Abstract:
By use of the vias a microfluidic autoregulator is fabricated comprising an origin of a fluid, a sink for the fluid, a main flow channel coupling the origin and the sink, a valve communicated to the main flow channel to selectively control flow of fluid therethrough, and means dependent on flow through the main flow channel for creating a pressure differential across the valve to at least partially activate the valve to control flow of fluid through the main flow channel. The means for dependent on flow for creating a pressure differential comprises either a dead-end detour channel from the flow channel to the valve, or a loop channel fed back to the control chamber of the valve.

Description:
RELATED APPLICATIONS  
       [0001]     The present application is related to U.S. Provisional Patent Applications: Ser. No. 60/740,988, filed on Nov. 30, 2005 and Ser. No. 60/764,245, filed on Feb. 1, 2006, each of which are incorporated herein by reference and to which priority is claimed pursuant to 35 USC 119. 
     
    
     BACKGROUND OF THE INVENTION  
       [0002]     1. Field of the Invention  
         [0003]     The invention relates to the field of microfluidic devices with nonlinear responses.  
         [0004]     2. Description of the Prior Art  
         [0005]     Microfluidics is a technology that is establishing itself as an innovative practical tool in biological and biomedical research. Microfluidics offers the advantages of economy of reagents, small sample handling, portability, and speed. PDMS (polydimethylsiloxane) microfluidics in particular also offers industrial up-scalability, parallel fabrication, and a unique capability for complex fluid handling schemes through fluidic networks containing integrated valves and pumps.  
         [0006]     Up to now, the configuration of such devices fell into two distinct categories, “pushup” and “pushdown” devices as shown in side cross-sectional view in  FIGS. 1   a  and  1   b  depending on which direction the microvalve membranes deflected to shut off reagent flow. Both types of devices have advantages and disadvantages, which limit their usefulness in specific applications. For example, pushdown devices are used in applications where the reagents need to access the glass surface of the substrate, e.g. when chips are aligned on top of DNA or protein microarrays printed on the glass substrate. On the other hand, pushup devices allow the practical valving of significantly deeper reagent channels (˜40 μm instead of ˜10 μm), e.g. in applications involving mammalian cells. It is clear then that none of the available configurations is usable in applications demanding both deep channels and access to the glass substrate, e.g. on-chip mammalian cells expression analysis by printed microarrays. Finally, in both currently available configurations, the reagent flow is restricted to two dimensions, which severely limits the attainable device complexity.  
         [0007]     Over the decade of its existence, PDMS (polydimethylsiloxane) microfluidics has progressed from the plain microchannel (1) through pneumatic valves and pumps to an impressive set of specialized components organized by the thousands in multilayer large-scale-integration devices. These devices have become the hydraulic elastomeric embodiment of Richard Feynman&#39;s dreams of infinitesimal machines. The now established technology has found successful application in protein crystallization, DNA sequencing, nanoliter PCR, cell sorting and cytometry, nucleic acids extraction and purification, immunoassays, cell studies, and chemical synthesis, while also sewing as the fluid handling component in emerging integrated MEMS (microelectromechanical) devices.  
         [0008]     The prior art has developed an ingenious scheme wherein a complex system of multilayer photoresist molds, photoresist pre-masters, and PDMS masters were fabricated and then used in an involved many-step process to produce a 70 μm-thick PDMS layer with 100 μm-wide vertical cylinders connecting 70 μm-tall channels fabricated in thick PDMS slabs. The resulting three dimensional technique was successfully used in protein and cell patterning, but the challenging and labor-intensive fabrication of the devices has largely dissuaded researchers from further work along the same path.  
         [0009]     The energetic pursuit of applications however has resulted in a premature attention shift away from fundamental microfluidics. What is needed is a fundamental technological advance that allows a simple and easy access to a large increase in the architectural complexity of microfluidic devices, as well as new possibilities for technical developments and consequent applications.  
       BRIEF SUMMARY OF THE INVENTION  
       [0010]     The illustrated embodiments of the invention employ in their implementation a “via”, in analogy to semiconductor electronics and as described in U.S. patent application Ser. No. ______, incorporated herein by reference. Vias are vertical micropassages that connect channels fabricated in different layers of the same PDMS multilayer chip. The functional result is three dimensional channels that break the restrictions of the traditional architecture wherein channels could never leave their layer and two channels within the same layer could never cross without mixing.  
