Implementation of microfluidic components in a microfluidic system

A system and method for integrating microfluidic components in a microfluidic system enables the microfluidic system to perform a selected microfluidic function. A capping module includes a microfluidic element for performing a microfluidic function. The capping module is stacked on a microfluidic substrate having microfluidic plumbing to incorporate the microfluidic function into the system. An infusion pump for delivering a fluid from a fluid source may be integrated in a microfluidic chip using a capping module having pumping components formed therein.

FIELD OF THE INVENTION

The present invention relates to a microfluidic system for handling fluid samples on a microfluidic level. More particularly, the present invention relates to a system and method for implementing microfluidic functions in a microfluidic system.

BACKGROUND OF THE INVENTION

Microfluidic devices and systems provide improved methods of performing chemical, biochemical and biological analysis and synthesis. Microfluidic devices and systems allow for the performance of multi-step, multi-species chemical operations in chip-based micro chemical analysis systems. Chip-based microfluidic systems generally comprise conventional ‘microfluidic’ elements, particularly capable of handling and analyzing chemical and biological specimens. Typically, the term microfluidic in the art refers to systems or devices having a network of processing nodes, chambers and reservoirs connected by channels, in which the channels have typical cross-sectional dimensions in the range between about 1.0 μm and about 500 μm. In the art, channels having these cross-sectional dimensions are referred to as ‘microchannels’.

In the chemical, biomedical, bioscience and pharmaceutical industries, it has become increasingly desirable to perform large numbers of chemical operations, such as reactions, separations and subsequent detection steps, in a highly parallel fashion. The high throughput synthesis, screening and analysis of (bio)chemical compounds, enables the economic discovery of new drugs and drug candidates, and the implementation of sophisticated medical diagnostic equipment. Of key importance for the improvement of the chemical operations required in these applications are an increased speed, enhanced reproducibility, decreased consumption of expensive samples and reagents, and the reduction of waste materials.

In the fields of biotechnology, and especially cytology and drug screening, there is a need for high throughput filtration of particles. Examples of particles that require filtration are various types of cells, such as blood platelets, white blood cells, tumorous cells, embryonic cells and the like. These particles are especially of interest in the field of cytology. Other particles are (macro) molecular species such as proteins, enzymes and polynucleotides. This family of particles is of particular interest in the field of drug screening during the development of new drugs.

In addition, it may be desirable to be able to pump small, controllable volumes of fluid from a fluid source to a destination, such as the body of a patient, while minimizing risk of contamination.

SUMMARY OF THE INVENTION

The present invention provides a system and method for integrating microfluidic components in a microfluidic system to enable the microfluidic system to perform a selected microfluidic function. The present invention utilizes a capping module including a microfluidic element for performing a microfluidic function. The capping module is stacked on a microfluidic substrate having microfluidic plumbing to incorporate the microfluidic function into the system.

According to one aspect, the invention provides a microfiltration system in a microfluidic chip for separating a substance, such as a compound, moving through a closed channel system of capillary size into different components. The filtration system of the invention provides a filtration module that can be assembled at low cost while providing an accurate means of filtering a large amount of compounds per unit of time. The microfiltration system integrates conventional membrane filter technology into a microfluidic system formed of glass, plastic or other suitable material. The microfabricated filtration system may comprise a sub-system designed to be inserted into a standard microfluidic system to provide on-chip filtration. An illustrative filtration system includes two flow paths separated by a membrane, which separates a substance flowing through a first flow path by size discrimination. Reservoirs are formed on either side of the membrane in communication with the flow paths. A microfabricated cap is affixed to the membrane to define the reservoir on the top side of the membrane.

According to another aspect, a pump, such as an infusion pump, may be incorporated into a microfluidic system using a plurality of capping structures having pump components formed therein. A first capping module is used to form a first fluid regulating device, such an inlet valve, for the pump. A second capping module forms a pump chamber in communication with the first fluid regulating device. A third capping module forms a fluid regulating device, such as an outlet valve, in communication with the pump chamber for regulating fluid flow from the pump chamber. Each capping module includes a membrane for selectively blocking flow through one or more communication ports in a substrate and an actuator assembly for controlling the position of the membrane.

According to yet another aspect, a microfluidic system comprises a first microchannel formed in a substrate, a first communication port coupling the first microchannel to a surface of the substrate, a first capping module defining a chamber, wherein the capping module is adapted to be stacked on the substrate and placed in communication with the microchannel, a movable membrane connected to the chamber, and an external actuator for selectively moving the membrane to vary the size of the chamber to control fluid flow from the first microchannel through the chamber.

