 100nL, 1 fL to 10 nL, 100 fL to 1 nL, and 1 pL to 100 pL
• The extremely small volumes capable of being delivered by pumps andvalves in accordance with the present invention represent a substantial advantage.Specifically, the smallest known volumes of fluid capable of being manually metered isaround 0.1 µl. The smallest known volumes capable of being metered by automatedsystems is about ten-times larger (1 µl). Utilizing pumps and valves in accordance withthe present invention, volumes of liquid of 10 nl or smaller can routinely be metered and dispensed. The accurate metering of extremely small volumes of fluid enabled by thepresent invention would be extremely valuable in a large number of biologicalapplications, including diagnostic tests and assays.
• Equation 1 represents a highly simplified mathematical model ofdeflection of a rectangular, linear, elastic, isotropic plate of uniform thickness by anapplied pressure:(1)   w = (BPb4)/(Eh3),where:
• w = deflection of plate;
• B = shape coefficient (dependent upon length vs. width and support ofedges of plate);
• P = applied pressure;
• b = plate width
• E = Young's modulus; and
• h = plate thickness.
• Thus even in this extremely simplified expression, deflection of an elastomeric membranein response to a pressure will be a function of: the length, width, and thickness of themembrane, the flexibility of the membrane (Young's modulus), and the applied actuationforce. Because each of these parameters will vary widely depending upon the actualdimensions and physical composition of a particular elastomeric device in accordancewith the present invention, a wide range of membrane thicknesses and elasticities,channel widths, and actuation forces are contemplated by the present invention.
• It should be understood that the formula just presented is only anapproximation, since in general the membrane does not have uniform thickness, themembrane thickness is not necessarily small compared to the length and width, and thedeflection is not necessarily small compared to length, width, or thickness of themembrane. Nevertheless, the equation serves as a useful guide for adjusting variableparameters to achieve a desired response of deflection versus applied force.
• Figs. 21a and 21b illustrate valve opening vs. applied pressure for a 100µm widefirst flow channel 30 and a 50 µm widesecond flow channel 32. The membraneof this device was formed by a layer of General Electric Silicones RTV 615 having athickness of approximately 30µm and a Young's modulus of approximately 750 kPa.Figs. 21a and 21b show the extent of opening of the valve to be substantially linear over most of the range of applied pressures. While the present invention does not require thislinear actuation behavior, embodiments of the invention <insert here>.
• Air pressure was applied to actuate the membrane of the device through a10 cm long piece of plastic tubing having an outer diameter of 0.025" connected to a 25mm piece of stainless steel hypodermic tubing with an outer diameter of 0.025" and aninner diameter of 0.013". This tubing was placed into contact with the control channel byinsertion into the elastomeric block in a direction normal to the control channel. Airpressure was applied to the hypodermic tubing from an external LHDA miniaturesolenoid valve manufactured by Lee Co.
• Connection of conventional microfluidic devices to an external fluid flowposes a number of problems avoided by the external configuration just described. Onesuch problem is the fragility of their connections with the external environment.Specifically, conventional microfluidic devices are composed of hard, inflexible materials(such as silicon), to which pipes or tubing allowing connection to external elements mustbe joined. The rigidity of the conventional material creates significant physical stress atpoints of contact with small and delicate external tubing, rendering conventionalmicrofluidic devices prone to fracture and leakage at these contact points.
• By contrast, the elastomer of the present invention is flexible and can beeasily penetrated for external connection by a tube composed a hard material. Forexample, in an elastomer structure fabricated utilizing the method shown in Figs. 1-7B, ahole extending from the exterior surface of the structure into the control channel can bemade by penetrating the elastomer with metal hypodermic tubing after the upperelastomer piece has been removed from the mold (as shown in Fig. 3) and before thispiece has been bonded to the lower elastomer piece (as shown in Fig. 4). Between thesesteps, the roof of the control channel is exposed to the user's view and is accessible toinsertion and proper positioning of the hole. Following completion of fabrication of thedevice, the metal hypodermic tubing is inserted into the hole to complete the fluidconnection.
• Moreover, the elastomer of the present invention will flex in response tophysical strain at the point of contact with an external connection, rendering the externalphysical connection more robust. This flexibility substantially reduces the chance ofleakage or fracture of the present device.
• Another disadvantage of conventional microfluidic devices is the difficultyin establishing an effective seal between the device and its external links. Because of the extremely narrow diameter of the channels of these devices, even moderate rates of fluidflow can require extremely high pressures. Unwanted leakage at the junction between thedevice and external connections may result. However, the flexibility of the elastomer ofthe present device also aids in overcoming leakage relating to pressure. In particular, theflexible elastomeric material flexes to conform around inserted tubing in order to form apressure resistant seal.
• While control of the flow of material through the device has so far beendescribed utilizing applied gas pressure, other fluids could be used. For example, air iscompressible, and thus experiences some finite delay between the time of application ofpressure by the external solenoid valve and the time that this pressure is experienced bythe membrane. In an alternative embodiment of the present invention, pressure could beapplied from an external source to a noncompressible fluid such as water or hydraulicoils, resulting in a near-instantaneous transfer of applied pressure to the membrane.However, if the displaced volume of the valve is large or the control channel is narrow,higher viscosity of a control fluid may contribute to delay in actuation. The optimalmedium for transferring pressure will therefore depend upon the particular applicationand device configuration, and both gaseous and liquid media are contemplated by theinvention.
• While external applied pressure as described above has been applied by apump/tank system through a pressure regulator and external miniature valve, othermethods of applying external pressure are also contemplated in the present invention,including gas tanks, compressors, piston systems, and columns of liquid. Alsocontemplated is the use of naturally occurring pressure sources such as may be foundinside living organisms, such as blood pressure, gastric pressure, the pressure present inthe cerebro-spinal fluid, pressure present in the intra-ocular space, and the pressureexerted by muscles during normal flexure. Other methods of regulating external pressureare also contemplated, such as miniature valves, pumps, macroscopic peristaltic pumps,pinch valves, and other types of fluid regulating equipment such as is known in the art.
• As can be seen, the response of valves in accordance with embodiments ofthe present invention have been experimentally shown to be almost perfectly linear over alarge portion of its range of travel, with minimal hysteresis. Accordingly, the presentvalves are ideally suited for microfluidic metering and fluid control. The linearity of thevalve response demonstrates that the individual valves are well modeled as Hooke's Lawsprings. Furthermore, high pressures in the flow channel (i.e.: back pressure) can be countered simply by increasing the actuation pressure. Experimentally, the presentinventors have achieved valve closure at back pressures of 70 kPa, but higher pressuresare also contemplated. The following is a nonexclusive list of pressure rangesencompassed by the present invention: 10 Pa - 25 MPa; 100 Pa - 10 Mpa, 1 kPa - 1 MPa,1 kPa - 300 kPa, 5 kPa-200 kPa, and 15 kPa - 100 kPa.
• While valves and pumps do not require linear actuation to open and close,linear response does allow valves to more easily be used as metering devices. In oneembodiment of the invention, the opening of the valve is used to control flow rate bybeing partially actuated to a known degree of closure. Linear valve actuation makes iteasier to determine the amount of actuation force required to close the valve to a desireddegree of closure. Another benefit of linear actuation is that the force required for valveactuation may be easily determined from the pressure in the flow channel. If actuation islinear, increased pressure in the flow channel may be countered by adding the samepressure (force per unit area) to the actuated portion of the valve.
• Linearity of a valve depends on the structure, composition, and method ofactuation of the valve structure. Furthermore, whether linearity is a desirablecharacteristic in a valve depends on the application. Therefore, both linearly and nonlinearlyactuatable valves are contemplated in the present invention, and the pressureranges over which a valve is linearly actuatable will vary with the specific embodiment.
• Fig. 22 illustrates time response (i.e.: closure of valve as a function of timein response to a change in applied pressure) of a 100µm×100µm×10µm RTV microvalvewith 10-cm-long air tubing connected from the chip to a pneumatic valve as describedabove.
• Two periods of digital control signal, actual air pressure at the end of thetubing and valve opening are shown in Fig. 22. The pressure applied on the control lineis 100 kPa, which is substantially higher than the ∼40 kPa required to close the valve.Thus, when closing, the valve is pushed closed with apressure 60 kPa greater thanrequired. When opening, however, the valve is driven back to its rest position only by itsown spring force (≤ 40 kPa). Thus, τ_close is expected to be smaller than τ_open. There isalso a lag between the control signal and control pressure response, due to the limitationsof the miniature valve used to control the pressure. Calling such lags t and the 1/e timeconstants τ, the values are: t_open = 3.63 ms, τ_open = 1.88 ms, t_close = 2.15 ms, τ_close = 0.51 ms. If 3τ each are allowed for opening and closing, the valve runs comfortably at 75 Hzwhen filled with aqueous solution.
• If one used another actuation method which did not suffer from openingand closing lag, this valve would run at ∼375 Hz. Note also that the spring constant canbe adjusted by changing the membrane thickness; this allows optimization for either fastopening or fast closing. The spring constant could also be adjusted by changing theelasticity (Young's modulus) of the membrane, as is possible by introducing dopant intothe membrane or by utilizing a different elastomeric material to serve as the membrane(described above in conjunction with Figs. 7C-7H.)
• When experimentally measuring the valve properties as illustrated in Figs.21 and 22, the valve opening was measured by fluorescence. In these experiments, theflow channel was filled with a solution of fluorescein isothiocyanate (FITC) in buffer (pH≥ 8) and the fluorescence of a square area occupying the center ∼1/3rd of the channel ismonitored on an epi-fluorescence microscope with a photomultiplier tube with a 10 kHzbandwidth. The pressure was monitored with a Wheatstone-bridge pressure sensor(SenSym SCC15GD2) pressurized simultaneously with the control line through nearlyidentical pneumatic connections.
Flow Channel Cross Sections:
• The flow channels of the present invention may optionally be designedwith different cross sectional sizes and shapes, offering different advantages, dependingupon their desired application. For example, the cross sectional shape of the lower flowchannel may have a curved upper surface, either along its entire length or in the regiondisposed under an upper cross channel). Such a curved upper surface facilitates valvesealing, as follows.