         [0011]     Vertical passages (vias), connecting channels located in different layers, are fabricated monolithically, in parallel, by simple and easy means. The resulting three dimensional connectivity greatly expands the potential complexity of microfluidic architecture. We apply the vias to building autoregulatory devices. A current source is demonstrated, while a diode and a rectifier are derived; all are building blocks for analog circuitry in Newtonian fluids.  
         [0012]     By use of the vias the illustrated embodiment of the invention is provided as a microfluidic autoregulator comprising an origin of a fluid, a sink for the fluid, a main flow channel coupling the origin and the sink, a valve communicated to the main flow channel to selectively control flow of fluid therethrough, and means dependent on flow through the main flow channel for creating a pressure differential across the valve to at least partially activate the valve to control flow of fluid through the main flow channel.  
         [0013]     The valve has a control port, and in one embodiment the means dependent on flow through the main flow channel for creating a pressure differential across the valve to at least partially activate the valve to control flow of fluid through the main flow channel comprises a dead-end detour channel communicated to the main channel at one end of the detour channel and communicated to a control port of the valve at an opposing end of the detour channel.  
         [0014]     In another embodiment the valve has a control chamber and the means dependent on flow through the main flow channel for creating a pressure differential across the valve to at least partially activate the valve to control flow of fluid through the main flow channel comprises a loop in the main channel which loops back through the control chamber of the valve to the sink.  
         [0015]     The means dependent on flow through the main flow channel for creating a pressure differential across the valve to at least partially activate the valve to control flow of fluid through the main flow channel comprises means for creating a pressure drop across the valve according to Poiseuille&#39;s law.  
         [0016]     The autoregulator further comprises a multilayer chip and the valve is provided in one layer of the chip and the main flow channel is defined in an adjacent layer of the chip. A via is also defined between the layers, and in one embodiment the valve is provided in one layer of the chip and the main flow channel is defined in an adjacent layer of the chip. The dead-end detour is defined in the same layer of the chip as the main flow channel and connected to the valve through the via.  
         [0017]     In another embodiment the loop is defined in the same layer of the chip as the valve and communicated to the main flow channel through the via.  
         [0018]     In still a further embodiment the loop is defined in the same layer of the chip as the main flow channel and communicated to the valve through the via.  
         [0019]     The illustrated embodiment of the invention also includes a compound autoregulator array comprising an origin of fluid, a sink of fluid, a first autoregulator with a corresponding first main flow channel, the first autoregulator communicated to the origin, and a second autoregulator with a corresponding second main flow channel, the second autoregulator communicated to the sink and coupled in series with the first autoregulator.  
         [0020]     In one embodiment the first and second autoregulators each have a direction of forward flow and are communicated with each other in a face-to-back configuration where forward flow through the first and second autoregulators is in the same direction.  
         [0021]     In another embodiment the first and second autoregulators each have a direction of forward flow and are communicated with each other in a back-to back configuration where forward flow through the first and second autoregulators is in opposite directions to each other.  
         [0022]     In one embodiment the first and second autoregulators are defined in the same layer of the chip or in a second embodiment are defined in different layers of the chip.  
         [0023]     In one embodiment the first and second autoregulators each include a dead-end detour channel communicated to the main flow channel at one end of the detour channel and communicated to the valve at an opposing end of the detour channel.  
         [0024]     In another embodiment the first and second autoregulators each include a loop in the main flow channel which loops back through the valve.  
         [0025]     The illustrated embodiment also includes a microfluidic rectifier comprising an output channel, two ports and four microfluidic diode arrays, the four microfluidic diode arrays communicated with each other and with the two ports to be configured as a full-wave bridge to provide rectification of fluid flow between the two ports into the output channel.  
         [0026]     It is to be understood that the invention contemplates within its scope any combination of autoregulators in all possible logical combinations and all possible topological fluidic circuits.  
         [0027]     The invention further contemplates within its scope the method by which each of the above devices, autoregulators or arrays thereof operate.  