According to another aspect of the invention, an infusion pump for delivering a substance is provided. The infusion pump comprises a substrate having a plurality of microchannels formed therein, wherein each microchannel includes one or more communication ports for connecting the microchannel to a surface of the substrate, a first capping module forming a pump chamber in communication with a first microchannel and second microchannel, a second capping module forming an inlet fluid regulating device in communication with the pump chamber via the first microchannel for controlling fluid flow into the pump chamber and a third capping module forming an outlet fluid regulating device communication with the pump chamber via the second microchannel for controlling fluid flow out of the pump chamber.

According to still another aspect of the invention, a method of delivering a fluid from a fluid source is provided. The method comprises a first step of providing a pump comprising a microfluidic substrate having a first capping module stacked thereon to form a pump chamber, a second capping module stacked thereon to form an inlet fluid regulating device to the pump chamber and a third capping module stacked thereon to form an outlet fluid regulating device from the pump chamber, each capping module defining a chamber in communication with an inlet channel and an outlet channel formed the microfluidic substrate and having a flexible membrane forming a side wall of the chamber to selectively block fluid flow through the chamber. A second step comprises selectively deflecting at least one of the membranes of the capping modules to pump fluid from the fluid source through the infusion pump.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a microfabricated pump system for allowing on-chip pumping of a sample. The microfabricated pump system may be used in a wide variety of applications, including, but not limited to infusion pumps for delivering a drug to a patient, and other microfluidic applications. The present invention will be described below relative to an illustrative embodiment. Those skilled in the art will appreciate that the present invention may be implemented in a number of different applications and embodiments and is not specifically limited in its application to the particular embodiments depicted herein.

As used herein, the term “microfluidic” refers to a system or device for handling, processing, ejecting and/or analyzing a fluid sample including at least one channel having microscale dimensions.

The terms “channel” and “flow channel” as used herein refers to a pathway formed in or through a medium that allows for movement of fluids, such as liquids and gases. The channel in the microfluidic system preferably have cross-sectional dimensions in the range between about 1.0 μm and about 500 μm, preferably between about 25 μm and about 250 μm and most preferably between about 50 μm and about 150 μm. One of ordinary skill in the art will be able to determine an appropriate volume and length of the flow channel. The ranges are intended to include the above-recited values as upper or lower limits. The flow channel can have any selected shape or arrangement, examples of which include a linear or non-linear configuration and a U-shaped configuration.

The term “microfluidic element” as used herein refers to a component in a microfluidic system for performing a microfluidic function. Examples of suitable microfluidic elements include, but are not limited to, passive check valves, active valves, pressure sensors, connecting channels, membrane filtration units, threaded taps for external connecting tubes, compression chambers, pumps, and others known to those of ordinary skill in the art.

The term “filter” as used herein refers to a material of any suitable composition and size, which may used to separate or filter substances by size exclusion or other measures.

The term “substrate” as used herein refers to a support structure having channels formed therein for conveying a fluid.

The terms “cap” or “capping module” as used herein refer to a structure, which is the same size as or smaller than a substrate, having any selected size or shape and formed of any selected material, and having a microfluidic element. The capping module is configured to stack on or communicate with the substrate to fully or partially complete a fluid path.

The term “substance” as used herein refers to any material used in a microfluidic process, including, but not limited to chemical compounds, molecules, viruses, cells, particles, beads, buffers, or any other material used in a microfluidic process.

The term “microfluidic function” as used herein refers to any operation, function or process performed or expressed on a fluid or sample in a microfluidic system, including, but not limited to: filtration, dialysis, pumping, fluid flow regulation, controlling fluid flow and the like.

The term “port” refers to a structure for providing fluid communication between two elements.

As used herein, “pump” or “pumping element” refers to any fluid-transferring device suitable for intaking and/or discharging fluids, which can have different sizes, including microscale dimensions, herein referred to as “micropump” or “microfluidic pump” or “pumping element”.

The present invention allows implementation of different microfluidic functions into a microfluidic chip using a capping module having a microfluidic element for performing a microfluidic function. As shown inFIG. 1, a microfluidic chip10suitable for implementing an embodiment of the invention comprises a substrate11having one or more flow channels3, illustrated as a microchannel, disposed therein. The flow channels transport fluid through the microfluidic system10for processing, handling, and/or performing any suitable operation on a liquid sample. The microfluidic system10may comprise any suitable number of flow channels3for transporting fluids through the microfluidic system10.