• Referring to Fig. 19, a cross sectional view (similar to that of Fig. 7B)throughflow channels 30 and 32 is shown. As can be seen, flowchannel 30 is rectangularin cross sectional shape. In an alternate preferred aspect of the invention, as shown inFig. 20, the cross-section of aflow channel 30 instead has an upper curved surface.
• Referring first to Fig. 19, whenflow channel 32 is pressurized, themembrane portion 25 ofelastomeric block 24separating flow channels 30 and 32 willmove downwardly to the successive positions shown by the dottedlines 25A, 25B, 25C, 25D, and 25E. As can be seen, incomplete sealing may possibly result at the edges offlow channel 30 adjacentplanar substrate 14.
• In the alternate preferred embodiment of Fig. 20, flow channel 30a has acurvedupper wall 25A. Whenflow channel 32 is pressurized,membrane portion 25 willmove downwardly to the successive positions shown by dotted lines 25A2, 25A3, 25A4and 25A5, with edge portions of the membrane moving first into the flow channel,followed by top membrane portions. An advantage of having such a curved upper surfaceatmembrane 25A is that a more complete seal will be provided whenflow channel 32 ispressurized. Specifically, the upper wall of theflow channel 30 will provide a continuouscontacting edge againstplanar substrate 14, thereby avoiding the "island" of contact seenbetweenwall 25 and the bottom offlow channel 30 in Fig. 19.
• Another advantage of having a curved upper flow channel surface atmembrane 25A is that the membrane can more readily conform to the shape and volumeof the flow channel in response to actuation. Specifically, where a rectangular flowchannel is employed, the entire perimeter (2x flow channel height, plus the flow channelwidth) must be forced into the flow channel. However where an arched flow channel isused, a smaller perimeter of material (only the semi-circular arched portion) must beforced into the channel. In this manner, the membrane requires less change in perimeterfor actuation and is therefore more responsive to an applied actuation force to block theflow channel
• In an alternate aspect, (not illustrated), the bottom offlow channel 30 isrounded such that its curved surface mates with the curvedupper wall 25A as seen in Fig.20 described above.
• In summary, the actual conformational change experienced by themembrane upon actuation will depend upon the configuration of the particularelastomeric structure. Specifically, the conformational change will depend upon thelength, width, and thickness profile of the membrane, its attachment to the remainder ofthe structure, and the height, width, and shape of the flow and control channels and thematerial properties of the elastomer used. The conformational change may also dependupon the method of actuation, as actuation of the membrane in response to an appliedpressure will vary somewhat from actuation in response to a magnetic or electrostaticforce.
• Moreover, the desired conformational change in the membrane will alsovary depending upon the particular application for the elastomeric structure. In the simplest embodiments described above, the valve may either be open or closed, withmetering to control the degree of closure of the valve. In other embodiments however, itmay be desirable to alter the shape of the membrane and/or the flow channel in order toachieve more complex flow regulation. For instance, the flow channel could be providedwith raised protrusions beneath the membrane portion, such that upon actuation themembrane shuts off only a percentage of the flow through the flow channel, with thepercentage of flow blocked insensitive to the applied actuation force.
• Many membrane thickness profiles and flow channel cross-sections arecontemplated by the present invention, including rectangular, trapezoidal, circular,ellipsoidal, parabolic, hyperbolic, and polygonal, as well as sections of the above shapes.More complex cross-sectional shapes, such as the embodiment with protrusions discussedimmediately above or an embodiment having concavities in the flow channel, are alsocontemplated by the present invention.
Alternate Valve Actuation Techniques:
• In addition to pressure based actuation systems described above, optionalelectrostatic and magnetic actuation systems are also contemplated, as follows.
• Electrostatic actuation can be accomplished by forming oppositely chargedelectrodes (which will tend to attract one another when a voltage differential is applied tothem) directly into the monolithic elastomeric structure. For example, referring to Fig.7B, an optional first electrode 70 (shown in phantom) can be positioned on (or in)membrane 25 and an optional second electrode 72 (also shown in phantom) can bepositioned on (or in)planar substrate 14. Whenelectrodes 70 and 72 are charged withopposite polarities, an attractive force between the two electrodes will causemembrane25 to deflect downwardly, thereby closing the "valve" (i.e.: closing flow channel 30).
• For the membrane electrode to be sufficiently conductive to supportelectrostatic actuation, but not so mechanically stiff so as to impede the valve's motion, asufficiently flexible electrode must be provided in or overmembrane 25. Such anelectrode may be provided by a thin metallization layer, doping the polymer withconductive material, or making the surface layer out of a conductive material.
• In an exemplary aspect, the electrode present at the deflecting membranecan be provided by a thin metallization layer which can be provided, for example, bysputtering a thin layer of metal such as 20 nm of gold. In addition to the formation of ametallized membrane by sputtering, other metallization approaches such as chemical epitaxy, evaporation, electroplating, and electroless plating are also available. Physicaltransfer of a metal layer to the surface of the elastomer is also available, for example byevaporating a metal onto a flat substrate to which it adheres poorly, and then placing theelastomer onto the metal and peeling the metal off of the substrate.
• Aconductive electrode 70 may also be formed by depositing carbon black(i.e. Cabot Vulcan XC72R) on the elastomer surface, either by wiping on the dry powderor by exposing the elastomer to a suspension of carbon black in a solvent which causesswelling of the elastomer, (such as a chlorinated solvent in the case of PDMS).Alternatively, theelectrode 70 may be formed by constructing theentire layer 20 out ofelastomer doped with conductive material (i.e. carbon black or finely divided metalparticles). Yet further alternatively, the electrode may be formed by electrostaticdeposition, or by a chemical reaction that produces carbon. In experiments conducted bythe present inventors, conductivity was shown to increase with carbon blackconcentration from 5.6 x 10^-16 to about 5 x 10^-3 (Ω-cm)^-1. Thelower electrode 72, whichis not required to move, may be either a compliant electrode as described above, or aconventional electrode such as evaporated gold, a metal plate, or a doped semiconductorelectrode.
• Alternatively, magnetic actuation of the flow channels can be achieved byfabricating the membrane separating the flow channels with a magnetically polarizablematerial such as iron, or a permanently magnetized material such as polarized NdFeB. Inexperiments conducted by the present inventors, magnetic silicone was created by theaddition of iron powder (about 1 um particle size), up to 20% iron by weight.
• Where the membrane is fabricated with a magnetically polarizablematerial, the membrane can be actuated by attraction in response to an applied magneticfield Where the membrane is fabricated with a material capable of maintainingpermanent magnetization, the material can first be magnetized by exposure to asufficiently high magnetic field, and then actuated either by attraction or repulsion inresponse to the polarity of an applied inhomogenous magnetic field.
• The magnetic field causing actuation of the membrane can be generated ina variety of ways. In one embodiment, the magnetic field is generated by an extremelysmall inductive coil formed in or proximate to the elastomer membrane. The actuationeffect of such a magnetic coil would be localized, allowing actuation of individual pumpand/or valve structures. Alternatively, the magnetic field could be generated by a larger, more powerful source, in which case actuation would be global and would actuatemultiple pump and/or valve structures at one time.
• It is further possible to combine pressure actuation with electrostatic ormagnetic actuation. Specifically, a bellows structure in fluid communication with arecess could be electrostatically or magnetically actuated to change the pressure in therecess and thereby actuate a membrane structure adjacent to the recess.
• In addition to electrical or magnetic actuation as described above, optionalelectrolytic and electrokinetic actuation systems are also contemplated by the presentinvention. For example, actuation pressure on the membrane could arise from anelectrolytic reaction in a recess overlying the membrane. In such an embodiment,electrodes present in the recess would apply a voltage across an electrolyte in the recess.This potential difference would cause electrochemical reaction at the electrodes and resultin the generation of gas species, giving rise to a pressure differential in the recess.
• Alternatively, actuation pressure on the membrane could arise from anelectrokinetic fluid flow in the control channel. In such an embodiment, electrodespresent at opposite ends of the control channel would apply a potential difference acrossan electrolyte present in the control channel. Migration of charged species in theelectrolyte to the respective electrodes could give rise to a pressure differential.
• Finally, it is also possible to actuate the device by causing a fluid flow inthe control channel based upon the application of thermal energy, either by thermalexpansion or by production of gas from liquid. Similarly, chemical reactions generatinggaseous products may produce an increase in pressure sufficient for membrane actuation.
Networked Systems:
• Figs. 23A and 23B show a views of a single on/off valve, identical to thesystems set forth above, (for example in Fig. 7A). Figs. 24A and 24B shows a peristalticpumping system comprised of a plurality of the single addressable on/off valves as seenin Fig. 23, but networked together. Fig. 25 is a graph showing experimentally achievedpumping rates vs. frequency for the peristaltic pumping system of Fig. 24. Figs. 26A and26B show a schematic view of a plurality of flow channels which are controllable by asingle control line. This system is also comprised of a plurality of the single addressableon/off valves of Fig. 23, multiplexed together, but in a different arrangement than that ofFig. 23. Fig. 27 is a schematic illustration of a multiplexing system adapted to permit fluid flow through selected channels, comprised of a plurality of the single on/off valvesof Fig. 23, joined or networked together.
• Referring first to Figs. 23A and 23B, a schematic offlow channels 30 and32 is shown.Flow channel 30 preferably has a fluid (or gas) flow F passing therethrough.Flow channel 32, (which crosses overflow channel 30, as was already explained herein),is pressurized such thatmembrane 25 separating the flow channels may be depressed intothe path offlow channel 30, shutting off the passage of flow F therethrough, as has beenexplained. As such, "flow channel" 32 can also be referred to as a "control line" whichactuates a single valve inflow channel 30. In Figs. 23 to 26, a plurality of suchaddressable valves are joined or networked together in various arrangements to producepumps, capable of peristaltic pumping, and other fluidic logic applications.
• Referring to Fig. 24A and 24B, a system for peristaltic pumping isprovided, as follows. Aflow channel 30 has a plurality of generally parallel flow channels(i.e.: control lines) 32A, 32B and 32C passing thereover. By pressurizingcontrol line32A, flow F throughflow channel 30 is shut off undermembrane 25A at the intersectionofcontrol line 32A and flowchannel 30. Similarly, (but not shown), by pressurizingcontrol line 32B, flow F throughflow channel 30 is shut off undermembrane 25B at theintersection ofcontrol line 32B and flowchannel 30, etc.