         [0028]     While the apparatus and method has or will be described for the sake of grammatical fluidity with functional explanations, it is to be expressly understood that the claims, unless expressly formulated under 35 USC 112, are not to be construed as necessarily limited in any way by the construction of “means” or “steps” limitations, but are to be accorded the full scope of the meaning and equivalents of the definition provided by the claims under the judicial doctrine of equivalents, and in the case where the claims are expressly formulated under 35 USC 112 are to be accorded full statutory equivalents under 35 USC 112. The invention can be better visualized by turning now to the following drawings wherein like elements are referenced by like numerals. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0029]      FIGS. 1   a - 1   d  are schematic diagrams of various embodiments of autoregulator detour and loop devices devised according to the invention.  
         [0030]      FIGS. 2   a - 2   f  are schematic diagrams of various embodiments of compound autoregulator devices devised according to the invention.  
         [0031]      FIGS. 3   a  and  3   b  are schematic diagrams of various embodiments of compound autoregulator devices having differing saturation currents and configured to allow large flows or currents in one direction and low flows or currents in the other direction to function like a diode according to the invention.  
         [0032]      FIG. 4  is a schematic of the embodiment of  FIG. 3   a  used in combination to provide a fluidic full wave rectifier bridge.  
         [0033]      FIG. 5   a  is a graph of experimental results for the throughput as a function of applied pressure, for a set of detour autoregulators, where the only varying parameter was the main channel distance between T-connection split and valve.  
         [0034]      FIG. 5   b  is a graph of experimental results for the same devices graphed in  FIG. 5   a  which were then reverse-biased by exchanging the roles of origin and sink. In reverse bias, the devices function linearly as plain channels.  
         [0035]      FIG. 6  is an idealized graph of the throughput T as a function of pressure P in the devices of  FIGS. 3   a  and  3   b.   
     
    
       [0036]     The invention and its various embodiments can now be better understood by turning to the following detailed description of the preferred embodiments which are presented as illustrated examples of the invention defined in the claims. It is expressly understood that the invention as defined by the claims may be broader than the illustrated embodiments described below.  
       DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0037]     The future will witness many important advances in patterning, as made possible by the microfluidic via technology presented in the incorporated patent application referenced above. In the multilayer world of microfluidic valves, vias remove the distinction between control and flow channels, because the same three dimensional channel can now be a control channel in one section of the chip and a flow channel in another. Therefore, the same three dimensional channel can act as a control channel upon itself. This feature forms the basis of autoregulatory devices, which are disclosed below. Previous work in microfluidic autoregulation utilized the non-Newtonian rheological properties of concentrated polymeric solutions. By contrast, the invention is the first to show microfluidic autoregulation in Newtonian fluids and thus in environments typical to most microfluidic applications.  
         [0038]     While fluidic devices of similarly nonlinearity have been reported in the prior art, those devices can work only in very special non-Newtonian fluids, while the device  10  presented here as well as each of its embodiments and permutations function with Newtonian fluids as well. This characteristic is especially significant as most of the work in microfluidics employs water or aqueous solutions as the universal medium for biological applications.  
         [0039]     Herein, we describe a family of new microfluidic devices that have a non-linear response of throughput with applied pressure. That property engenders autoregulation. Primitive autoregulators can then be utilized, modified, and arranged to produce tunable current sources, regenerable fuses, compound autoregulators, microfluidic diodes, and microfluidic rectifiers.  
         [0040]     Multilayer PDMS microfluidics has previously been limited to working in planes without fluidic cross connection. The introduction of microfluidic vias as disclosed in the incorporated copending application above offers new possibilities for control. Instead of one layer controlling another by applied pressure in either pushdown or pushup microfluidic devices, vias make it possible that channels control themselves by selectively controlled fluidic connection to another layer.  