As shown inFIG. 1, the flow channel3is formed in a substrate11, and may connect to the surface of the substrate via one or more communication ports13aand13b.A capping module15including a microfluidic element18, such as a filter, one or more valves, pressure sensors or other component for performing a microfluidic function, is placed over the substrate11to form a closed fluid path. According to an alternate embodiment, the capping module may include a connector channel for re-routing fluid flow through the microchannel around another structure. The illustrative substrate11includes two communication ports13a,13b,each connecting unconnected segments3a,3bof the flow channel3to the substrate surface, though one skilled in the art will recognize that variations may be made in the size, number and configuration of the communication ports and flow channels.

The illustrative capping module15may include connector ports for interfacing with the communication ports of the substrate, and/or a chamber12or channel to provide a fluidic path between the first connector port and the second connector port. One skilled in the art will recognize that the capping module may have alternate configurations and is not limited to the embodiment shown inFIG. 1.

Using the capping module15, microfluidic functions, such as filtration, dialysis, pumping, flow control and so on, may be integrated into the microfluidic system10without requiring significant modification of the substrate11. A substrate including any number and arrangement of conduits or channels3for conveying fluids can be transformed into a functional fluidic circuit by selecting and placing one or more capping modules15with a functional microfluidic element18on the substrate, i.e. chip. According to an illustrative embodiment, the same automated “pick and place” surface mount equipment technology used to make integrated circuits may be used to form fluidic circuits on a substrate having microchannels using various capping structures. Suitable pick and place equipment is manufactured by Manncorp, Inc. (Huntingdon Valley, Pa.), among others.

To fabricate a fluidic circuit, the channels3in the substrate11may be manufactured by chip microfabrication. The channels or plumbing may be fabricated by etching half-channels in a first substrate, followed by bonding and/or lamination of a second substrate to enclose the half-channels, forming a microchannel. The substrate may be formed of one or more layers containing etched channels if more complex fluidic networks are required. The communication ports may then be fabricated in the substrate to connect the microchannel to an exterior surface of the substrate. Suitable techniques for fabricating the communication ports include drilling, laser etching, powder blasting or other techniques known in the art. After the fabrication of the substrate and communication ports, a capping module having a desired functionality is bonded to the substrate to form a microfluidic component in the larger microfluidic circuit.

A variety of capping module number and sizes may be bonded to the substrate to impart various microfluidic functions to form a microfluidic system. The capping modules may be removable and replaceable so that a substrate may be re-used.

According to the illustrative embodiment, the capping module has a cross-sectional dimension of between about 1 millimeter and about 5 centimeters, though those skilled in the art will recognize that the invention is not limited to this range. The capping module may be formed of any suitable material, including, but not limited to plastic, glass, silicon and other materials known in the art.

FIG. 2illustrates the architecture of an illustrative microfluidic diagnostic chip that may be fabricated according to the teachings of the invention. The diagnostic chip20may include one or more microfluidic components, alone or in combination, configured to facilitate processing of a sample. For example, as shown, the diagnostic chip20includes a microfiltration system100for separating substances in solution, such as separating selected particles from cells or other particles in a suspension. The diagnostic chip20may further include one or more reservoirs90for storing and supplying sample, reagent or other compounds to the system, as well as one or more waste reservoirs91for collecting sample waste. The diagnostic chip may further include one or more aliquoting, mixing and incubation components, such as an on-chip sample dilution system, for processing a sample, such as performing a mixture of a specific amount of sample and reagent. For example, the illustrative system includes a mixing component60and an incubation region61. The chip may also include a detector70for analyzing a filtered product from the microfiltration system100. The detector70may utilize any suitable detection modality, including, but not limited to fluorescence, electrochemical analysis, dielectrophoresis, and surface plasma resonance (SPR), radio-frequency, thermal analysis and combinations thereof. The chip10may employ valves for selectively controlling the flow of fluid through the channels and one or more drive units, located on or off the chip, for driving the movement of fluid through the channels3of the chip. One skilled in the art will recognize that the microfluidic system is not limited to the diagnostic chip ofFIG. 2and that variations in the configuration, position, number and combination of the various microfluidic components may be made in accordance with the present invention.