• Each ofcontrol lines 32A, 32B, and 32C is separately addressable.Therefore, peristalsis may be actuated by the pattern of actuating 32A and 32C together,followed by 32A, followed by 32A and 32B together, followed by 32B, followed by 32Band C together, etc. This corresponds to a successive "101, 100, 110, 010, 011, 001"pattern, where "0" indicates "valve open" and "1" indicates "valve closed." Thisperistaltic pattern is also known as a 120° pattern (referring to the phase angle ofactuation between three valves). Other peristaltic patterns are equally possible, including60° and 90° patterns.
• In experiments performed by the inventors, a pumping rate of 2.35 nL/swas measured by measuring the distance traveled by a column of water in thin (0.5 mmi.d.) tubing; with 100x100x10 µm valves under an actuation pressure of 40 kPa. Thepumping rate increased with actuation frequency until approximately 75 Hz, and then wasnearly constant until above 200 Hz. The valves and pumps are also quite durable and theelastomer membrane, control channels, or bond have never been observed to fail. Inexperiments performed by the inventors, none of the valves in the peristaltic pump described herein show any sign of wear or fatigue after more than 4 million actuations. Inaddition to their durability, they are also gentle. A solution ofE. Coli pumped through achannel and tested for viability showed a 94% survival rate.
• Fig. 25 is a graph showing experimentally achieved pumping rates vs.frequency for the peristaltic pumping system of Fig. 24.
• Figs. 26A and 26B illustrates another way of assembling a plurality of theaddressable valves of Fig. 21. Specifically, a plurality ofparallel flow channels 30A, 30B,and 30C are provided. Flow channel (i.e.: control line) 32 passes thereover acrossflowchannels 30A, 30B, and 30C. Pressurization ofcontrol line 32 simultaneously shuts offflows F1, F2 and F3 by depressingmembranes 25A, 25B, and 25C located at theintersections ofcontrol line 32 andflow channels 30A, 30B, and 30C.
• Fig. 27 is a schematic illustration of a multiplexing system adapted toselectively permit fluid to flow through selected channels, as follows. The downwarddeflection of membranes separating the respective flow channels from a control linepassing thereabove (for example,membranes 25A, 25B, and 25C in Figs. 26A and 26B)depends strongly upon the membrane dimensions. Accordingly, by varying the widths offlowchannel control line 32 in Figs. 26A and 26B, it is possible to have a control linepass over multiple flow channels, yet only actuate (i.e.: seal) desired flow channels. Fig.27 illustrates a schematic of such a system, as follows.
• A plurality ofparallel flow channels 30A, 30B, 30C, 30D, 30E and 30Fare positioned under a plurality ofparallel control lines 32A, 32B, 32C, 32D, 32E and32F.Control channels 32A, 32B, 32C, 32D, 32E and 32F are adapted to shut off fluidflows F1, F2, F3, F4, F5 and F6 passing throughparallel flow channels 30A, 30B, 30C,30D, 30E and 30F using any of the valving systems described above, with the followingmodification.
• Each ofcontrol lines 32A, 32B, 32C, 32D, 32E and 32F have both wideand narrow portions. For example,control line 32A is wide in locations disposed overflow channels 30A, 30C and 30E. Similarly,control line 32B is wide in locationsdisposed overflow channels 30B, 30D and 30F, and controlline 32C is wide in locationsdisposed overflow channels 30A, 30B, 30E and 30F.
• At the locations where the respective control line is wide, its pressurizationwill cause the membrane (25) separating the flow channel and the control line to depresssignificantly into the flow channel, thereby blocking the flow passage therethrough.Conversely, in the locations where the respective control line is narrow, membrane (25) will also be narrow. Accordingly, the same degree of pressurization will not result inmembrane (25) becoming depressed into the flow channel (30). Therefore, fluid passagethereunder will not be blocked.
• For example, whencontrol line 32A is pressurized, it will block flows F1,F3 and F5 inflow channels 30A, 30C and 30E. Similarly, whencontrol line 32C ispressurized, it will block flows F1, F2, F5 and F6 inflow channels 30A, 30B, 30E and30F. As can be appreciated, more than one control line can be actuated at the same time.For example,control lines 32A and 32C can be pressurized simultaneously to block allfluid flow except F4 (with 32A blocking F1, F3 and F5; and 32C blocking F1, F2, F5 andF6).
• By selectively pressurizing different control lines (32) both together and invarious sequences, a great degree of fluid flow control can be achieved. Moreover, byextending the present system to more than six parallel flow channels (30) and more thanfour parallel control lines (32), and by varying the positioning of the wide and narrowregions of the control lines, very complex fluid flow control systems may be fabricated. Aproperty of such systems is that it is possible to turn on any one flow channel out ofnflow channels with only 2(log₂n) control lines.
• The inventors have succeeded in fabricating microfluidic structures withdensities of 30 devices /mm², but greater densities are achievable.
Selectively Addressable Reaction Chambers Along Flow Lines:
• In a further embodiment of the invention, illustrated in Figs. 28A, 28B,28C and 28D, a system for selectively directing fluid flow into one more of a plurality ofreaction chambers disposed along a flow line is provided.
• Fig. 28A shows a top view of aflow channel 30 having a plurality ofreaction chambers 80A and 80B disposed therealong. Preferably flowchannel 30 andreaction chambers 80A and 80B are formed together as recesses into the bottom surfaceof afirst layer 100 of elastomer.
• Fig. 28B shows a bottom plan view of anotherelastomeric layer 110 withtwocontrol lines 32A and 32B each being generally narrow, but having wide extendingportions 33A and 33B formed as recesses therein.
• As seen in the exploded view of Fig. 28C, and assembled view of Fig.28D,elastomeric layer 110 is placed overelastomeric layer 100.Layers 100 and 110 arethen bonded together, and the integrated system operates to selectively direct fluid flow F (through flow channel 30) into either or both ofreaction chambers 80A and 80B, asfollows. Pressurization ofcontrol line 32A will cause the membrane 25 (i.e.: the thinportion ofelastomer layer 100 located below extendingportion 33A and overregions82A ofreaction chamber 80A) to become depressed, thereby shutting off fluid flowpassage inregions 82A, effectively sealingreaction chamber 80 fromflow channel 30. Ascan also be seen, extendingportion 33A is wider than the remainder ofcontrol line 32A.As such, pressurization ofcontrol line 32A will not result incontrol line 32Asealing flowchannel 30.
• As can be appreciated, either or both ofcontrol lines 32A and 32B can beactuated at once. When bothcontrol lines 32A and 32B are pressurized together, sampleflow inflow channel 30 will enter neither ofreaction chambers 80A or 80B.
• The concept of selectably controlling fluid introduction into variousaddressable reaction chambers disposed along a flow line (Figs. 28) can be combinedwith concept of selectably controlling fluid flow through one or more of a plurality ofparallel flow lines (Fig. 27) to yield a system in which a fluid sample or samples can becan be sent to any particular reaction chamber in an array of reaction chambers. Anexample of such a system is provided in Fig. 29, in whichparallel control channels 32A,32B and 32C with extending portions 34 (all shown in phantom) selectively direct fluidflows F1 and F2 into any of the array ofreaction wells 80A, 80B, 80C or 80D asexplained above; while pressurization ofcontrol lines 32C and 32D selectively shuts offflows F2 and F1, respectively.
• In yet another novel embodiment, fluid passage between parallel flowchannels is possible. Referring to Fig. 30, either or both ofcontrol lines 32A or 32D canbe depressurized such that fluid flow through lateral passageways 35 (betweenparallelflow channels 30A and 30B) is permitted. In this aspect of the invention, pressurization ofcontrol lines 32C and 32D would shutflow channel 30A between 35A and 35B, andwould also shutlateral passageways 35B. As such, flow entering as flow F1 wouldsequentially travel through 30A, 35A and leave 30B as flow F4.
Switchable Flow Arrays
• In yet another novel embodiment, fluid passage can be selectively directedto flow in either of two perpendicular directions. An example of such a "switchable flowarray" system is provided in Figs. 31A to 31D. Fig. 31A shows a bottom view of a firstlayer ofelastomer 90, (or any other suitable substrate), having a bottom surface with a pattern of recesses forming a flow channel grid defined by an array ofsolid posts 92, eachhaving flow channels passing therearound.
• In preferred aspects, an additional layer of elastomer is bound to the topsurface oflayer 90 such that fluid flow can be selectively directed to move either indirection F1, or perpendicular direction F2. . Fig. 31 is a bottom view of the bottomsurface of the second layer ofelastomer 95 showing recesses formed in the shape ofalternating "vertical"control lines 96 and "horizontal" control lines 94. "Vertical"controllines 96 have the same width therealong, whereas "horizontal"control lines 94 havealternating wide and narrow portions, as shown.
• Elastomeric layer 95 is positioned over top ofelastomeric layer 90 suchthat "vertical"control lines 96 are positioned overposts 92 as shown in Fig. 31C and"horizontal"control lines 94 are positioned with their wide portions betweenposts 92, asshown in Fig. 31D.
• As can be seen in Fig. 31C, when "vertical"control lines 96 arepressurized, the membrane of the integrated structure formed by the elastomeric layerinitially positioned betweenlayers 90 and 95 inregions 98 will be deflected downwardlyover the array of flow channels such that flow in only able to pass in flow direction F2(i.e.: vertically), as shown.
• As can be seen in Fig. 31D, when "horizontal"control lines 94 arepressurized, the membrane of the integrated structure formed by the elastomeric layerinitially positioned betweenlayers 90 and 95 inregions 99 will be deflected downwardlyover the array of flow channels, (but only in the regions where they are widest), such thatflow in only able to pass in flow direction F1 (i.e.: horizontally), as shown.
• The design illustrated in Figs. 31 allows a switchable flow array to beconstructed from only two elastomeric layers, with no vertical vias passing betweencontrol lines in different elastomeric layers required. If all verticalflow control lines 94are connected, they may be pressurized from one input. The same is true for all horizontalflow control lines 96.
Biopolymer Synthesis
• The present elastomeric valving structures can also be used in biopolymersynthesis, for example, in synthesizing oligonucleotides, proteins, peptides, DNA, etc. Ina preferred aspect, such biopolymer synthesis systems may comprise an integrated systemcomprising an array of reservoirs, fluidic logic (according to the present invention) for selecting flow from a particular reservoir, an array of channels or reservoirs in whichsynthesis is performed, and fluidic logic (also according to the present invention) fordetermining into which channels the selected reagent flows. An example of such asystem200 is illustrated in Fig. 32, as follows.
• Fourreservoirs 150A, 150B, 150C and 150D have bases A, C, T and Grespectively disposed therein, as shown. Fourflow channels 30A, 30B, 30C and 30D areconnected toreservoirs 150A, 150B, 150C and 150D. Fourcontrol lines 32A, 32B, 32Cand 32D (shown in phantom) are disposed thereacross withcontrol line 32A permittingflow only throughflow channel 30A (i.e.: sealingflow channels 30B, 30C and 30D),whencontrol line 32A is pressurized. Similarly,control line 32B permits flow onlythroughflow channel 30B when pressurized. As such, the selective pressurization ofcontrol lines 32A, 32B, 32C and 32D sequentially selects a desired base A, C, T and Gfrom a desiredreservoir 150A, 150B, 150C or 150D. The fluid then passes throughflowchannel 120 into a multiplexedchannel flow controller 125, (including, for example, anysystem as shown in Figs. 26A to 31D) which in turn directs fluid flow into one or more ofa plurality of synthesis channels orchambers 122A, 122B, 122C, 122D or 122E in whichsolid phase synthesis may be carried out.