         [0041]     As a direct embodiment of this novel idea, we have designed a device, generally denoted by reference numeral  10 , and various embodiments as shown in  FIGS. 1   a - 1   d.  Fluid flows from origin  12  to a sink  14  along channels  16  in the upper and/or lower channels  18 . The vias  20  connect the channels  14  and  16 . The device  10  is referenced as a “detour” device inasmuch a detour is provided from a T connection  26  through a via  20  to a valve  22  or  24  placed in the flow channel  16 . The pushdown valve  22  in  FIG. 1   a  or pushup valve  24  in  FIG. 1   b  experiences the same static pressure as the static pressure in the preceding T-junction  26 . Simultaneously the channel  16  below valve  22  in  FIG. 1   a  or above the valve  24  in  FIG. 1   b  has lower static pressure due to Poiseuille&#39;s law. Poiseuille&#39;s law states that the volume flow of an incompressible fluid or of a Newtonian fluid through a circular tube is equal to π/8 times the pressure differences between the ends of the tube, times the fourth power of the tube&#39;s radius divided by the product of the tube&#39;s length and the dynamic viscosity of the fluid. In other words, flowing fluid will exhibit a pressure drop as a function of the volume of flow among other parameters. In other words, within the detour autoregulator device of  FIGS. 1   a  and  1   b  static pressure decreases from origin  12  to sink  14  as fluid flows along the flow channel  16 . Meanwhile, static pressure remains constant along the dead-end detour channel  17  leading to the valve  22  or  24 . Therefore, the valve  22  and  24  experiences an effective pressure equal to the static pressure drop between the T connection  26  and the flow channel  16  adjacent to valve  22  or  24 . Due to Poiseuille&#39;s law and geometry, that pressure drop scales with applied pressure. As the drop increases, the valve membrane (not shown) deforms and constricts the main channel  16 . Hence, total resistance increases with applied pressure and the device behaves non-linearly with Newtonian fluids.  
         [0042]     The difference in pressure on each side of valve  22 ,  24  activates the valve  22 ,  24  to choke the flow of fluid through it. The higher the pressure differential, the more constricted the channel  16  in  FIG. 1   a  or channel  18  in  FIG. 1   b,  the higher the flow resistance. As a result, the device throughput has a nonlinear response with applied pressure. In devices  10  of  FIGS. 1   c  and  1   d  the role of the T-junction  26  is replaced with a loop  28  utilizing the same pressure drop principle communicated with valve  22 ,  24 , while the origin  12  and sink  14  are now in different layers. The loop  28  eliminates the need for a detour channel  17  but requires that the main channel  16  returns to the starting point pressure. Depending on the application or overall device  10 , either architecture can be used.  
         [0043]     As the applied pressure Increases, the pressure difference between the origin  12  and the valve  22 ,  24  increases as well. That difference produces a force on the membrane of the valve  22 ,  24  that makes the valve  22 ,  24  to start closing. The decreased vertical dimension Increases the resistance of the segment of channel  16  under the valve  22 ,  24  and thus the overall resistance of the fluidic device  10  from origin  12  to sink  14 . Increased resistance at the same applied pressure means less flow or “current” using an electrical circuit analogy, which also means a smaller pressure drop from the origin  12  to the valve  22 ,  24  and thus less force on the membrane of the valve  22 ,  24 .  
         [0044]     This negative feedback makes throughput flow or “current’ increase more slowly than linearly with an increase in applied pressure. Thus the device  10  regulates its own resistance to flow as a hardwired function of applied pressure Used in this pressure domain, device  10  acts as an autoregulator.  
         [0045]     We constructed a set of detour autoregulator devices  10  of  FIG. 1   a  on the same chip, where the only varying parameter was the main-channel distance X between split and valve. All valves  22 ,  24  were 100×100 μm, all lower channels were 7×100 μm, and all upper channels were 36×100 μm in lateral dimensions. The length of all main channels was L=14.2 mm. The autoregulator set had X/L={0.80, 0.68, 0.57, 0.46, 0.23}. The 60-μm-square vias  20  were rounded and the PDMS was spun at 5,000 rpm. High-purity water was flowed through each device.  
         [0046]     Throughput for the device  10  of  FIG. 1   a  is shown in the graph of  FIG. 5   a  which was measured by timing the advance of the water meniscus in transparent tubing connected to the sink  14 . Larger T connection-to-valve distances monotonically correspond to lower saturation points, because identical valves  22  experience larger percentages of the same total applied pressure. These experimental results offer a confirmation of the above qualitative predictions. They also demonstrate that the saturation throughput and saturation pressure of the device  10  can be tuned by varying the split-to-valve length as a percentage of the main-channel length. Hence, these devices  10  can be used as microfluidic current sources with saturation characteristics that are tunable by architectural design.  