The filtration system100of the present invention integrates conventional membrane filter technology into a microfluidic chip using a capping module. The filtration system can be inserted into an existing microfluidic chip to enable filtration of particles, cells or other substances in suspension without requiring significant or expensive modification of the chip structure.

FIGS. 3,4and6illustrate a microfabricated filtration subsystem100suitable for implementation in the microfluidic system ofFIG. 2according to one embodiment of the invention.FIG. 5illustrates the capping module15used to fabricate the filtration system100according to one embodiment of the invention. The filtration subsystem is utilized to separate a substance, such as a sample comprising a mixture of particles and fluid, through a semi-permeable membrane filter110and subsequently collect the separated components. According to an illustrative embodiment, the filtration subsystem is used to separate blood cells from plasma, though one skilled in the art will recognize that other applications are included in the invention. According to other applications, the filtration system may be used to separate viruses from cells, beads from cells, chemical compounds, molecules or other substances that a membrane filter may be used to separate. As shown the filtration subsystem100is formed directly on the microfluidic chip to add filtration capability to the chip without requiring significant modification or expense.

The filtration subsystem100utilizes a conventional membrane filter110separating two flow paths in the substrate11to provide small volume controllable filtration of a sample. The illustrative filtration system is a four-port transverse filter, which includes a first fluid flow path120for supplying a substance to the filtration system, such as a mixture of particles and fluid, and a second fluid flow path130for receiving and conveying a filtered product (i.e., a filtrate) from the filtration system. The first fluid flow path120includes a first communication port, illustrated as a first inlet channel121that intersects the filtration system at a first inlet121a.The first fluid flow path120includes a second communication port, illustrated as a first outlet channel122including an outlet122afrom the filtration chamber for receiving and conveying a retentate of the substance from the filtration system. The second fluid flow path includes an inlet channel131intersecting a filtrate chamber below the membrane filter110at a second inlet and a second outlet channel132for transferring the filtered product from the filtration system. The second fluid flow path130may include a carrier fluid for conveying the filtered product. A flow source drives the flow of the mixture through the filtration system to effect separation of the components through the membrane filter. The flow source may comprise an off-chip syringe pump, a microfabricated peristaltic pump, a microfabricated syringe, or any suitable flow source known in the art, such as those described in U.S. Provisional Patent Application Ser. No. 60/391,868 entitled “Microfluidic System and Components”, the contents of which are herein incorporated by reference.

The illustrative microfabricated filtration system100has a relatively small footprint (less than about one mm2), resulting in a compact structure, low cost and relatively simple fabrication. The particle separator further provides relatively low strain rates with reduced or no blockage. The amount of fluid retained can be significant, if desired, and the design is scalable and repeatable for additional parsing steps, if desired.

The filtration subsystem of the present invention may be formed by providing a microfluidic chip including an intersection101of the two flow channels120,130. The assembly process integrates simple batch fabricated components, and is relatively simple and low cost at high volume. According to an illustrative embodiment, the chip forms a recess140in communication with the second flow channel130at the intersection101. The first flow channel120is initially separated from and divided by the recess140. A suitable membrane filter110is affixed to the microfluidic chip, using an appropriate adhesive or other suitable fastening mechanism, to cover the recess, thereby defining a reservoir below the membrane filter for receiving the filtered product and transmitting the filter product through the second flow channel130. The membrane filter may comprise any suitable filtering membrane known in the art.

The illustrative microfabricated capping module15, shown inFIG. 4, is affixed above the membrane filter110to define a filtration chamber.161in communication with the first flow channel120. The cap15may be affixed using an appropriate adhesive or other suitable fastening mechanism. The illustrative capping module15includes an inlet162and an outlet163in communication with the filtration chamber to connect the first flow channel120with the filtration chamber161and enable flow of a composition to be filtered through the filtration chamber over the membrane filter. Alternatively, the membrane filter110is affixed directly to the capping module15and the capping module is affixed to the substrate to integrate the filtration system onto the substrate. One skilled in the art will recognize that the capping module is not limited to the illustrative embodiment and that variations may be made in accordance with the teachings of the invention.

FIG. 7illustrates the microfluidic system10including channels3prior formed therein prior to assembly of the capping module15including the membrane filter110.FIG. 8is a top view of the capped microfluidic system10incorporating filtering capability.

The composition to be filtered is introduced to the filtration subsystem from the inlet channel and passes into the filtration chamber and over the membrane filter110. The components of the substance are fractionated by the membrane filter110, with the smaller components, such as plasma, passing through the membrane filter, into the reservoir140and through the second flow channel130. The remaining portion, such as blood cells, passes through the filtration chamber to the outlet of the first flow channel120.