• Fig. 33 shows a further extension of this system on which a plurality ofreservoirs R1 to R13 (which may contain bases A, T, C and G, or any other reactants,such as would be used in combinatorial chemistry), are connected tosystems 200 as setforth in Figs. 32.Systems 200 are connected to a multiplexedchannel flow controller125, (including, for example, any system as shown in Figs. 26A to 31D) which is in turnconnected to a switchable flow array (for example as shown in Figs. 31). An advantage ofthis system is that both of multiplexedchannel flow controllers 125 andfluid selectionsystems 200 can be controlled by thesame pressure inputs 170 and 172, provided a"close horizontal" and a "close vertical" control lines (160 and 162, in phantom) are alsoprovided.
• In further alternate aspects of the invention, a plurality of multiplexedchannel flow controllers (such as 125) may be used, with each flow controller initiallypositioned stacked above one another on a different elastomeric layer, with vertical viasor interconnects between the elastomer layers (which may be created by lithographicallypatterning an etch resistant layer on top of a elastomer layer, then etching the elastomerand finally removing the etch resist before adding the last layer of elastomer).
• For example, a vertical via in an elastomer layer can be created by etchinga hole down onto a raised line on a micromachined mold, and bonding the next layer suchthat a channel passes over that hole. In this aspect of the invention, multiple synthesiswith a plurality of multiplexedchannel flow controllers 125 is possible.
• The bonding of successive layers of molded elastomer to form a multi-layerstructure is shown in Fig. 34, which is an optical micrograph of a section of a teststructure composed of seven layers of elastomer. The scale bar of Fig. 34 is 200 µm.
• One method for fabricating an elastomer layer having the vertical viafeature utilized in a multi-layer structure is shown in FIGS. 35A-35D. FIG. 35A showsformation ofelastomer layer 3500 overmicromachined mold 3502 including raisedline3502a.
• FIG. 35B shows formation of metaletch blocking layer 3504 overelastomer layer 3500, followed by the patterning ofphotoresist mask 3506 overetchblocking layer 3504 to covermasked regions 3508 and leave exposed unmaskedregions3510. FIG. 35C shows the exposure to solvent which removesetch blocking layer 3504in unmaskedregions 3510.
• FIG. 35D shows removal of the patterned photoresist, followed bysubsequent etching ofunderlying elastomer 3500 in unmaskedregions 3510 to formvertical via 3512. Subsequent exposure to solvent removes remainingetch blocking layer3504 inmasked regions 3508 selective to the surroundingelastomer 3500 andmold 3502.This elastomer layer may then be incorporated into an elastomer structure by multilayersoft lithography.
• This series of steps can be repeated as necessary to form a multi-layeredstructure having the desired number and orientation of vertical vias between channels ofsuccessive elastomer layers.
• The inventors of the present invention have succeeded in etching viasthrough GE RTV 615 layers using a solution of Tetrabutylammonium fluoride in organicsolvent. Gold serves as the etch blocking material, with gold removed selective to GERTV 615 utilizing a KI/I₂/H₂O mixture.
• Alternatively, vertical vias between channels in successive elastomerlayers could be formed utilizing a negative mask technique. In this approach, a negativemask of a metal foil is patterned, and subsequent formation of an etch blocking layer isinhibited where the metal foil is present. Once the etch blocking material is patterned, the negative metal foil mask is removed, permitting selective etching of the elastomer asdescribed above.
• In yet another approach, vertical vias could be formed in an elastomerlayer using ablation of elastomer material through application of radiation from anapplied laser beam.
• While the above approach is described in connection with the synthesis ofbiopolymers, the invention is not limited to this application. The present invention couldalso function in a wide variety of combinatorial chemical synthesis approaches.
Other Applications:
• Advantageous applications of the present monolithic microfabricatedelastomeric valves and pumps are numerous. Accordingly, the present invention is notlimited to any particular application or use thereof. In preferred aspects, the followinguses and applications for the present invention are contemplated.
1. Cell/DNA Sorting
• The present microfluidic pumps and valves can also be used in flowcytometers for cell sorting and DNA sizing. Sorting of objects based upon size isextremely useful in many technical fields.
• For example, many assays in biology require determination of the size ofmolecular-sized entities. Of particular importance is the measurement of lengthdistribution of DNA molecules in a heterogeneous solution. This is commonly doneusing gel electrophoresis, in which the molecules are separated by their differing mobilityin a gel matrix in an applied electric field, and their positions detected by absorption oremission of radiation. The lengths of the DNA molecules are then inferred from theirmobility.
• While powerful, electrophoretic methods pose disadvantages. For mediumto large DNA molecules, resolution, i.e. the minimum length difference at which differentmolecular lengths may be distinguished, is limited to approximately 10% of the totallength. For extremely large DNA molecules, the conventional sorting procedure is notworkable. Moreover, gel electrophoresis is a relatively lengthy procedure, and mayrequire on the order of hours or days to perform.
• The sorting of cellular-sized entities is also an important task.Conventional flow cell sorters are designed to have a flow chamber with a nozzle and are based on the principle of hydrodynamic focusing with sheath flow. Most conventionalcell sorters combine the technology of piezo-electric drop generation and electrostaticdeflection to achieve droplet generation and high sorting rates. However, this approachoffers some important disadvantages. One disadvantage is that the complexity, size, andexpense of the sorting device requires that it be reusable in order to be cost-effective.Reuse can in turn lead to problems with residual materials causing contamination ofsamples and turbulent fluid flow.
• Therefore, there is a need in the art for a simple, inexpensive, and easilyfabricated sorting device which relies upon the mechanical control of fluid flow ratherthan upon electrical interactions between the particle and the solute.
• FIG. 36 shows one embodiment of a sorting device in accordance with thepresent invention.Sorting device 3600 is formed from a switching valve structure createdfrom channels present in an elastomeric block. Specifically,flow channel 3602 is T-shaped,withstem 3602a offlow channel 3602 in fluid communication withsamplereservoir 3604 containingsortable entities 3606 of different types denoted by shape(square, circle, triangle, etc.).Left branch 3602b offlow channel 3602 is in fluidcommunication withwaste reservoir 3608.Right branch 3602c offlow channel 3602 isin communication withcollection reservoir 3610.
• Control channels 3612a, 3612b, and 3612c overlie and are separated fromstem 3602a offlow channel 3602 byelastomeric membrane portions 3614a, 3614b, and3614c respectively. Together, stem 3602a offlow channel 3602 andcontrol channels3612a, 3612b, and 3612c form firstperistaltic pump structure 3616 similar to thatdescribed at length above in connection with FIG. 24a.
• Control channel 3612d overlies and is separated fromright branch 3602cofflow channel 3602 byelastomeric membrane portion 3614d. Together,right branch3602c offlow channel 3602 andcontrol channels 3612d forms first valve structure 3618a.Control channel 3612e overlies and is separated fromleft branch 3602c offlow channel3602 byelastomeric membrane portion 3614e. Together,left branch 3602c offlowchannel 3602 andcontrol channel 3612e formssecond valve structure 3618b.
• As shown in FIG. 36,stem 3602a offlow channel 3602 narrowsconsiderably as it approachesdetection widow 3620 adjacent to the junction ofstem3602a,right branch 3602b, and leftbranch 3602c.Detection window 3620 is ofsufficient width to allow for uniform illumination of this region. In one embodiment, the width of the stem narrows from 100 µm to 5 µm at the detection window. The width ofthe stem at the detection window can be precisely formed using the soft lithography orphotoresist encapsulation fabrication techniques described extensively above, and will bedepend upon the nature and size of the entity to be sorted.
• Operation of sorting device in accordance with one embodiment of thepresent invention is as follows.
• The sample is diluted to a level such that only a single sortable entitywould be expected to be present in the detection window at any time.Peristaltic pump3616 is activated by flowing a fluid throughcontrol channels 3612a-c as describedextensively above. In addition,second valve structure 3618b is closed by flowing fluidthroughcontrol channel 3612e. As a result of the pumping action ofperistaltic pump3616 and the blocking action ofsecond valve 3618b, fluid flows fromsample reservoir3604 throughdetection window 3620 intowaste reservoir 3608. Because of thenarrowing ofstem 3604, sortable entities present insample reservoir 3604 are carried bythis regular fluid flow, one at a time, throughdetection window 3620.
• Radiation 3640 fromsource 3642 is introduced intodetection window3620. This is possible due to the transmissive property of the elastomeric material.Absorption or emission ofradiation 3640 bysortable entity 3606 is then detected bydetector 3644.
• If sortable entity 3606a withindetection window 3620 is intended to besegregated and collected by sortingdevice 3600, first valve 3618a is activated andsecondvalve 3618b is deactivated. This has the effect of drawing sortable entity 3606a intocollection reservoir 3610, and at the same time transferring second sortable entity 3606bintodetection window 3620. If secondsortable entity 3602b is also identified forcollection,peristaltic pump 3616 continues to flow fluid throughright branch 3602c offlow channel 3602 intocollection reservoir 3610. However, if second entity 3606b is notto be collected, first valve 3618a opens andsecond valve 3618b closes, and firstperistaltic pump 3616 resumes pumping liquid throughleft branch 3602b offlow channel3602 intowaste reservoir 3608.
• While one specific embodiment of a sorting device and a method foroperation thereof is described in connection with FIG. 36, the present invention is notlimited to this embodiment. For example, fluid need not be flowed through the flowchannels using the peristaltic pump structure, but could instead be flowed under pressure with the elastomeric valves merely controlling the directionality of flow. In yet anotherembodiment, a plurality of sorting structures could be assembled in series in order toperform successive sorting operations, with the waste reservoir of FIG. 36 simplyreplaced by the stem of the next sorting structure.
• Moreover, a high throughput method of sorting could be employed,wherein a continuous flow of fluid from the sample reservoir through the window andjunction into the waste reservoir is maintained until an entity intended for collection isdetected in the window. Upon detection of an entity to be collected, the direction of fluidflow by the pump structure is temporarily reversed in order to transport the desiredparticle back through the junction into the collection reservoir. In this manner, the sortingdevice could utilize a higher flow rate, with the ability to backtrack when a desired entityis detected. Such an alternative high throughput sorting technique could be used whenthe entity to be collected is rare, and the need to backtrack infrequent.
• Sorting in accordance with the present invention would avoid thedisadvantages of sorting utilizing conventional electrokinetic flow, such as bubbleformation, a strong dependence of flow magnitude and direction on the composition ofthe solution and surface chemistry effects, a differential mobility of different chemicalspecies, and decreased viability of living organisms in the mobile medium.