         [0047]     The graph of  FIG. 5   b  shows the behavior of the same devices  10  when used in reverse bias. Then, the effective pressure acts on the valve  22  in the opening rather than closing direction and the devices  10  act like plain channels. The small curvature upward in both forward and reverse bias is due to slight dilation of the elastomeric channels  16  at higher pressures and the third-power dependence of throughput on the smaller lateral dimension in Poiseuille&#39;s law. In forward bias, a detour (or loop) autoregulator of  FIGS. 1   a ,  1   b  or  FIGS. 1   c ,  1   d  respectively can be used alone as a fluidic current source when operated in its saturation regime.  
         [0048]     Due to the third power dependence of flow resistance with the small vertical dimension of the channel  16  in the illustrated embodiment, small changes in the pressure difference produce small changes in the height of the channel  16 , but large changes in the flow resistance. Thus a strong stabilization is expected at high pressures. As a result, the derivative of throughput or flow with respect to the applied pressure should approach zero asymptotically at high pressure. In that pressure domain, the device  10  can thus be used as a fluidic current source. Thus, the fabrication parameters determine dimensions which in their own turn tune the saturation flow or “current” as desired.  
         [0049]     Up to this point, we have assumed a gradual or quasi-static increase in pressure. If we relax that limitation, pressure pulses are allowed. If in addition we allow for a flabby, sticky PDMS membrane of the autoregulator&#39;s valve  22 ,  24 , then a pressure pulse of sufficient magnitude from origin  12  to sink  14  could completely close off the valve  22 ,  24 . At zero flow or throughput, the pressure everywhere between the origin  12  and valve  22 ,  24  is the same, while the flabby sticky membrane flip will not flick back and open by itself, but latches closed. The result is a microfluidic fuse that shuts off flow when excessive pressure is applied, The fluidic circuit can be reopened by applying a reverse pressure from the direction of the sink  14 . Thus the described device  10  functions a regenerable microfluidic fuse.  
         [0050]     Now that we have described a new microfluidic device  10 , a number of architectural permutations become available. For example, a plurality of these devices  10  can be arranged in series and pointing in the same direction to produce a more complex response curve of overall throughput verses applied pressure and that capability significantly expands the space of available tunable behaviors. The resulting device arrays  30  are compound autoregulators, as distinct from the “primitive” or simple autoregulators discussed above.  FIGS. 2   a - 2   c  show the various permutations of two series communicated devices  10  to form an array  30  each using a feedback T-connection  26  as described in  FIGS. 1   a  and  1   b .  FIG. 2   a  is an array  30  in which valves  22  are both pushdown valves.  FIG. 2   b  is an array  30  in which one valves  22  is a pushdown valve and the other valve  24  is a pull up valve.  FIG. 2   c  is an array  30  in which valves  24  are both pull up valves.  FIGS. 2   d - 2   f  shows three embodiments of two series communicated devices  10  to form an array  30  each using a feedback loop  28  as described in  FIGS. 1   c  and  1   d .  FIG. 2   d  is an array  30  in which valves  22  are both pushdown valves.  FIG. 2   e  is an array  30  in which one valves  22  is a pushdown valve and the other valve  24  is a pull up valve.  FIG. 2   f  is an array  30  in which valves  24  are both pull up valves. It must be understood that according to the invention the number of logical combinations can be multiplied by providing the various logical permutations of three or more devices  10  communicated in series and/or parallel arrangements of any combination or circuit topology desired.  
         [0051]     If two devices  10  are arranged in opposite directions then what is produced is an overall array  32  that can act as a current source of potentially different saturation currents depending on the direction of the flow. Then each device  10  in the array  32  would act as a current source in its forward bias, and as a plain channel in its reverse bias. The respective saturation points can be made to differ widely by architectural design. For example, the device  10  built around valve  22   a  would saturate at higher pressure P and throughput T in the 1-to-2 bias than in the 2-to-1 bias of the device  10  built around valve  22   b.  An appropriately tuned design would ensure different saturation throughputs T in the different directions of applying pressure P as depicted in the graphs of  FIGS. 5   a  and  5   b.    