According to the illustrative embodiment, the substrate of the microfluidic chip may be formed of glass, plastic, silicon, quartz, ceramics or any other suitable material. In a microfluidic chip manufactured from glass, the chip may comprise two layers: the chip and the cap affixed to the chip to define the filtration subsystem. In a microfluidic chip formed of plastic, the components may be stamped into the plastic substrate.

According to an alternate embodiment, shown inFIGS. 9aand9b,the microfiltration subsystem may comprise a two-port direct filter180comprising a membrane filter110inserted into a fluid flow path181. As shown, the two-port direct filter181comprises a fluid flow path181formed in a microfluidic substrate, which is divided into two sections181a,181b.The second section181bdefines a recess182and the membrane filter110is adhered over the recess to define a filtrate chamber for receiving a filtered product. A microfabricated cap15including a recess186defining a filtration chamber is attached to substrate above the membrane filter to connect the flow path181. The substance to be filtered is conveyed through the fluid flow path181into the filtration chamber186and passes through the membrane filter110. The membrane filter110separates the substance by trapping larger molecules and the filtered product, comprising the remaining molecules, passes through the membrane filter along the fluid flow path181into the recess182and out of the microfiltration system for further analysis, processing collection, etc.

According to yet another embodiment, shown inFIGS. 10aand10b,the microfiltration system may comprise a three port direct filter190. The three port direct filter190includes two inlet flow channels191,192for inputting two samples to a filtration chamber195and a single outlet channel193for conveying a filtered product from the filter190. The three-port direct filter includes a microfabricated cap15defining the filtration chamber and a membrane filter110separating the filtration chamber from the outlet channel193. In operation, two samples may be provided through the inlet channels191,192. The samples mix together in the filtration chamber195and the sample mixture is filtered through the membrane filter, which separates the components of the sample mixture. The filtered product that passes through the membrane filter is conveyed through the outlet channel for further processing, analysis, collection etc.

One skilled in the art of membrane based separations will recognize that the filtration system described here can be used to implement on-chip separations of all types for which membranes may be found, including separating molecules by size or beads from molecules or small particles from large particles or viruses from cells or other separations known to those skilled in the art.

According to another embodiment of the invention, the capping module15may be used to incorporate an electromagnetic valve into a microfluidic system. An example of an electromagnetic valve component housed in a capping structure for implementation in a microfluidic system according to the teachings of the invention is shown inFIG. 11. As shown, the electromagnetic module150comprises a cap15defining an interior chamber151, a membrane154for selectively blocking flow through one or both of the communication ports in the substrate and an actuator assembly160for deflecting the membrane154. The membrane154used in the electromagnetic valve is preferably impermeable to liquids, in contrast to the membrane used in filtration systems described above which is semipermeable to allow selected substances to flow therethrough. According to the illustrative embodiment, the actuator assembly comprises a coil162and a magnet164. One skilled in the art will recognize that other suitable means for deflecting the membrane may be used, including piezoelectric actuators.

The electromagnetic capping module110may be stacked on the substrate11such that the membrane, when deflected, blocks one or more of the communication ports13aand13b.The electromagnetic capping module110thus integrates a valve for selectively blocking flow through the channel3into the microfluidic flow path. As described above, the electromagnetic capping module may be placed on the substrate using automated “pick and place” equipment or through any suitable means known in the art.

Another microfluidic element that may be integrated into a basic fluidic chip using a capping module is a pump, as shown inFIG. 12. A pumping function may be integrated into a capping module through a microfluidic element capable of performing the pumping function and introduced to a microfluidic chip by stacking the capping module onto the substrate of the chip. For example, in the embodiment ofFIG. 12, the microfluidic pumping element comprises a flexible membrane281forming a wall of a chamber282defined by the capping module15. As shown, when the capping module15is stacked on the substrate11, the chamber282is placed into communication with the channels13a,13bon the chip. A first channel13ainterfaces with the chamber via an inlet communication port230aand forms an inlet for the chamber282. A second channel13binterfaces with the chamber282via an outlet communication port230band forms an outlet from the chamber. An actuator283in communication with the capping module15selectively actuates the pumping element, for example, by deflecting the membrane281to increase or decrease the size of the chamber282. The communication ports230a,230bof the fluidic chip may be selectively opened or closed to facilitate the pumping action.