2. Semiconductor Processing
• Systems for semiconductor gas flow control, (particularly for epitaxialapplications in which small quantities of gases are accurately metered), are alsocontemplated by the present invention. For example, during fabrication of semiconductordevices solid material is deposited on top of a semiconductor substrate utilizing chemicalvapor deposition (CVD). This is accomplished by exposing the substrate to a mixture ofgas precursor materials, such that these gases react and the resulting product crystallizeson top of the substrate.
• During such CVD processes, conditions must be carefully controlled toensure uniform deposition of material free of defects that could degrade the operation ofthe electrical device. One possible source of nonuniformity is variation in the flow rate ofreactant gases to the region over the substrate. Poor control of the gas flow rate can alsolead to variations in the layer thicknesses from run to run, which is another source oferror. Unfortunately, there has been a significant problem in controlling the amount of gas flowed into the processing chamber, and maintaining stable flow rates in conventionalgas delivery systems.
• Accordingly, FIG. 37A shows one embodiment of the present inventionadapted to convey, at precisely-controllable flow rates, processing gas over the surface ofa semiconductor wafer during a CVD process. Specifically,semiconductor wafer 3700 ispositioned uponwafer support 3702 located within a CVD chamber.Elastomericstructure 3704 containing a large number of evenly distributed orifices 3706 is positionedjust above the surface ofwafer 3700.
• A variety of process gases are flowed at carefully controlled rates fromreservoirs 3708a and 3708b, through flow channels inelastomeric block 3704, and out oforifices 3706. As a result of the precisely controlled flow of process gases abovewafer3700,solid material 3710 having an extremely uniform structure is deposited.
• Precise metering of reactant gas flow rates utilizing valve and/or pumpstructures of the present invention is possible for several reasons. First, gases can beflowed through valves that respond in a linear fashion to an applied actuation pressure, asis discussed above in connection with Figs. 21A and 21B. Alternatively or in addition tometering of gas flow using valves, the predictable behavior of pump structures inaccordance with the present invention can be used to precisely meter process gas flow.
• In addition to the chemical vapor deposition processes described above,the present technique is also useful to control gas flow in techniques such as molecularbeam epitaxy and reactive ion etching.
3. Micro Mirror Arrays
• While the embodiments of the present invention described thus far relateto operation of a structure composed entirely of elastomeric material, the presentinvention is not limited to this type of structure. Specifically, it is within the scope of thepresent invention to combine an elastomeric structure with a conventional, silicon-basedsemiconductor structure.
• For example, further contemplated uses of the present microfabricatedpumps and valves are in optical displays in which the membrane in an elastomericstructure reflects light either as a flat planar or as a curved surface depending uponwhether the membrane is activated. As such, the membrane acts as a switchable pixel.An array of such switchable pixels, with appropriate control circuitry, could be employedas a digital or analog micro mirror array.
• Accordingly, FIG. 38 shows an exploded view of a portion of oneembodiment of a micro mirror array in accordance with the present invention.
• Micro mirror array 3800 includesfirst elastomer layer 3802 overlying andseparated from andunderlying semiconductor structure 3804 bysecond elastomer layer3806. Surface 3804a ofsemiconductor structure 3804 bears a plurality ofelectrodes3810.Electrodes 3810 are individually addressable through conducting row and columnlines, as would be known to one of ordinary skill in the art.
• Firstelastomeric layer 3802 includes a plurality ofintersecting channels3822 underlying an electrically conducting, reflectingelastomeric membrane portion3802a. Firstelastomeric layer 3802 is aligned over secondelastomeric layer 3806 andunderlying semiconductor device 3804 such that points of intersection ofchannels 3822overlie electrodes 3810.
• In one embodiment of a method of fabrication in accordance with thepresent invention, firstelastomeric layer 3822 may be formed by spincoating elastomericmaterial onto a mold featuring intersecting channels, curing the elastomer, removing theshaped elastomer from the mold, and introducing electrically conducting dopant intosurface region of the shaped elastomer. Alternatively as described in connection withFigs. 7C-7G above, firstelastomeric layer 3822 may be formed from two layers ofelastomer by inserting elastomeric material into a mold containing intersecting channelssuch that the elastomeric material is flush with the height of the channel walls, and thenbonding a separate doped elastomer layer to the existing elastomeric material to form amembrane on the top surface.
• Alternatively, the firstelastomeric layer 3802 may be produced fromelectrically conductive elastomer, where the electrical conductivity is due either to dopingor to the intrinsic properties of the elastomer material.
• During operation of reflectingstructure 3800, electrical signals arecommunicated along a selected row line and column line to electrode 3810a. Applicationof voltage to electrode 3810a generates an attractive force between electrode 3810a andoverlying membrane 3802a. This attractive force actuates a portion ofmembrane 3802a,causing this membrane portion to flex downward into the cavity resulting fromintersection of thechannels 3822. As a result of distortion ofmembrane 3802a fromplanar to concave, light is reflected differently at this point in the surface ofelastomerstructure 3802 than from the surrounding planar membrane surface. A pixel image isthereby created.
• The appearance of this pixel image is variable, and may be controlled byaltering the magnitude of voltage applied to the electrode. A higher voltage applied to theelectrode will increase the attractive force on the membrane portion, causing furtherdistortion in its shape. A lower voltage applied to the electrode will decrease theattractive force on the membrane, reducing distortion in its shape from the planar. Eitherof these changes will affect the appearance of the resulting pixel image.
• A variable micro mirror array structure as described could be used in avariety of applications, including the display of images. Another application for avariable micro mirror array structure in accordance with an embodiment of the presentinvention would be as a high capacity switch for a fiber optics communications system,with each pixel capable of affecting the reflection and transfer of a component of anincident light signal.
5. Refracting Structures
• The micro-mirror array structure just described controls reflection ofincident light. However, the present invention is not limited to controlling reflection. Yetanother embodiment of the present invention enables the exercise of precise control overrefraction of incident light in order to create lens and filter structures.
• FIG. 39 shows one embodiment of a refractive structure in accordancewith the present invention.Refractive structure 3900 includes firstelastomeric layer3902 and secondelastomeric layer 3904 composed of elastomeric material capable oftransmitting incident light 3906.
• Firstelastomeric layer 3902 hasconvex portion 3902a which may becreated by curing elastomeric material formed over a micromachined mold having aconcave portion. Secondelastomeric layer 3904 has aflow channel 3905 and may becreated from a micromachined mold having a raised line as discussed extensively above.
• First elastomer layer 3902 is bonded tosecond elastomer layer 3904 suchthatconvex portion 3902a is positioned aboveflow channel 3905. This structure canserve a variety of purposes.
• For example, light incident toelastomeric structure 3900 would be focusedinto the underlying flow channel, allowing the possible conduction of light through theflow channel. Alternatively, in one embodiment of an elastomeric device in accordancewith the present invention, fluorescent or phosphorescent liquid could be flowed through the flow channel, with the resulting light from the fluid refracted by the curved surface toform a display.
• FIG. 40 shows another embodiment of a refractive structure in accordancewith the present invention.Refractive structure 4000 is a multilayer optical train basedupon a Fresnel lens design. Specifically,refractive structure 4000 is composed of foursuccessive elastomer layers 4002, 4004, 4006, and 4008, bonded together. The uppersurfaces of each of first, second, andthird elastomer layers 4002, 4004, and 4006bearuniform serrations 4010 regularly spaced by a distance X that is much larger than thewavelength of the incident light.Serrations 4010 serve to focus the incident light, andmay be formed through use of a micromachined mold as described extensively above.First, second, andthird elastomer layers 4002, 4004, and 4006 function as Fresnel lensesas would be understood of one of ordinary skill in the art.
• Fourthelastomeric layer 4008 bearsuniform serrations 4012 having amuch smaller size than the serrations of the overlying elastomeric layers.Serrations 4012are also spaced apart by a much smaller distance Y than the serrations of the overlyingelastomeric layers, with Y on the order of the wavelength of incident light. such thatelastomeric layer 4008 functions as a diffraction grating.
• FIG. 41 illustrates an embodiment of a refractive structure in accordancewith the present invention which utilizes difference in material refractive index toprimarily accomplish diffraction.Refractive structure 4100 includes lowerelastomericportion 4102 covered by upper elastomeric portion 4104. Both lowerelastomeric portion4102 and upper elastomeric portion 4104 are composed of material transmittingincidentlight 4106. Lowerelastomeric portion 4102 includes a plurality of serpentine flowchannels 4108 separated byelastomeric lands 4110. Flow channels 4108 include fluid4112 having a different refractive index than the elastomeric material making uplands4110. Fluid 4112 is pumped through serpentine flow channels 4108 by the operation ofpump structure 4114 made up of parallel control channels 4116a and 4116b overlying andseparated from inlet portion 4108a of flow channel 4108 bymoveable membrane 4118.
• Light 4106 incident torefractive structure 4100 encounters a series ofuniformly-spaced fluid-filled flow channels 4108 separated byelastomeric lands 4110.As a result of the differing optical properties of material present in these respectivefluid/elastomer regions, portions of the incident light are not uniformly refracted andinteract to form an interference pattern. A stack of refractive structures of the manner justdescribed can accomplish even more complex and specialized refraction of incident light.
• The refractive elastomeric structures just described can fulfill a variety ofpurposes. For example, the elastomeric structure could act as a filter or optical switch toblock selected wavelengths of incident light. Moreover, the refractive properties of thestructure could be readily adjusted depending upon the needs of a particular application.
• For example, the composition (and hence refractive index) of fluid flowedthrough the flow channels could be changed to affect diffraction. Alternatively, or inconjunction with changing the identity of the fluid flowed, the distance separatingadjacent flow channels can be precisely controlled during fabrication of the structure inorder to generate an optical interference pattern having the desired characteristics.
6. Normally-Closed Valve Structure
• FIGS. 7B and 7H above depict a valve structure in which the elastomericmembrane is moveable from a first relaxed position to a second actuated position inwhich the flow channel is blocked. However, the present invention is not limited to thisparticular valve configuration.
• FIGS. 42A-42J show a variety of views of a normally-closed valvestructure in which the elastomeric membrane is moveable from a first relaxed positionblocking a flow channel, to a second actuated position in which the flow channel is open,utilizing a negative control pressure.
• FIG. 42A shows a plan view, and FIG. 42B shows a cross sectional viewalongline 42B-42B', of normally-closedvalve 4200 in an unactuated state.Flow channel4202 andcontrol channel 4204 are formed inelastomeric block 4206overlying substrate4205.Flow channel 4202 includes afirst portion 4202a and asecond portion 4202bseparated by separatingportion 4208.Control channel 4204 overlies separatingportion4208. As shown in FIG. 42B, in its relaxed, unactuated position, separatingportion 4008remains positioned betweenflow channel portions 4202a and 4202b, interruptingflowchannel 4202.
• FIG. 42C shows a cross-sectional view ofvalve 4200 wherein separatingportion 4208 is in an actuated position. When the pressure withincontrol channel 4204 isreduced to below the pressure in the flow channel (for example by vacuum pump),separatingportion 4208 experiences an actuating force drawing it intocontrol channel4204. As a result of thisactuation force membrane 4208 projects intocontrol channel4204, thereby removing the obstacle to a flow of material throughflow channel 4202 andcreating apassageway 4203. Upon elevation of pressure withincontrol channel 4204, separatingportion 4208 will assume its natural position, relaxing back into andobstructingflow channel 4202.
• The behavior of the membrane in response to an actuation force may bechanged by varying the width of the overlying control channel. Accordingly, FIGS. 42D-42Hshow plan and cross-sectional views of an alternative embodiment of a normally-closedvalve 4201 in whichcontrol channel 4207 is substantially wider than separatingportion 4208. As shown in cross-sectional views Fig. 42E-F alongline 42E-42E' of Fig.42D, because a larger area of elastomeric material is required to be moved duringactuation, the actuation force necessary to be applied is reduced.
• FIGS. 42G and H show a cross-sectional views along line 40G-40G' ofFig. 40D. In comparison with the unactuated valve configuration shown in FIG. 42G,FIG. 42H shows that reduced pressure withinwider control channel 4207 may undercertain circumstances have the unwanted effect of pullingunderlying elastomer 4206away fromsubstrate 4205, thereby creatingundesirable void 4212.
• Accordingly, Fig. 421 shows a plan view, and 42J a cross-sectional viewalongline 42J-42J' of Fig. 421, ofvalve structure 4220 which avoids this problem byfeaturingcontrol line 4204 with a minimum width except in segment 4204a overlappingseparatingportion 4208. As shown in Fig. 42J, even under actuated conditions thenarrower cross-section ofcontrol channel 4204 reduces the attractive force on theunderlying elastomer material 4206, thereby preventing this elastomer material frombeing drawn away fromsubstrate 4205 and creating an undesirable void.
• While a normally-closed valve structure actuated in response to pressure isshown in Figs. 42A-42J, a normally-closed valve in accordance with the present inventionis not limited to this configuration. For example, the separating portion obstructing theflow channel could alternatively be manipulated by electric or magnetic fields, asdescribed extensively above.
7. Separation of Materials
• In a further application of the present invention, an elastomeric structurecan be utilized to perform separation of materials. Fig. 43 shows one embodiment ofsuch a device.
• Separation device 4300 features anelastomeric block 4301 includingfluidreservoir 4302 in communication withflow channel 4304. Fluid is pumped from fluidreservoir 4306 through flow channel 4308 byperistaltic pump structure 4310 formed bycontrol channels 4312overlying flow channel 4304, as has been previously described atlength. Alternatively, where a peristaltic pump structure in accordance with the presentinvention is unable to provide sufficient back pressure, fluid from a reservoir positionedoutside the elastomeric structure may be pumped into the elastomeric device utilizing anexternal pump.
• Flow channel 4304 leads toseparation column 4314 in the form of achannel packed withseparation matrix 4316 behindporous frit 4318. As is well known inthe art of chromatography, the composition of theseparation matrix 4316 depends uponthe nature of t32ehe materials to be separated and the particular chromatographytechnique employed. The elastomeric separation structure is suitable for use with avariety of chromatographic techniques, including but not limited to gel exclusion, gelpermeation, ion exchange, reverse phase, hydrophobic interaction, affinitychromatography, fast protein liquid chromatography (FPLC) and all formats of highpressure liquid chromatography (HPLC). The high pressures utilized for HPLC mayrequire the use of urethane, dicyclopentadiene or other elastomer combinations.
• Samples are introduced into the flow of fluid intoseparation column 4314utilizingload channel 4319.Load channel 4319 receives fluid pumped fromsamplereservoir 4320 throughpump 4321. Upon opening ofvalve 4322 and operation ofpump4321, sample is flowed fromload channel 4319 intoflow channel 4304. The sample isthen flowed throughseparation column 4314 by the action ofpump structure 4312. As aresult of differential mobility of the various sample components inseparation matrix4316, these sample components become separated and are eluted fromcolumn 4314 atdifferent times.
• Upon elution fromseparation column 4314, the various samplecomponents pass intodetection region 4324. As is well known in the art ofchromatography, the identity of materials eluted intodetection region 4324 can bedetermined utilizing a variety of techniques, including but not limited to fluorescence,UV/visible/IR spectroscopy, radioactive labeling, amperometric detection, massspectroscopy, and nuclear magnetic resonance (NMR).
• A separation device in accordance with the present invention offers theadvantage of extremely small size, such that only small volumes of fluid and sample areconsumed during the separation. In addition, the device offers the advantage of increasedsensitivity. In conventional separation devices, the size of the sample loop will prolongthe injection of the sample onto the column, causing width of the eluted peaks to potentially overlap with one another. The extremely small size and capacity of the loadchannel in general prevents this peak diffusion behavior from becoming a problem.
• The separation structure shown in Fig. 43 represents only one embodimentof such a device, and other structures are contemplated by the present invention. Forexample, while the separation device of Fig. 43 features a flow channel, load loop, andseparation column oriented in a single plane, this is not required by the present invention.One or more of the fluid reservoir, the sample reservoir, the flow channel, the load loop,and the separation column could be oriented perpendicular to one another and/or to theplane of the elastomeric material utilizing via structures whose formation is described atlength above in connection with Fig. 35A-D.
8. Cell Pen/Cell Cage/Cell Grinder
• In yet a further application of the present invention, an elastomericstructure can be utilized to manipulate organisms or other biological material. Figs. 44A-44Dshow plan views of one embodiment of a cell pen structure in accordance with thepresent invention.
• Cell pen array 4400 features an array of orthogonally-orientedflowchannels 4402, with an enlarged "pen"structure 4404 at the intersection of alternatingflow channels.Valve 4406 is positioned at the entrance and exit of eachpen structure4404.Peristaltic pump structures 4408 are positioned on each horizontal flow channeland on the vertical flow channels lacking a cell pen structure.
• Cell pen array 4400 of Fig. 44A has been loaded with cells A-H that havebeen previously sorted, perhaps by a sorting structure as described above in conjunctionwith Fig. 36. Figs. 44B-44C show the accessing and removal of individually stored cell Cby 1) openingvalves 4406 on either side ofadjacent pens 4404a and 4404b, 2) pumpinghorizontal flow channel 4402a to displace cells C and G, and then 3) pumpingverticalflow channel 4402b to remove cell C. Fig. 44D shows that second cell G is moved backinto its prior position incell pen array 4400 by reversing the direction of liquid flowthroughhorizontal flow channel 4402a.
• Thecell pen array 4404 described above is capable of storing materialswithin a selected, addressable position for ready access. However, living organisms suchas cells may require a continuous intake of foods and expulsion of wastes in order toremain viable. Accordingly, Figs. 45A and 45B show plan and cross-sectional views (alongline 45B-45B') respectively, of one embodiment of a cell cage structure inaccordance with the present invention.
• Cell cage 4500 is formed as anenlarged portion 4500a of aflow channel4501 in anelastomeric block 4503 in contact withsubstrate 4505.Cell cage 4500 issimilar to an individual cell pen as described above in Figs. 44A-44D, except that ends4500b and 4500c ofcell cage 4500 do not completely encloseinterior region 4500a.Rather, ends 4500a and 4500b ofcage 4500 are formed by a plurality ofretractable pillars4502.Pillars 4502 may be part of a membrane structure of a normally-closed valvestructure as described extensively above in connection with Figs. 42A-42J.
• Specifically,control channel 4504 overliespillars 4502. When thepressure incontrol channel 4504 is reduced,elastomeric pillars 4502 are drawn upwardintocontrol channel 4504, thereby openingend 4500b ofcell cage 4500 and permitting acell to enter. Upon elevation of pressure incontrol channel 4504,pillars 4502 relaxdownward againstsubstrate 4505 and prevent a cell from exitingcage 4500.
• Elastomeric pillars 4502 are of a sufficient size and number to preventmovement of a cell out ofcage 4500, but also includegaps 4508 which allow the flow ofnutrients into cage interior 4500a in order to sustain cell(s) stored therein.Pillars 4502 onopposite end 4500c are similarly configured beneathsecond control channel 4506 topermit opening of the cage and removal of the cell as desired.
• Under certain circumstances, it may be desirable to grind/disrupt cells orother biological materials in order to access component pieces.
• Accordingly, Figs. 46A and 46B show plan and cross sectional views(alongline 46B-46B') respectively, of one embodiment ofcell grinder structure 4600 inaccordance with the present invention.Cell grinder 4600 includes a system ofinterdigitated posts 4602 withinflow channel 4604 which close together upon actuationofintegral membrane 4606 by overlyingcontrol channel 4608. By closing together,posts4602 crush material present between them.
• Posts 4602 may be spaced at intervals appropriate to disrupt entities (cells)of a given size. For disruption of cellular material, spacing ofposts 4602 at an interval ofabout 2 µm is appropriate. In alternative embodiments of a cell grinding structure inaccordance with the present invention,posts 4602 may be located entirely on the above-lyingmembrane, or entirely on the floor of the control channel.
9. Pressure Oscillator
• In yet a further application of the present invention, an elastomericstructure can be utilized to create a pressure oscillator structure analogous to oscillatorcircuits frequently employed in the field of electronics. Fig. 47 shows a plan view of oneembodiment of such a pressure oscillator structure.
• Pressure oscillator 4700 comprises anelastomeric block 4702 featuringflow channel 4704 formed therein.Flow channel 4704 includes an initial portion 4704aproximate to pressuresource 4706, and aserpentine portion 4704b distal frompressuresource 4706. Initial portion 4704a is in contact with via 4708 in fluid communicationwithcontrol channel 4710 formed inelastomeric block 4702 above the level offlowchannel 4704. At a location more distal frompressure source 4706 than via 4708,controlchannel 4710 overlies and is separated fromflow channel 4704 by an elastomericmembrane, thereby formingvalve 4712 as previously described.
• Pressure oscillator structure 4700 operates as follows. Initially,pressuresource 4706 provides pressure alongflow channel 4704 andcontrol channel 4710 throughvia 4708. Because of the serpentine shape offlow channel 4704b, pressure is lower inregion 4704b as compared withflow channel 4710. Atvalve 4712, the pressuredifference between serpentineflow channel portion 4704b andoverlying control channel4710 eventually causes the membrane ofvalve 4712 to project downward into serpentineflow channel portion 4704b, closingvalve 4712. Owing to the continued operation ofpressure source 4706 however, pressure begins to build up in serpentineflow channelportion 4704b behindclosed valve 4712. Eventually the pressure equalizes betweencontrol channel 4710 and serpentineflow channel portion 4704b, andvalve 4712 opens.
• Given the continuos operation of the pressure source, the above-describedbuild up and release of pressure will continue indefinitely, resulting in a regularoscillation of pressure. Such a pressure oscillation device may perform any number ofpossible functions, including but not limited to timing.
9. Side-Actuated Valve
• While the above description has focused upon microfabricated elastomericvalve structures in which a control channel is positioned above and separated by anintervening elastomeric membrane from an underlying flow channel, the presentinvention is not limited to this configuration. Figs. 48A and 48B show plan views of one embodiment of a side-actuated valve structure in accordance with one embodiment of thepresent invention.
• Fig. 48A shows side-actuatedvalve structure 4800 in an unactuatedposition.Flow channel 4802 is formed inelastomeric layer 4804.Control channel 4806abuttingflow channel 4802 is also formed inelastomeric layer 4804.Control channel4806 is separated fromflow channel 4802 byelastomeric membrane portion 4808. Asecond elastomeric layer (not shown) is bonded over bottomelastomeric layer 4804 toencloseflow channel 4802 andcontrol channel 4806.
• Fig. 48B shows side-actuatedvalve structure 4800 in an actuated position.In response to a build up of pressure withincontrol channel 4806,membrane 4808deforms intoflow channel 4802, blockingflow channel 4802. Upon release of pressurewithincontrol channel 4806,membrane 4808 would relax back intocontrol channel 4806andopen flow channel 4802.
• While a side-actuated valve structure actuated in response to pressure isshown in Figs. 48A and 48B, a side-actuated valve in accordance with the presentinvention is not limited to this configuration. For example, the elastomeric membraneportion located between the abutting flow and control channels could alternatively bemanipulated by electric or magnetic fields, as described extensively above.
10. Additional Applications
• The following represent futher aspects of the present invention: presentvalves and pumps can be used for drug delivery (for example, in an implantable drugdelivery device); and for sampling of biological fluids (for example, by storing samplessequentially in a column with plugs of spacer fluid therebetween, wherein the samplescan be shunted into different storage reservoirs, or passed directly to appropriatesensor(s). Such a fluid sampling device could also be implanted in the patient's body.
• The present systems can also be used for devices which relieve overpressurein vivo using a micro-valve or pump. For example, an implantable bio-compatiblemicro-valve can be used to relieve over-pressures in the eye which result fromglaucoma. Other contemplated uses of the present switchable micro-valves includeimplantation in the spermatic duct or fallopian tube allowing reversible long-term orshort-term birth control without the use of drugs.
• Further uses of the present invention include DNA sequencing wherebythe DNA to be sequenced is provided with a polymerase and a primer, and is then exposed to one type of DNA base (A, C, T, or G) at a time in order to rapidly assay forbase incorporation. In such a system, the bases must be flowed into the system and excessbases washed away rapidly. Pressure driven flow, gated by elastomeric micro-valves inaccordance with the present invention would be ideally suited to allow for such rapid flowand washing of reagents.
• Other contemplated uses of the present micro-valve and micro-pumpsystems include uses with DNA chips. For example, a sample can be flowed into alooped channel and pumped around the loop with a peristaltic action such that the samplecan make many passes over the probes of the DNA array. Such a device would give thesample that would normally be wasted sitting over the non-complimentary probes thechance to bind to a complimentary probe instead. An advantage of such a looped-flowsystem is that it would reduce the necessary sample volume, and thereby increase assaysensitivity.
• Further applications exist in high throughput screening in whichapplications could benefit by the dispensing of small volumes of liquid, or by bead-basedassays wherein ultrasensitive detection would substantially improve assay sensitivity.
• Another contemplated application is the deposition of array of variouschemicals, especially oligonucleotides, which may or may not have been chemicallyfabricated in a previous action of the device before deposition in a pattern or array on asubstrate via contact printing through fluid channel outlets in the elastomeric device inclose proximity to a desired substrate, or by a process analogous to ink-jet printing.
• The present microfabricated elastomeric valves and pumps could also beused to construct systems for reagent dispensing, mixing and reaction for synthesis ofoligonucleotides, peptides or other biopolymers.
• Further applications for the present invention include ink jet printer heads,in which small apertures are used to generate a pressure pulse sufficient to expel adroplet. An appropriately actuated micro-valve in accordance with the present inventioncan create such a pressure pulse. The present micro-valves and pumps can also be used todigitally dispense ink or pigment, in amounts not necessarily as small as single droplets.The droplet would be brought into contact with the medium being printed on rather thanbe required to be fired through the air.
• Yet other uses of the present systems are in fluidic logic circuits whichoffer the advantages of being useable in radiation resistant applications. A further advantage of such fluidic logic circuits is that, being non-electronic, such fluidic logiccircuitry may not be probed by electro magnetic sensors, thus offering a security benefit.
• Yet further uses of the present invention would take advantage of the readyremoval and reattachment of the structure from an underlying substrate such as glass,utilizing a glass substrate patterned with a binding or other material. This allows separateconstruction of a patterned substrate and elastomer structure. For instance, a glasssubstrate could be patterned with a DNA microarray, and an elastomer valve and pumpstructure sealed over the array in a subsequent step.
11. Additional Aspects of the Invention
• The following represent further aspects of the present invention: the use ofa deflectable membrane to control flow of a fluid in a microfabricated channel of anelastomeric structure; the use of elastomeric layers to make a microfabricated elastomericdevice containing a microfabricated movable portion; and the use of an elastomericmaterial to make a microfabricated valve or pump.
• A microfabricated elastomeric structure in accordance with oneembodiment of the present invention comprises an elastomeric block formed withmicrofabricated recesses therein, a portion of the elastomeric block deflectable when theportion is actuated. The recesses comprise a first microfabricated channel and a firstmicrofabricated recess, and the portion comprises an elastomeric membrane deflectableinto the first microfabricated channel when the membrane is actuated. The recesses havea width in the range of 10 µm to 200 µm and the portion has a thickness of between about2 µm and 50 µm. The microfabricated elastomeric structure may be actuated at a speedof 100 Hz or greater and contains substantially no dead volume when the portion isactuated.
• A method of actuating an elastomeric structure comprises providing anelastomeric block formed with first and second microfabricated recesses therein, the firstand second microfabricated recesses separated by a membrane portion of the elastomericblock deflectable into one of the first and second recesses in response to an actuationforce, and applying an actuation force to the membrane portion such that the membraneportion is deflected into one of the first and the second recesses.
• A method of microfabricating an elastomeric structure in accordance withone embodiment of the present invention comprises forming a first elastomeric layer on a substrate, curing the first elastomeric layer, and patterning a first sacrificial layer over thefirst elastomeric layer. A second elastomeric layer is formed over the first elastomericlayer, thereby encapsulating the first patterned sacrificial layer between the first andsecond elastomeric layers, the second elastomeric layer is cured, and the first patternedsacrificial layer is removed selective to the first elastomeric layer and the secondelastomeric layer, thereby forming at least one first recess between the first and secondlayers of elastomer.
• An alternative embodiment of a method of fabricating further comprisespatterning a second sacrificial layer over the substrate prior to forming the firstelastomeric layer, such that the second patterned sacrificial layer is removed duringremoval of the first patterned sacrifical layer to form at least one recess along a bottom ofthe first elastomeric layer.
• A microfabricated elastomeric structure in accordance with oneembodiment of the present invention comprises an elastomeric block, a first channel and asecond channel separated by a separating portion of the elastomeric structure, and amicrofabricated recess in the elastomeric block adjacent to the separating portion suchthat the separating portion may be actuated to deflect into the microfabricated recess. 66.Deflection of the separating portion opens a passageway between the first and secondchannels.
• A method of controlling fluid or gas flow through an elastomeric structurecomprises providing an elastomeric block, the elastomeric block having first, second, andthird microfabricated recesses, and the elastomeric block having a first microfabricatedchannel passing therethrough, the first, second and third microfabricated recessesseparated from the first channel by respective first, second and third membranesdeflectable into the first channel, and deflecting the first, second and third membranesinto the first channel in a repeating sequence to peristaltically pump a flow of fluidthrough the first channel.
• A method of microfabricating an elastomeric structure, comprisingmicrofabricating a first elastomeric layer, microfabricating a second elastomeric layer;positioning the second elastomeric layer on top of the first elastomeric layer; and bondinga bottom surface of the second elastomeric layer onto a top surface of the first elastomericlayer.
• While the present invention has been described herein with reference toparticular embodiments thereof, a latitude of modification, various changes and substitutions are intended in the foregoing disclosure, and it will be appreciated that insome instances some features of the invention will be employed without a correspondinguse of other features without departing from the scope of the invention as set forth.Therefore, many modifications may be made to adapt a particular situation or material tothe teachings of the invention without departing from the essential scope and spirit of thepresent invention. It is intended that the invention not be limited to the particularembodiment disclosed as the best mode contemplated for carrying out this invention, butthat the invention will include all embodiments and equivalents falling within the scopeof the claims.
• Incorporated herein as part of the present specification is the entirecontents of Appendix A, "Monolithic Microfabricated Valves and Pumps by MultilayerSoft Lithography", Unger et al.,Science, Vol. 288, pp. 113-116 (April 7, 2000), whichappears herein before the claims and which is to be construed as part of the presentspecification for all purposes.

  

  

  

  

Claims (33)

1. A microfabricated elastomeric structure, comprising:

   an elastomeric block formed with microfabricated recesses therein, aportion of the elastomeric block deflectable when the portion is actuated.
2. The microfabricated elastomeric structure of claim 1 wherein therecesses have a width in the range of 10 µm to 200 µm.
3. The microfabricated elastomeric structure of claim 1, wherein theportion has a thickness of between about 2 µm and 50 µm.
4. The microfabricated elastomeric structure of claim 1, wherein theportion responds linearly to an applied actuation force.
5. The microfabricated elastomeric structure of claim 1 wherein:

   the recesses comprise a first microfabricated channel and a secondmicrofabricated channel; and

   the portion comprises an elastomeric membrane deflectable into either ofthe first or second microfabricated channels when the membrane is actuated.
6. A microfabricated elastomeric structure of claim 1 wherein;

   the recesses comprise a first microfabricated channel and a firstmicrofabricated recess; and

   the portion comprises an elastomeric membrane deflectable into the firstmicrofabricated channel when the membrane is actuated.
7. A microfabricated elastomeric structure of claim 6 wherein the firstmicrofabricated recess comprises a second microfabricated channel.
8. The microfabricated elastomeric structure of claim 6 wherein themembrane is deflectable into the first channel when the first microfabricated recess ispressurized.
9. The microfabricated elastomeric structure of claim 7, furthercomprising:

   third and fourth channels disposed parallel to the second channel, whereinthe second, third and fourth channels are separated from the first channel by first, secondand third membranes respectively, deflectable into the first channel.
10. The microfabricated elastomeric structure of claim 9, wherein thefirst, second, and third membranes are deflectable into the first channel when the second,third and fourth channels, respectively, are pressurized.
11. The microfabricated elastomeric structure of claim 7 furthercomprising a third microfabricated channel parallel to the first channel, the secondchannel having both wide and narrow portions disposed along its length, with a wideportion being disposed adjacent the first channel and a narrow portion being disposedadjacent the third channel.
12. The microfabricated elastomeric structure of claim 6 wherein themembrane has a curved bottom surface such that the top of the first channel is curved.
13. The microfabricated elastomeric structure of claim 1 wherein theelastomeric structure comprises a material selected from the group consisting of:

    polyisoprene, polybutadiene, polychloroprene, polyisobutylene,poly(styrene-butadiene-styrene), the polyurethanes, and silicones.
14. The microfabricated elastomeric structure of claim 1 wherein theelastomeric structure comprises a material selected from the group consisting of:

    poly(bis(fluoroalkoxy)phosphazene) (PNF, Eypel-F), poly(carborane-siloxanes)(Dexsil), poly(acrylonitrile-butadiene) (nitrile rubber), poly(1-butene),poly(chlorotrifluoroethylene-vinylidene fluoride) copolymers (Kel-F), poly(ethyl vinylether), poly(vinylidene fluoride), poly(vinylidene fluoride - hexafluoropropylene)copolymer (Viton).
15. The microfabricated elastomeric structure of claim 1 wherein theelastomeric structure comprises a material selected from the group consisting of:

    elastomer compositions of polyvinylchloride (PVC), polysulfone,polycarbonate, polymethylmethacrylate (PMMA), or polytertrafluoroethylene (Teflon).
16. The microfabricated elastomeric structure of claim 13 wherein theelastomeric structure comprises a material selected from the group consisting of:

    polydimethylsiloxane (PDMS) such as General Electric RTV 615, DowChemical Corp. Sylgard 182, 184, or 186, and aliphatic urethane diacrylates such asEbecryl 270 or Irr 245 from UCB Chemicals.
17. A method of actuating an elastomeric structure comprising:

    providing an elastomeric block formed with first and secondmicrofabricated recesses therein, the first and second microfabricated recesses separatedby a membrane portion of the elastomeric block deflectable into one of the first andsecond recesses in response to an actuation force; and

    applying an actuation force to the membrane portion such that themembrane portion is deflected into one of the first and the second recesses.
18. The method of claim 17 wherein the step of applying an actuationforce comprises applying a pressure to the second microfabricated recess to deflect themembrane portion into the first microfabricated recess.
19. A method of controlling fluid or gas flow through an elastomericstructure comprising:

    providing an elastomeric block, the elastomeric block having first, second,and third microfabricated recesses, and the elastomeric block having a firstmicrofabricated channel passing therethrough, the first, second and third microfabricatedrecesses separated from the first channel by respective first, second and third membranesdeflectable into the first channel; and

    deflecting the first, second and third membranes into the first channel in arepeating sequence to peristaltically pump a flow of fluid through the first channel.
20. The method of claim 19 wherein the first, second and thirdmembranes are deflected into the first channel by increasing pressure within the first,second and third channels.
21. A method of microfabricating an elastomeric structure, comprising:

    microfabricating a first elastomeric layer;

    microfabricating a second elastomeric layer;

    positioning the second elastomeric layer on top of the first elastomericlayer; and

    bonding a bottom surface of the second elastomeric layer onto a topsurface of the first elastomeric layer.
22. The method of claim 21 wherein:

    the first elastomeric layer is fabricated on a first micromachined moldhaving at least one raised protrusion which forms at least one recess in the bottom of thefirst elastomeric layer; and

    the second elastomeric layer is fabricated on a second micromachinedmold having at least one raised protrusion which forms at least one recess in the bottomof the first elastomeric layer.
23. The method of claim 21 further comprising:

    sequential addition of further elastomeric layers, whereby each layer isadded by:

    microfabricating a successive elastomeric layer; and

    bonding the bottom surface of the successive elastomeric layer onto a topsurface of the elastomeric structure.
24. A method of microfabricating an elastomeric structure comprising:

    providing a first microfabricated elastomeric structure;

    providing a second microfabricated elastomeric structure; and

    bonding a surface of the first elastomeric structure onto a surface of thesecond elastomeric structure.
25. The method of claim 21 wherein the first and second elastomericlayers are made of the same material.
26. The method of claim 25 wherein both the first and secondelastomeric layers comprise a crosslinking agent.
27. The method of claim 21 wherein the first and second layers arebonded by a layer of adhesive.
28. The method of claim 27 wherein the adhesive comprises anuncured elastomer which is cured to bond the first and second elastomeric layers together.
29. The use of a deflectable membrane to control flow of a fluid in amicrofabricated channel of an elastomeric structure.
30. The use of elastomeric layers to make a microfabricated elastomericdevice containing a microfabricated movable portion.
31. The use of an elastomeric material to make a microfabricated valve orpump.
32. The microfabricated elastomeric structure of claim 1, wherein theportion is actuated at a speed of 100 Hz or greater.
33. The microfabricated elastomeric structure of claim 1, wherein thestructure contains substantially no dead volume when the portion is actuated.

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