         [0052]     Taken to the extreme, such an array  32  with a very low saturation current in one direction, but a very high saturation current in the other direction of flow functions as a microfluidic diode. In such a microfluidic diode, a small tight valve plus a small pressure drop would define a high current in one direction, and a large flabby valve plus a large pressure drop would define the low current direction.  FIGS. 3   a  and  3   b  illustrate embodiments that utilize pushdown linear and pushdown circular configurations respectively, but the same result can be accomplished by a combination of pushup/pushdown and liner/looping arrays of the type described in  FIGS. 2   a - 2   f.  In  FIG. 3   a  a linear device  32  is shown in which pushdown valves  22   a  and  22   b  are employed using T connections  26 . The input/output ports  34  and  36  function either as origins or sinks according to the direction of pressure and flow through device  32 . Valve  22   a  is a small tight valve across which a small pressure drop is arranged. Valve  22   b  is large flabby valve across which a large pressure drop is arranged. Thus, flow from valve  22   a  toward valve  22   b  is a high current or flow direction. Flow from valve  22   b  toward valve  22   a  is a low current or flow direction as suggested by the analogous electrical diode polarities shown in the figures.  FIG. 6  is a graph which illustrates the idealized throughput function of array  32  as a function of pressure P.  
         [0053]     The ability to make a microfluidic diode  32  also provides the ability to make to make any fluidic circuit equivalent to any electrical circuitry utilizing diodes. For example, electrical diodes can be arranged to produce an electrical rectifier, which outputs the same polarity regardless of the polarity of the input. Thus autoregulator fluidic diodes  32  can be arranged to produce a microfluidic rectifier as shown in  FIG. 4  in direct analogy with the respectively electrical rectifier circuit schematically shown in the center of  FIG. 4 . The fluid flows the same direction in the outer channel  42  regardless of choice of origin  12  or sink  14  between ports  38  and  40 .  
         [0054]     Here four linear fluidic diodes  32   a - 32   d  of the type described in  FIG. 3   a  are arranged in a loop and are configured with respect to their high and low flow directions with respect to ports  38  and  40  as are the identically enumerated circuit nodes are in the analogous electrical schematic in the center of  FIG. 4 . As before, the fluidic circuitry can utilize a combination of pushdown/pushup and linear/looping devices  10  instead of illustrated pushdown valves  22  shown as an example in  FIG. 4 .  
         [0055]     The microfluidic devices  10  and arrays  30  and  32  enhance and expand the capabilities of PDMS microfluidic technology and its scope of applications by providing autoregulation of throughput in Newtonian fluids.  
         [0056]     As such, the described overall device is a new type of a microfluidic diode. This diode can be used as a building block to produce more advanced devices, such a microfluidic rectifier bridge, in direct analogy with their electronic counterparts. It is clear that the above devices form the basis of novel microfluidic analog logic with Newtonian fluids.  
         [0057]     Many alterations and modifications may be made by those having ordinary skill in the art without departing from the spirit and scope of the invention. Therefore, it must be understood that the illustrated embodiment has been set forth only for the purposes of example and that it should not be taken as limiting the invention as defined by the following invention and its various embodiments.  
         [0058]     Therefore, it must be understood that the illustrated embodiment has been set forth only for the purposes of example and that it should not be taken as limiting the invention as defined by the following claims. For example, notwithstanding the fact that the elements of a claim are set forth below in a certain combination, it must be expressly understood that the invention includes other combinations of fewer, more or different elements, which are disclosed in above even when not initially claimed in such combinations. A teaching that two elements are combined in a claimed combination is further to be understood as also allowing for a claimed combination in which the two elements are not combined with each other, but may be used alone or combined in other combinations. The excision of any disclosed element of the invention is explicitly contemplated as within the scope of the invention.  
         [0059]     The words used in this specification to describe the invention and its various embodiments are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification structure, material or acts beyond the scope of the commonly defined meanings. Thus if an element can be understood in the context of this specification as including more than one meaning, then its use in a claim must be understood as being generic to all possible meanings supported by the specification and by the word itself.  
         [0060]     The definitions of the words or elements of the following claims are, therefore, defined in this specification to include not only the combination of elements which are literally set forth, but all equivalent structure, material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result. In this sense it is therefore contemplated that an equivalent substitution of two or more elements may be made for any one of the elements in the claims below or that a single element may be substituted for two or more elements in a claim. Although elements may be described above as acting in certain combinations and even initially claimed as such, it is to be expressly understood that one or more elements from a claimed combination can in some cases be excised from the combination and that the claimed combination may be directed to a subcombination or variation of a subcombination.  
         [0061]     Insubstantial changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated as being equivalently within the scope of the claims. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements.  
         [0062]     The claims are thus to be understood to include what is specifically illustrated and described above, what is conceptionally equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the invention.