The pump280formed by the capping module15may be used to deliver fluids, such as drugs, from a source, such as a reservoir, to a destination, such as a patient. As shown, a tube1601connected to a reservoir1600may be placed in communication with the inlet channel13avia a suitable fitting1602to deliver fluids to the pump280. A delivery tube1603is placed in communication with the outlet channel13bvia a fitting1605. The delivery tube may be connected to a syringe1607or other device for delivering fluids pumped through the pump280to a patient. The fittings1603and1605preferably seal the tubes to the channels to ensure no leakage of the fluid. Suitable fittings are known in the art and include, but are not limited to luer connectors, rubber septum, an internal or external threaded connection, fittings that couple components through interference fit or any suitable means known in the art for coupling a first component to a second component.

According to another embodiment of the invention, a plurality of capping modules15may be used to incorporate a pump, such as an infusion pump for delivering a drug to a patient, into a microfluidic system. An example of a pump formed using a plurality of capping modules according to the teachings of the invention is shown inFIGS. 13A and 13B. According to the embodiment ofFIG. 13A, the illustrative infusion pump1200is formed using three capping module mounted on a substrate11having channels formed therein. A first capping module15aforms a pump chamber1201for pumping fluids, while a second capping module15bforms a fluid regulating device, such as an inlet valve, to regulate flow to the pump chamber and a third capping module15cforms a fluid regulating device, such as an outlet valve, to regulate flow from the pump chamber. The second capping module communicates with an inlet channel13ain the substrate, while the third capping module communicates with an outlet channel13bin the substrate. A first connecting channel1505formed in the substrate places the first capping module and the second capping module in fluid communication with each other, while a second connecting channel1204formed in the substrate places the first capping module in fluid communication with the third capping module, when the capping modules are stacked on the substrate.

According to the illustrative embodiment, each capping module15a,15band15cfurther includes a membrane1530a,1530b,1530c,respectively, for selectively blocking the flow of fluid through the pump component formed by the respective capping module. An external actuator1531a,1531b,1531cselectively actuates each membrane, as described in detail below.FIG. 13Billustrates the capping modules assembled on the chip11with the membranes removes to illustrate the configuration and connection of each capping module15a,15b,and15cwhen assembled.

As shown inFIGS. 13A and 13B, the first capping module15aforms a pump chamber component1200aand includes a recess or opening defining the pump chamber1201. The pump chamber1201is placed over communication ports in the substrate11, so that a first communication port forms an inlet port1202to the pump chamber1201and a second communication port forms an outlet port1203to the pump chamber1201when the capping module is stacked on the substrate. In an alternate embodiment, a recess may be formed in the substrate11to form the pump chamber1201when the capping module15ais coupled to the substrate.

A second capping module15bforms an inlet valve1200bfor the pump chamber1201. The inlet valve1200bincludes an inlet valve chamber1504aformed by a recess or opening in the capping module15b,an inlet port1501aforming an interface between the chamber1504aand an inlet channel13aformed in the substrate11. An outlet port1503aforms an interface between the chamber1504aand an outlet channel1505formed in the substrate11. The inlet channel13amay be connected to a reservoir containing a supply of liquid, such as a drug, to be pumped through the pump1200through any suitable means, such as a tube1601connecting the reservoir to the inlet channel and a fitting1602for sealingly connecting an end of the tube to the inlet channel13a.The outlet channel1505of the inlet valve connects to the pump chamber1201via the chamber inlet port1202. In one embodiment, the substrate11may have a recess around the ports1501aand1503ato form the inlet valve chamber1504awhen the second capping module15bis coupled to the substrate.

The third capping module15cforms an outlet valve1200cfrom the pump chamber1201.FIG. 14is a cross-sectional view of the outlet valve1200caccording to an illustrative embodiment of the invention. The outlet valve1200cincludes an outlet valve chamber1504bformed by a recess in the capping module, an inlet port1501b,and an outlet port1503b.The inlet port1501bof the outlet valve1200ccommunicates with an outlet channel1204extending from the pump chamber1201, such that liquid pumped from the pump chamber passes through the outlet valve15c.The outlet port1503bof the outlet valve connects to an outlet channel13bfor the pump1200. According to an illustrative embodiment, the outlet channel13bis connected to a patient to deliver fluid, such as a drug, pumped through the pump1200to the patient. The outlet channel13bcan be connected to a patient through any suitable means known in the art, such as through a tube sealingly coupled to the outlet channel13bthrough a fitting or other suitable device. In one embodiment, the substrate11may have a recess around the ports1501band1503bto form the inlet valve chamber1504bwhen the third capping module15cis coupled to the substrate.

Each capping module may be coupled to the substrate to form the associated pump component through any suitable means. For example, the substrate11may includes recesses configured to receive complementary portions of the capping module when the capping module is stacked on the substrate. Alternatively, the substrate11may include protrusions or other features configured to be inserted in recesses formed in the sidewalls of the capping modules. In another embodiment, an adhesive film or other suitable bonding means may be used to adhere or otherwise bond the capping module to the substrate. The capping modules may be manually assembled on the substrate or assembled using automated machinery.

In the embodiments shown inFIGS. 13A,13B and14, the opening forming each chamber1201,1504a,1504bextend through the respective capping module, and each capping module15a,15b,15cincludes a membrane1530a,1530b1530cforming an upper wall of the chamber1504a,1504b,1504c,respectively. An external actuator1531a,1531band1531cis provided for selectively moving each membrane1530a,1530bor1530cby a predetermined amount to selectively block the inlet port1501band/or the outlet port1503bassociated with the capping module. The external actuators can be mounted in a holder1532, which may include a controller1534and associated electronics for controlling the actuation of each actuator. A battery (not shown) or other suitable power source may be used to power the actuators1531a,1531band1531c.

The membrane may comprise any suitable material suitable for selectively controlling fluid flow through the associated capping module. The illustrative membranes1530a,1530b,1530bhave a stiffness such that the membrane returns to a rest position when the associated actuator1531is not activated. In other embodiments, the actuator can actively return the membrane to a rest position. According to one embodiment, the membrane1530afor the pump chamber1201is formed of a relatively stiff material, such as stainless steel. The valve membranes1530band1530cmay be formed of a relatively compliant material, such as corrugated metal or plastic, to ensure a seal when the membrane is deflected over a port of the inlet or outlet valve. In an illustrative embodiment, the pump chamber membrane1230ais formed of stainless steel that is about fifty millimeters thick, while the valve membranes1230b,1230care formed of plastic that is about fifty millimeters thick. The membranes may be shaped or bossed to achieve desirable deflection characteristics. In the illustrative embodiment, the membrane is rigidly clamped at the edges and undergoes linear elastic deformation to control fluid flow. In another embodiment, the membrane may be circular in shape and move like a piston in the vertical direction to control fluid flow.

The actuators can comprise any suitable component for selectively deflecting a membrane. According to the illustrative embodiment, the actuator1531may comprise a solenoid, piezo stack, electromagnetic component or other suitable component for actuating the membrane to selectively block fluid flow through a capping module. The actuator is selected to provide a suitable force to drive the associated membrane to a specified deflection distance, provide a suitable pressure drop for a target flow rate and overcome back pressure to return the membrane to a rest position.

In one embodiment, the actuators mounted in the holder1532form permanent components of the pump1200, while the capping modules and substrate form relatively cheap, disposable components. In this manner, the components that are exposed to fluids, and capable of contamination may be disposed after a single use, while the actuator components, which are relatively expensive, can be used multiple times for different substrates and capping modules.

In the embodiments shown inFIGS. 13A,13B and14, all three capping modules15a,15b,15cforming the pump1200are formed on the same surface of the substrate11. One skilled in the art will recognize that the invention is not limited to the illustrative configuration. For example, the one or more of the capping modules may be stacked on a different surface of the substrate from the other capping modules forming the pump. The capping modules may be placed in any suitable location on the substrate such that a chamber formed in the capping module is placed in communication with communication ports of the substrate.

FIG. 15illustrates a capping module suitable for forming the valves1200aor1200caccording to an alternative embodiment of the invention. As shown, the capping module can include a recess1504′ formed in a surface of the capping module15′ facing away from the substrate when the capping module is stacked on the substrate. In this embodiment, the capping module15′ includes channels1501′,1503′ extending from the recess to the opposite surface of the capping module configured to abut the substrate. When the capping module is stacked on the substrate, the channels are placed in communication with the ports on the substrate to provide fluid communication between the recess and the substrate channels. The membrane then covers the recess to form and seal the valve chamber.

As shown inFIGS. 13B-15, the chambers1504aand1504bforming the valves1200a,1200bmay be tapered towards the outlet valve1503a1503b,respectively. The tapered shape of the chamber facilitates fluid flow through the valve chamber, and directs fluid flowing into the chamber1504aor1504btowards the outlet port1503aor1503b,respectively. One skilled in the art will recognize that the invention is not limited to the illustrated valve chamber configuration and that the chambers forming the valves and the pump chamber may have any suitable size, shape and configuration.

FIGS. 16A-16Dillustrate the operation sequence of the illustrated pump1200. As described, the inlet port1501a of the inlet valve1200bis connected, via an inlet channel13a,to a reservoir1600containing a supply of fluid, such as a drug, to be pumped. The outlet port1503bof the outlet valve1200cis connected, via the outlet channel13bto a receiver of the fluid, for example, the body1700of a patient. In a first step, the inlet valve1200bis sealed to isolate the reservoir1600from the pump chamber1201. According to the illustrative embodiment, the inlet valve1200bis sealed by depressing the membrane1530b,such that the membrane covers and seals the inlet port1501aof the inlet valve. In the illustrative embodiment, an external actuator (not shown) selectively depresses the membrane to seal the inlet valve, though one skilled in the art will recognize that any suitable means may be used to selectively seal the inlet valve of the pump1200.

In a second step, shown inFIG. 16B, a pump chamber actuator, or other suitable mechanism, deflects the pump chamber membrane1530ato exhaust fluid from the pump chamber1201through the outlet valve1200c.As shown, in the second step, the membrane1530bof the inlet valve1200bremains in a deflected state to keep the inlet valve1200bclosed and sealed and prevent backflow of the fluid. The outlet valve1200cis open to allow fluid from the pump chamber1201to freely flow therethrough. In an illustrative embodiment, the pump chamber exhausts a drug through the outlet valve to infuse a drug into the body1700of a patient.

In a third step, shown inFIG. 16C, the outlet valve actuator1531c,or other suitable mechanism, deflects the outlet valve membrane1530cto block the inlet port1501bof the outlet valve1200c,thereby sealing the outlet valve1200c.At the same time, the membrane1530bof the inlet valve1200breturns to a rest position, opening the inlet valve1200bto allow fluid flow therethrough. During this step, the membrane1530aof the pump chamber remains in a deflected state to prevent fluid flow through the pump chamber1201.

In a fourth step, shown inFIG. 15D, the pump chamber membrane1530ais released, causing the membrane to return to a rest position. As the membrane1530aretracts, the pump chamber1201draws fluid from the reservoir1600into the pump chamber1201via the open inlet valve1200b.

After the fourth step, the inlet valve1200bmay then be sealed to isolate the pump chamber1201from the reservoir1600, as shown inFIG. 16A. The operation sequence illustrated inFIGS. 16A-16Drepeats to continue pumping fluid from the reservoir to the body1700or other fluid receiving component.

The illustrated pump1200formed using capping modules stacked on a microfluidic substrate according to an illustrative embodiment of the invention has a relatively small, compact size, low cost, while providing accurate flows. The pump1200is capable of delivering fluids, such as drugs for infusion, at a flow rate of between about 0.1 ml/hour and about 900 ml/hour. Because the external actuators displace the membranes by a fixed amount, the pump1200can provide a fixed dispensed volume per cycle independent of fluid viscosity. The pump1200can then operate independently of the viscosity of the fluid being pumped. In addition, the use of permanent components for the actuators, which can be relatively expensive, and disposable, low-cost components for the fluid paths of the pump allows for a relatively low cost, compact design. The pump design can be readily modified according to the desired flow rates, the actuator force required, cost, volume, lifetime or other parameters.

One skilled in the art will recognize that the capping module is not limited to the illustrative embodiment and that other elements may be implemented to add other microfluidic functions, in addition to or in place of, filtration and flow control.

A microfluidic system compiled using a capping module according to an embodiment of the present invention advantageously combines the power and scope of conventional membrane technology with the small volume dynamic flow control inherent in microfabricated/microstructure microfluidic systems. The present invention provides cost effective mixing of any suitable polymer membrane with a microfluidic network. The microfiltration system is simple and inexpensive to add to a microfluidic system, as the incremental cost of assembling the microfiltration system in a microfluidic chip is relatively low above the cost of the microfluidic system itself

A microfluidic system according to the present invention may comprise one or more of the above-described components, alone or in combination with other components.

The present invention has been described relative to an illustrative embodiment. Since certain changes may be made in the above constructions without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense.