WO2002057744A2 - Automated microfabrication-based biodetector - Google Patents
Automated microfabrication-based biodetector Download PDFInfo
- Publication number
- WO2002057744A2 WO2002057744A2 PCT/US2002/002005 US0202005W WO02057744A2 WO 2002057744 A2 WO2002057744 A2 WO 2002057744A2 US 0202005 W US0202005 W US 0202005W WO 02057744 A2 WO02057744 A2 WO 02057744A2
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- WIPO (PCT)
- Prior art keywords
- pump
- set forth
- chamber
- diaphragm
- magnetic member
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
- F04B43/00—Machines, pumps, or pumping installations having flexible working members
- F04B43/02—Machines, pumps, or pumping installations having flexible working members having plate-like flexible members, e.g. diaphragms
- F04B43/04—Pumps having electric drive
- F04B43/043—Micropumps
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
- F04B43/00—Machines, pumps, or pumping installations having flexible working members
- F04B43/02—Machines, pumps, or pumping installations having flexible working members having plate-like flexible members, e.g. diaphragms
- F04B43/04—Pumps having electric drive
- F04B43/043—Micropumps
- F04B43/046—Micropumps with piezoelectric drive
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0681—Filter
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0433—Moving fluids with specific forces or mechanical means specific forces vibrational forces
- B01L2400/0439—Moving fluids with specific forces or mechanical means specific forces vibrational forces ultrasonic vibrations, vibrating piezo elements
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L7/00—Heating or cooling apparatus; Heat insulating devices
- B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
Definitions
- microfabrication capabilities exist to fabricate devices having dimensions on a micrometer scale. This is referred to as microfabrication. Multiple microfabricated components involved in processes for conducting biological and chemical analysis can be integrated onto a single microfluidic system 104 that fits in a handheld device.
- the components may include filters, valves, pumps, mixers, channels, reservoirs, and actuators.
- Biochemical analysis typically involves preparing a sample, adding reagents, further method-specific manipulations such as heating and cooling, and reading and interpreting raw data.
- state-of-the-art automated systems have mechanized, rather than eliminated, many of these steps, they have not been able to combine a number of different methodologies or technologies into a single system.
- bio-sensor that is capable of processing a sample from start to finish within a single instrument, without complicated intervention or processing by the operator.
- bio-sensor it is desirable for the bio-sensor to be a hand-held, portable device that includes multiple microfabricated components a disposable microfluidic system 104 for performing a complete series of processes, as required, for biological and chemical analysis.
- bio-sensor it is desirable for the bio-sensor to provide cost-effective, yet highly sensitive and accurate analytical capabilities that provide results in a relatively short period of time.
- the bio-sensor should be configurable to perform a variety of different analytic processes. It is also desirable to provide capabilities for transferring information from the bio-sensor over an information network for access by other users.
- the present invention provides a system, apparatus, and method for processing a sample for chemical and/or biological analysis, and detecting one or more target substances.
- a variety of component configurations can be implemented in a device in accordance with the present invention, and a variety of different processes can be performed, depending on the configuration of components.
- the device incorporates microfabricated components in a handheld device.
- the device can also be networked with other information processing devices and share data regarding substances detected from the sample.
- the apparatus includes a first system of microfabricated components including at least a reservoir and a channel, and a second system of detection components including at least a lens.
- the lens is focused on a region (hereinafter
- sensing platform of the first system.
- the sensing platform is coupled to the reservoir by the channel.
- the second system includes a fluorescence detection system.
- fluorescence detection systems can be utilized with the present invention including detection systems with a laser that is positioned to illuminate a sample in the sensing platform.
- the microfabricated components include one or more pumps, such as a pump that is actuated electro-magnetically or piezoelectrically. The pumps can be used to transfer the sample from the reservoir to the sensing platform.
- One embodiment of a structure in accordance with the present invention includes a substrate with a pump chamber and at least two ports in communication with the pump chamber for transporting a substance into and out of the pump chamber.
- a flexible diaphragm overlies the pump chamber and the ports when the diaphragm is not deflected.
- a magnetic member is attached to or deposited on the diaphragm.
- the magnetic member can either be a permanent magnet or a ferromagnetic material such as iron.
- a magnet, such as an electromagnet is positioned to alternately attract and repel the magnetic member over one range of frequencies to pump a substance in one direction, and another range of frequencies to pump the substance in another direction.
- the flexibility characteristics of the diaphragm can be selected to achieve a desired pump rate as well as direction of flow.
- a control system can also be coupled to the pump-valve structure to adjust actuation frequency to achieve a desired flow rate and direction of flow.
- the present invention advantageously provides a pump-valve structure with a minimum number of moving parts to improve reliability and cost-effectiveness.
- the pump-valve structure is also physically separate from the actuating mechanism.
- the advantage of this feature is that the pump-valve structure can be included in a disposable portion of a system, while the more expensive actuating mechanism can be included on a non-disposable portion of the system and can be used to actuate other pump-valve structures.
- the absence of any electrically driven actuating mechanism on the pump- valve structure simplifies its fabrication out of low-cost polymer materials, making its use as a disposable device very cost-effective.
- the microfabricated components also include one or more valves that control flow of the fluid between the reservoir and the sensing platform.
- the microfabricated components also include one or more mixers that combine the sample with reagents or wash solutions.
- a mixer includes a nozzle that is positioned to inject a substance into the reservoir.
- the microfabricated components can also include one or more filters for extracting the target substance from the sample.
- Another feature that can be included in the apparatus is a thermoelectric cooler that is positioned to control the temperature of at least one of the microfabricated components. This feature can be used to heat and cool the sample during processing.
- Another feature of the apparatus is one or more driver units that are coupled to provide control signals to at least one of the microfabricated components, such as the pumps and the heater, as well as one or more of the detection components, such as the laser.
- the first system can be disposed of after processing a sample, and a new first system can be used for the next sample to be processed. This has the advantage of reducing the risk of contaminating the sample.
- the microfabricated components can be etched in a silicon substrate.
- a biosensor system for processing a sample and detecting one or more target substances in the sample includes data processing and control unit, a microfluidic system coupled to communicate with the data processing and control unit, and a detection system coupled to receive a processed sample from the microfluidic system. The detection system also transmits signals regarding the target substances to the data processing and control unit.
- a handheld housing houses the data processing and control unit, the microfluidic system, and the detection system.
- One feature of the system is a user interface coupled to receive input from a user and provide output to the user.
- the user interface is also coupled to provide the input from the user to the data processing and control unit.
- the system can be used to process and detect more than one type of substance, and the user can input information regarding the processes to be performed and the target substances to be detected.
- a method for purifying and detecting one or more target substances in a sample using a handheld biosensor system includes processing the sample using microfabricated components in the biosensor system, transferring the processed sample to a sensing platform in the biosensor system; and detecting the one or more target substances on the sensing platform using a detection system in the biosensor system.
- the method can include concentrating, filtering, heating, cooling, washing, and mixing the sample with other substances.
- Figure 1 is a block diagram of components included in an embodiment of a biosensor system in accordance with the present invention.
- Figure 1 A is a block diagram of components included in an embodiment of a biosensor device of Fig. 1 in accordance with the present invention.
- Figures lAA-1 AW are schematic diagrams of circuits included in an embodiment of the bio-sensor device of Fig. 1 in accordance with the present invention.
- Figure IB is a top view of components included in an embodiment of a biosensor device of Fig. 1 in accordance with the present invention.
- Figure IC is a side cross-section view of components included in an embodiment of a bio-sensor device of Fig. 1 in accordance with the present invention.
- Figure ID shows a flowchart of an example of a process for configuring communication between USB port and any components in biosensor system which can be identified as being coupled to communicate via the USB port.
- Figures. IE and IF show flowcharts of an example of a process for controlling temperature of the TEC.
- Figure 1 G shows a flowchart of an example of a process for controlling pump coils and valves based on a desired frequency and duration of the pumping cycle.
- Figure IH shows a flowchart of an example of a process for controlling PMT and outputting the information detected by the PMT.
- Figure 2 is a block diagram of components included in an embodiment of a microfluidic system for the bio-sensor device of Fig. 1 in accordance with the present invention.
- Figure 2 A is a flowchart of protocols for detecting viruses, bacteria, and toxins using the biosensor system of Fig. 1 in accordance with the present invention.
- Figure 3 A is a side of view of a filtration/concentration assembly that may be used to introduce a sample in the biosensor system of Fig. 1.
- Figure 3B is a side of view of a portion of the filtration/concentration assembly of Fig. 3A.
- Figure 3 C-l is a side of view of the electro-magnetically actuated pump in accordance with the present invention.
- Figure 3C-2 is a top view of the electro-magnetically actuated pump and check valve in accordance with the present invention.
- Figure 3D-1 is a cut-away side view of the electro-magnetically actuated pump- valve structure in the biosensor system of Fig. 1 in accordance with the present invention.
- Figure 3D-2 is a cut-away top view of the electro-magnetically actuated pump valve structure of Fig. 3D-1.
- Figure 3D-3 shows a portion of a pump-valve structure of Fig. 3D-1 during the supply mode of "variable gap" operation.
- Figure 3D-4 shows a portion of a pump-valve structure of Fig. 3D-1 during the pump mode of "variable gap” operation.
- Figure 3D-5 shows a portion of a pump-valve structure of Fig. 3D-1 at the first switching step of "elastic chamber” operation.
- Figure 3D-6 shows, a portion of a pump-valve structure of Fig. 3D-1 during supply mode of "elastic chamber” operation.
- Figure 3D-7 shows a portion of a pump-valve structure of Fig. 3D-1 at the second switching step of "elastic chamber” operation.
- Figure 3D-8 is a portion of a pump-valve structure of Fig. 3D-1 during pump mode of "elastic chamber” operation.
- Figure 3D-9 is a graph showing pump rate versus actuation frequency for a piezo-electrically actuated pump-valve structure of Fig. 3D-1.
- Figure 3E is a block diagram of a microfluidic pump coupled to a feedback and control system that can be utilized in the biosensor system of Fig. 1.
- Figure 3F is a-diagram of a piezoelectric pump that can be utilized in the biosensor system of Fig. 1.
- Figure 3G is a diagram of a mixer that can be utilized in the biosensor system of Fig. 1.
- Figure 4 is a diagram of an information network that can be used to access information from the microfluidic system of Figure 1 a.
- biosensor system 100 is shown including biosensor device 102, microfluidic system 104, and network interface 106 to workstation 108.
- microfluidic system 104 incorporates components that are required for performing chemical and/or biological processes on a sample of a substance to be analyzed.
- Microfluidic system 104 can be inserted and removed from biosensor device 102.
- Biosensor device 102 is a portable, hand-held unit that includes a user interface and display, an interface to microfluidic system 104, and a network interface 106 to one or more workstations 108 that allows a user at workstation 108 to access data collected using biosensor system 100.
- Biosensor system 100 can also be used as a workstation 108.
- Power supply 110 provides operating power to various components on biosensor device 102 including digital signal (DSP) and input/output (I/O) processor 112, driver circuits 114, analog circuits 116, a display 118, valves 120, thermistor 122, thermo-electric cooler 124, pump coils 126, and detection system 128.
- Power supply 110 can be one or more commercially available power supplies, such as an internal DC battery or a power regulator that interfaces to an external AC supply.
- Power supply 110 is capable of providing one or more operating voltages at the levels required by the components of biosensor device 102.
- Biosensor device 102 can also be powered via a universal serial bus (USB) port 130 with the workstation 108.
- USB universal serial bus
- Figs. 1 AA through 1 AJ are schematic diagrams showing examples of interface circuits between DSP 131 and other components included in DSP and I O processor 112.
- the circuits shown in Figs. lAA through 1AW are examples of commercially available devices that are suitable for use with biosensor device 102, as follows:
- Fig. 1 AA shows an example 'of the DSP and I/O processor 112 implemented with an ADSP-2181 processor commercially available from Analog Devices, Inc., Norwood, Massachusetts.
- Fig. lAA shows the various pins of the ADSP-2181 and connections to push-button switches, a clock generator, and a LED indicator.
- Fig. lAB shows an example of a memory device 140 for storing DSP program instructions which is a commercially available EEPROM (memory) chip, part # CAT28F512 by Catalyst Semiconductor, Sunnyvale, California;
- Fig. 1AC shows an example of an interface to Analog to Digital converter (ADC) 148 which converts analog voltage level, for example, temperature and fluorescence level), to a digital signal which can be used by the DSPT and I O processor 112.
- ADC Analog to Digital converter
- An ADC that is suitable for use with biosensor device 100 is ADC model number AD7887, which is commercially available from Analog Devices, hie, Norwood, Massachusetts.
- Fig. IAD shows an example of an interface to digital to analog signal converter DAC 146 which provides analog output voltage.
- a DAC that is suitable for use with biosensor device 100 is DAC model number AD5332, which is commercially available from Analog Devices, Inc., Norwood, Massachusetts.
- Fig. lAE shows an example of an interface to memory 142 for non- volatile memory storage.
- a memory device that is suitable for use with biosensor device 100 is the model number 24LC256, which is commercially available from Microchip
- the 24LC256 is a 32K x 8 (256K-bit) Serial Electrically Erasable PROM memory with an I2CTM compatible 2-wire serial interface bus.
- Fig. 1AF shows an example of RS-232 serial interface 133 to data terminal equipment, as known in the art.
- a serial interface that is suitable for use with biosensor device 100 is the serial interface device model number DS14C232, which is commercially available from Dallas Semiconductor, Dallas, Texas.
- Fig. 1AG shows an example of an interface device between device indicators 144 and DSP and I O processor 131.
- An interface device that is suitable for use with biosensor system 102 is demultiplexer chip model number MC74HC138, which is commercially available from ON Semiconductor Corp., Phoenix, Arizona.
- Fig. 1AH and 1AJ shows an example of an interface devices (not shown??) between DSP and VO processor 131, and digital I/O circuit 150 and the driver circuits 114 digital output gates and flip-flop chips model numbers MC74HC32 and MC74HC574, which are commercially available from ON Semiconductor Corp., Phoenix, Arizona.
- Fig. lAI shows an example of an interface between DSP and I/O processor 131 and USB port 130 as a commercially available USB interface chip, part # PDIUSBD12D by Phillip Semiconductor, Sunnyvale, California, and gate 74HC08 by ON Semiconductor, Phoenix, Arizona.
- Fig. 1 AK is an example of a programmable gain amplifier included in analog circuits 116 that amplifies the signal from the photo-multiplier-tube (PMT) 184 with part numbers PGA103 by Burr-Brown Corporation/Texas Instruments, Dallas, Texas, and operational amplifier OP27 by Analog Devices, Norwood, Massachusetts.
- PMT photo-multiplier-tube
- Fig. lAL shows an example of a duty cycle switch that can be included in TEC driver 154 to control the amount of power to TEC 124.
- the duty cycle switch is implemented with shift register part number 74HC165 by ON Semiconductor, and inverters, part numbers 74HC14 and #74HC04 by ON Semiconductor, Phoenix, Arizona.
- Fig. 1AM shows an example of a DC to DC converter for power supply 110.
- the circuit in Fig. 1AM converts a +12 volt (V) supply voltage to +5V, +12V and regulated +12V and includes DC-DC converter chips COSEL_ZU, part # ZUS 1R5 1205 by Cosel USA, San Jose, CA and AA01D_DUAL, part # AA01D-012L-120D by Astec America, Carlsbad, California.
- Fig. IAN shows an example of an interface between DSP and I/O circuits 112, analog circuits 116, and driver circuits 114 for controlling operation of TEC 124 and laser 182.
- Figs. 1 AO and 1AP show examples of circuits which provide a set of digital control output signals for opening and closing, respectively, valves 120.
- the circuits receive input control signals from the DSP and I/O processor 131.
- the embodiments of the circuits shown in Figs. 1 AO and 1 AP are implemented with flip-flop, part # 74HC574 by ON Semiconductor, and gate 74HC32 also by ON Semiconductor, Phoenix, Arizona.
- Fig. 1AQ shows an example of a light emitting diode to indicate when power to the system 100 (Fig. 1) is turned ON.
- Fig. 1AR shows an example of a circuit for a piezoelectric buzzer for chip insert detection or user input detection.
- Fig. IAS shows an example of an interface connector for connecting DSP 131 to other components in DSP and I/O processor 112.
- Biosensor device 102 also includes bridge circuits, examples of which are shown in schematics in Figs. 1AI and 1AU.
- Fig. 1AT shows an example of a bridge circuit used in TEC driver circuit 154, which includes logic gates, part numbers 74HC14 and 74HC08 by ON Semiconductor, Phoenix, Arizona.
- Fig. 1AU shows an example of a bridge circuit used in pump coil driver circuit 156, which includes logic gates, part numbers 74HC14 and 74HC08 by ON Semiconductor, Phoenix, Arizona.
- Fig. 1AV shows an example of a laser driver circuit 158, which maintains a constant light output from the laser 182 (Fig. 1A) by regulating the current to the laser 182.
- the laser driver circuit 158 includes inverter part number 74HC14 by ON Semiconductor, Phoenix, Arizona, and laser diode driver, part # iC-WJ by iC-Haus, Bodenheim, Germany.
- Fig. 1 AW is an example of the connector 152 that can be used to interface the microfluidic system 104 to biosensor device 102.
- Microfluidic system 104 includes microfabricated components for performing biological and chemical analysis. Such components can include, for example, filters, valves, pumps, mixers, channels, reservoirs, and actuators.
- Detection system 128 is used to detect target molecules that are the subject of the assay(s) that are performed using microfluidic system 104.
- One such detection system 128 includes an infrared (IR) laser and detector which is used to illuminate and detect IR dye, respectively, known as deoxynucleotide triphosphates (dNTPs) that can be used in the assays performed by microfluidic system 104.
- IR infrared
- dNTPs deoxynucleotide triphosphates
- Other suitable detection systems can be implemented with microfluidic system 104 in addition to, or instead of, an IR detection system. Detection system 128, and microfluidic system 104 are discussed more fully herein below.
- microfluidic system 104 is disposable and can be inserted and removed from biosensor device 102 as required. This allows a new microfluidic system 104 to be used for each new sample to be analyzed, thereby reducing the risk of contamination from previous samples.
- DSP and I/O circuits 112 includes a digital signal processor (DSP) 131 for digital ' signal processing along with main program instructions 132 that control execution of components included in DSP and I/O circuits 112. Main program instructions 132 also control communication with components external to DSP 131.
- DSP 131 is a single microcomputer optimized for digital signal processing and other high speed numeric processing applications.
- DSP 131 includes one or more serial data interfaces such as RS2-32 interface 133 and Universal Serial Bus (USB) interface 130.
- a peripheral device interconnect USB 134 shown, for example, as PDIUSBD12, allows conventional peripherals to be upgraded to USB devices and take advantage of the "hot plug and play" capability of the USB, as known in the art.
- USB 134 interfaces with most devices such as imaging, mass storage, communications, printing and human interface devices.
- USB 134 communicates with DSP 131 using a high-speed, general- purpose parallel interface 138.
- Other data interfaces can be included in addition to or instead of interfaces 133 and 134.
- DSP 131 also interfaces with other devices well-known in the art, including program and data memory device 140, 142 for storing data and executing program instructions, device indicators 144, such as switches and lights, digital to analog (DAC) and analog to digital (ADC) converters 146, 148, and digital I/O circuit 150.
- DSP 131 can also include a programmable timer and interrupt capabilities, as known in the art. Power-down circuitry can also be provided to conserve power when operating biosensor device 102.
- One example of a microprocessor currently available that is suitable for use in one embodiment is model number ADSP-2181 manufactured by Analog Devices, Inc. in Norwood, Massachusetts.
- Driver circuits 114 interface with microfluidics system 104 via connector 152 to communicate with valves 120, thermistor 122, pumps 126. Driver circuits 114 also interface with thermoelectric cooler (TEC) 128 and detection system 128 in biosensor device 102.
- Connector 152 can be one of several connectors that are well known in the art and commercially available. One such connector is part # FH12-50S-0.5SH by Hirose Electric Co. Ltd.
- Driver circuits include thermistor driver 153 and TEC driver 154 which generate signals to control the operation of thermistor 122 and TEC 124, respectively.
- Pump driver 156 includes logic to determine voltage signals required to operate pumps 126.
- the signals input to microfluidic system 104 to drive pumps 126 can be based on information provided by flow sensors 157 in microfluidic system 104, wherein the sensors 157 indicate the amount or rate of flow of a substance through one or more pumps 126.
- Laser driver 158 generates signals to control operation of a laser in detection system 128. Such a laser is used for fluorescence detection, as further discussed hereinbelow.
- Insert detector 162 receives information from microfluidic system 104 that indicates when microfluidic system 104 is inserted in biosensor device 102. When microfluidic system 104 is inserted in biosensor device 102, circuits 112, 114, and 116 use the signal to begin operating other components in biosensor device 102.
- Valve driver 164 sends signals to open and close valves 120 microfluidic system 104.
- a variety of valve and pump configurations can be implemented in microfluidic system 104, depending on the processes to be performed. The processes typically occur in a particular sequence, and can also be timed.
- valve driver 164 includes instructions for opening and closing each valve in microfluidic system 104 for respective processes and reactions.
- Valve driver 164, pump coil driver 156, thermistor driver 153, TEC driver 154, and laser driver 158 can also share information to determine which functions to perform at the appropriate time.
- User interface (UI) module 168 provides information and/or options to a user that is presented on display 118 and via device indicators 144. UI module 168 also receives input from one or more of a variety of known user input devices such as a keyboard, mouse, light pen, audio commands, or other data input device known in the art. It is important to note that a variety of suitable user input devices and displays, including audio, visual, and tactile input/output devices, are known in the art and can be incorporated with the present invention. The foregoing examples are not intended to limit the present invention to any particular input or display device, or combination of devices.
- Detection system 128 generates data signals representing the substances detected by the microfluidic system 104, and the data signals are input to analog circuits module 116.
- Analog circuits module 116 includes appropriate signal conditioning components 174, as required, such as a sample and hold circuit, filter(s), and/or an amplifiers). For example, if the signal to noise ratio is low, then noise filtering prior to amplification can be included.
- the output from analog circuits module 116 is input to an analog to digital (AD) converter 148 in DSP and I/O circuits 112 for conversion from analog to digital form. This digital data can be further processed in DSP and I/O processor 112, and the results output to display 118 and/or network interface 106.
- AD analog to digital
- Biosensor device 102 provides signals to actuate valves, pumps, and mixers to control the flow and mixing of the sample and various reactants to and from reservoirs in microfluidic system 104.
- Biosensor device 102 also provides control signals to thermistor driver 153 and TEC driver 154, which in turn provide signals to control operation of thermistor 122 and TEC 124, respectively, during processes such as DNA/protein denaturation, single strand DNA annealing, and primer extension.
- Biosensor system 102 can be programmed to perform a variety of assays that are performed automatically, or when selected by a user through UI module 168.
- DSP and I/O processor 112 driver circuits 114, and analog circuits 116 in biosensor device 102 can be implemented using a combination of hardware circuits, software, and firmware, as known in the art.
- biosensor device 102 automating Polymerase Chain Reaction (PCR) analysis.
- PCR Polymerase Chain Reaction
- Nano-scale devices for automating PCR and post-PCR analysis are available in the prior art, however, sample preparation including DNA/RNA isolation, and detection by PCR are still carried out manually as two different processes. Therefore, to fully exploit the potential of PCR-based detection, biosensor device 102 advantageously integrates sample preparation, target amplification, and fluorescence detection into a single, portable, cost-effective device.
- Biosensor device 102 can also be used for biological and chemical analysis processes in addition to, or instead of, PCR- based analysis. Referring now to Figs. 1, 1A, IB, and IC, Figs.
- IB and IC show a top view and side cross-sectional view of components of biosensor system 100 with microfluidics system 104 inserted into the biosensor device 102.
- Electronic circuit cards 180 control the operation of the optics in biosensor system 100, including laser diode source 182 and photo-multiplier tube (PMT) 184.
- any other light source such as a blue LED, can be used instead of, or in addition to, laser diode source 182.
- Photodiode(s), or any other photo or electrical signal detection system can be used, instead of, or in addition to, photomultiplier tube 184 for fluorescence detection and/or measurement.
- Electronic circuit cards 180 include DSP and I/O processor 112, driver circuits 114, and analog circuits 116.
- Detection system 128 includes optical components such as mirrors 185, 186, diachroic filter 188, and objective lenses 190, 192.
- Incident light beams (excitation) from laser diode 182 pass through a diachroic filter 188 and are directed at a specific wavelength via a mirror 185 and an objective lens 190 in respective order, to the detection area on the microfluidic system 104.
- Reflected (emitted) light beams from the detection area on the microfluidic system 104 are directed via the objective lens 190, mirror 185, diachroic filter 188 and mirror 186 at a specific wavelength, in respective order, to the detector 184, i.e., photomultiplier tube/photodiode.
- Emitted fluorescence (reflected light) is sensed by the detector 184, i.e., photomultiplier tube/photodiode.
- Detector 184 generates data signals representing the emitted (reflected) light and the data signals are input to analog circuits 116 (Fig. 1) for signal conditioning and conversion from analog to digital signals.
- Microfluidic system 104 is inserted into biosensor device 102 and is guided to the appropriate position by one or more guide members 194 which slides the microfluidic system 104 into position to connect electrical connector 152. Following insertion of microfluidic system 104, loading lever 196 is released to allow spring member 198 to place TEC 124 in contact with microfluidic system 104. Additionally, electromagnetic pump coils 199 are positioned adjacent to the top side of the microfluidic system 104. One or more of these coils 199 can also be positioned on adjacent other sides of microfluidic system 104 to actuate pump(s) 126 (Fig. 1A).
- Figs. 1D-1H show flowcharts for portions of the computer program instructions, which include generating a user interface for prompting a user to enter parameters to control operation of the TEC 124, the pump coils, 126, and the PMT 184.
- Fig. ID shows a flowchart of an example of a process for configuring communication between USB port 130 and any components in biosensor system 100 which can be identified as being coupled to communicate via the USB port 130.
- Figs. IE and IF show flowcharts of an example of a process for controlling temperature of the TEC 124.
- FIG. 1G shows a flowchart of an example of a process for controlling pump coils 126 based on a desired frequency and duration of the pumping cycle.
- Fig. IH shows a flowchart of an example of a process for controlling PMT 184 and outputting the information detected by the PMT 184.
- microfluidic system 104 including a plurality of pumps, valves, filters, mixers, reservoirs, and channels as described below.
- Connector 152 is also shown in microfluidic system 104, however the connections between the connector 152 and other components on microfluidic system 104 are not shown for simplicity.
- the connections between connector 152 and the other components are used to communicate signals such as drive signals and detection signals.
- the components shown and their placement with respect to one another in Fig. 2 depends on the particular processes to be performed using biosensor device 102. Notably, the number of components and their position with respect to one another, can vary from the configuration shown in Fig. 2. Other types of components can be included in addition to those shown in Fig. 2.
- Microfluidic system 104 can be configured with enough components to perform one or more protocols concurrently, or at different times with respect to one another. Further, some applications may not require the use of all the components in a given configuration. For example, a particular configuration of microfluidic system 104 can be used for more than one type of process. In this situation, one or more of the reservoirs may be used in some of the processes, but not in others due to different steps being required to prepare and process the sample. Additionally, the components, operate independently of one another, and can be controlled by an external or an embedded control system.
- Microfluidic systems 104 can be included in microfluidic systems 104 to perform processes to detect genes, toxins, viruses, bacteria, and vegetative cells.
- Microfluidic system 104 is intended to include most, if not all, of the components required to perform the process from start to finish, and thus minimal user handling of the sample and intervention is required.
- Microfluidic system 104 is also designed to be low-cost and disposable by using mass manufacturing techniques and low cost materials. The disposable feature advantageously lower the risk of contaminating the sample during testing because there is no residue from the sample, reagents, and/or final product from previous tests. Further, microfluidic system 104 yields highly reproducible results while requiring a relatively small sample size. For example, a 2.25 square inch disposable microfluidic system 104 can accommodate a sample volume of 10 microliters.
- a sample can contain a low concentration of molecules to be detected.
- the dimensions of microfluidic system 104 can range from one to two inches in length and height, and be less than one millimeter in thickness. Due to the small size of microfluidic system 104, the sample may need to be filtered and concentrated prior to performing the extraction and detection processes.
- a sample containing varying amounts of targets i.e., cells, virions, or toxins, can be loaded in sample entry port 202 and subjected to a respective sample preparation procedure, such as concentration. This is accomplished by inputting the sample into filter 204 to remove impurities that are larger in size than the target cells, viruses, or concentrates in the sample.
- Fig. 2 A shows a flowchart of examples of protocols that may be implemented on microfluidic system 204 (Fig. 2), including bacteria protocol 260 for isolating and purifying DNA from bacterial cells, virus protocol 262 for isolating and purifying RNA from animal viruses, and toxin protocol 264 for isolating and purifying toxins. Protocols 260, 262, and 264 are representative of the types of assays that can be performed on an appropriately configured microfluidic system 104.
- DNA/RNA purification that is used in protocols 260 and 262 can be achieved as described in the following steps: 1.
- the sample is transferred to chamber 208 by actuating pump 206, which can be a push button pump or an electronically actuated pump.
- the sample is mixed/resuspended in lysozyme solution from reservoir 210, which is transferred to mixer 208 via actuation of pump 212.
- a chamber in mixer 208 is heated to 95 degrees centigrade for a period of time, for example, 2 minutes.
- Protease e.g. Proteinase K
- Protease in reservoir 214 is pumped into mixer 208 via pump 215.
- microfilter 216 is a one to two micrometer filter. In other implementations, the size of microfilter 216 is selected based on the size of the target molecule.
- a DNA wash solution (for example, Ethanol and salts buffer) is transferred from reservoir 224 to mixer 220 via pump 228.
- Steps 6 and 7 can be repeated to concentrate DNA/RNA at the microfilter 230 or nucleic acid binding agent, and to discard proteins as well as other contaminants.
- Aqueous solution from reservoir 222 is pumped in the reverse direction through the microfilter 230 to the DNA/RNA collection chamber 238 for PCR. At this point, the DNA/RNA is dissolved in the PCR reagents solution (containing fluorescenctly labeled dNTPs) and is no longer bound to microfilter 230.
- Collection chamber 238 can either contain magnetic micro-beads or a polynucleotide array with assay-specific primers.
- protocol 264 includes the following processes: 1.
- the sample is transferred to mixer 208 by actuating pump 206, which can be a push button pump or an electronically actuated pump.
- the toxin sample is mixed/resuspended in lysozyme solution from a reservoir such as 210, which is transferred to chamber 208 via actuation of pump 212.
- Protease inhibitor from a reservoir such as 214 is pumped into the lysis chamber 208 via pump 215.
- the sample is pumped through microfilter 216 into mixer 220 via pump 218.
- the sample + wash solution from mixer 220 is pumped to the wash discard reservoir 232 via pump 234 through a cationic microfilter 230 or a protein binding agent such as cationic beads.
- Steps 6 and 7 can be repeated to concentrate the toxin (protein) at the microfilter 230 or protein binding agent, and to discard nucleic acid as well as other contaminants and cell debris.
- From reservoir 222 is pumped through the cationic microfilter 230 to the protein collection chamber 238 for immuno-PCR.
- the protein is dissolved in the neutral buffer and is no longer bound to the microfilter 230 or the protein binding agent, hi the collection chamber the toxin is mixed with the respective antibodies conjugated with specific primers and allowed to bind at 37 degrees centigrade for a period of time, such as 5 minutes.
- the treated sample is transferred from the chamber 208 to the collection chamber 238 (PCR area) where a target bound to an antibody is captured for PCR-based signal amplification reaction and waste is discarded in reservoir 232.
- the collection chamber 238 can either contain magnetic micro-beads or a polynucleotide array with millions of assay-specific primers anchored to the surface.
- millions of copies of the primers can be anchored on magnetic beads, such as those available from Bangs Laboratories, Inc. in Fishers, Indiana.
- the target can be detected using known conjugating methods, such as streptavidin-biotin capture methods.
- an identical set of primers can also be supplied free in solution along with PCR reagents.
- the target is extracted, purified, and captured in the collection chamber 238, the target is denatured at 95 degrees centigrade, and allowed to anneal (hybridize) at 65° centigrade with the primers anchored to an array or magnetic microbeads.
- the two strands of DNA are separated and respective anchored primers, as well as primers free in solution (supplied as reagent), bind to the complimentary target sequences.
- enzyme DNA polymerase such as Taq DNA polymerase or rTth polymerase provided by, for example, PE Applied Biosystems in Foster City, California, elongates or synthesizes new complimentary strands in 5'- 3' incorporating labeled, i.e., fluorogenic dNTPs, at 72°C.
- This reaction occurs in collection/PCR chamber 238.
- newly synthesized strands amplicons serve as templates for exponential amplification of the target sequence.
- 3' extension of the primers anchored to the surface leads to synthesis of fluorophore labeled target sequences covalently bound to the surface.
- Fluorophore labeling is accomplished by incorporation of fluorophore-dNTPs such as Cy5 dye- dCTP/dUTP. After removing free dNTPs and other reagents by washing, fluorescence is measured by detection system 128 (Fig. 1 A).
- Microfluidic system 104 can be configured and adapted to any of the nucleic acid- based assays, i.e., target amplification and hybridization-based signal amplification methods, as discussed in an article entitled "A Review of Molecular Recognition Technologies for Detection of Biological Threat Agents" by Iqbal, S.S., Michael, M.W., Bruno, J.G., Bronk, B.V., Batt, C.A., Chambers, J.P., Review article . Biosensors and Bioelectronics, (15) 549-578, 2000
- a microfilter that is suitable for use as filter 204 can be fabricated by etching pillars that are spaced as closely as 1 micrometer apart in the substrate that is used as the base for microfluidic system 104.
- One or more of a variety of suitable materials can be used for the substrate, such as silicon and/or plastic.
- the pillars can be created by etching a material such as silicon, or by other processes that depend on the material being used, such as injection molding with plastic materials.
- the filter pillars can be fabricated along with the pump chambers, valves, and mixers. To create filters with smaller pore sizes, the pillars can be coated with a suitable material.
- silicon pillars can be coated with a conformal material such as low-pressure-chemical- vapor-deposition (LPCVD) polysilicon, which is a standard material that is well-known in microfabrication art.
- LPCVD low-pressure-chemical- vapor-deposition
- Fig. 3 A shows filtration/concentration assembly 300 than can be used instead of, or in addition to, filter 204.
- Assembly 300 includes a loading chamber 302, a receiving chamber 304, and a plunger 306.
- Loading chamber includes a funnel portion 308 that mates with another funnel portion 310 on receiving chamber 304 as shown in Fig. 3 A.
- Filter 312 is an appropriately sized microfilter, depending on the size of the molecule to be detected.
- a molecular weight cut off filter or a negatively charged fiber glass filter such as those commercially available from Memtec Limited, Timonium, Maryland, can be used.
- Receiving chamber 304 is open at the end to allow the excess solution to flow out.
- assembly 300 is disassembled, receiving chamber 304 is inverted and a volume of assay reagent is loaded in receiving chamber 304.
- the volume of assay reagent can be as low as 5 to 25 microliters, depending on the size of port 202 in the microfluidic system 104.
- Plunger 306 is inserted in the top of receiving chamber 304, and funnel portion 310 is inserted in port 202 (Fig. 2) in microfluidic system 104, as shown in Fig. 3B. Plunger 306 is pushed downward to force the assay reagent though filter 312. Analytes previously concentrated on filter 312 are dissolved in the assay reagent and transferred into microfluidic system 104 through port 202.
- thermoelectric cooler 124
- Fig. 1 A Any suitable, commercially available thermal cycling device, such as a thermoelectric cooler (TEC) 124 (Fig. 1 A) can be used to achieve repeated heating and cooling of the sample in chamber 238 as described in the steps above.
- thermocycling can be carried out at temperatures such as 95-65-72°C.
- Other non-contact heating techniques well known in the art, such as Infra-red (IR) heating can also be used instead of or in combination with a TEC. Size and power output of the TEC depends on the application.
- OptoTEC and ThermaTEC series TEC's by MELCOR Corporation in New Jersey are suitable for use in such in systems.
- resistive heaters microfabricated on the microfluidic system 104 can be used for heating while the TEC 124 can be used for cooling.
- TEC 124 is positioned on or near microfluidic system 104 (Fig. 1) in close enough proximity to the chambers to effectively heat or cool the fluid(s) of system 104.
- a silver- filled, heat resistant adhesive with high thermal conductivity such as for example, H35- 175MP by Epoxy Technology, Billerica, Massachusetts, can be used to attach TEC 124 to promote heat transfer.
- TEC 124 can be included in biosensor device 102 such that it is aligned and spring-loaded to rest in a position to heat or cool the contents of the desired chambers microfluidic system 104 when it is inserted into biosensor device 102.
- Temperature feedback for closed-loop control is provided by a thermocouple which is co-located with the TEC 124.
- Thermocouples are a commercially available from numerous companies, for example, Newark Electronics Corporation in Chicago, Illinois and WakeField Engineering, Inc. in Beverly, Massachusetts. Temperature feedback can also be provided by microfabricated temperature sensors that are built in to microfluidic system 104.
- the microfluidic system 104 (Fig. 1) is comprised of two substrates bonded together and covered by third layer which forms the diaphragm.
- the upper substrate contains the pump chamber and the lower substrate contains the channels and reservoirs.
- Reservoirs can be sized according to the amount of substance to be stored in them.
- Reservoirs, mixers, and pumps can include ports for loading sample(s) and reagents.
- the sample(s) and reagents can be introduced using a syringe and the holes can be sealed by laminating a film of a hydrophobic porous material, such as GORE-TEX® by W. L. Gore and Associates, Inc., which will act as a vent for trapped gases.
- microfluidic system 104 can be etched in silicon substrates using a deep anisotropic silicon etching process known as Bosch process (e.g. ICP Multiplex System by Surface Technology Systems ,United Kingdom) as well as other silicon etching techniques well known in the art .
- Bosch process e.g. ICP Multiplex System by Surface Technology Systems ,United Kingdom
- other silicon etching techniques well known in the art .
- microfluidic system 104 can be assembled together using silicon-silicon fusion bonding.
- a flexible cover (e.g. of glass or plastic) can be bonded to cover the top substrate and also form a diaphragm for combination pump-valve structures as further described hereinbelow.
- the flexible cover can be transparent to allow optical detection or viewing under a microscope.
- microfluidic system 104 can be embossed in polymer substrates using an embossing tool manufactured by companies such as Jenoptik Microtechnic GmBH in Germany.
- a mold or negative replica of microfluidic system 104 is first etched into silicon to form an embossing tool.
- the mold can also be created by UV-exposing and developing a thick photoresist.
- the tool is then embossed into the polymer substrate at an appropriate softening temperature and then retracted.
- the tool can be re-used to create more replicas, reducing the cost per piece.
- Ports can be drilled into the embossed polymer substrates.
- Two or more substrates can be chemically bonded together.
- a thin sheet of polymer can be chemically bonded to cover the topmost substrate and form a diaphragm.
- the structure can also be fabricated using polymer injection molding and casting using materials such as poly-dimethyl- siloxane (PDMS).
- PDMS poly-dimethyl-
- Figs. 3C-1 and 3C-2 show a cross-sectional side view and a top view, respectively, of a pump 320 that is suitable for use in microfluidic system 104 (Fig. 1).
- Pump 320 includes diaphragm 338 that causes alternating volumetric changes in a pump chamber 340 when deflected. When pump chamber 340 contains liquids or gases, they are transferred by the pumping action into another chamber or reservoir (not shown) via channels 342, 344 in substrate 346.
- Check valves 348, 350 are located in channels 342, 344, respectively, to control the flow of fluid into and out of chamber 340.
- the diaphragm 338 is actuated electro-magnetically with magnetic member 352 being controlled by magnetic core 354 and alternating current in solenoid 356.
- Techniques known in the art such as silicon etching, plastic injection molding, and hot embossing can also be used to fabricate microfluidic system 104.
- a combination of fabrication methods well-known in the art can be used to fabricate flow channels 342, 344, pump chamber 340, and check valves 348, 350 in substrate 346.
- the top side of microfluidic system 104 includes channels
- the top and bottom sides can include access holes 357, 367 for loading reagents and other substances into chamber 340, as required.
- the sample(s) and reagents can be introduced using a syringe and then access holes 357, 367 are sealed by chemically bonding layers 360, 362 to the top and/or bottom sides, respective.
- Microfluidic system 104 can also be fabricated out of one or more layers of molded or embossed polymers.
- channels, reservoirs, pump chambers, and check valves are embossed in substrate 346.
- a flexible layer is chemically bonded to the top of substrate 346, to form diaphragm 338 and seal the channels, reservoirs, and access holes on the top side.
- Magnetic members 352 for pumps 320 are positioned on top of the second layer.
- a top protective layer 360 and/or a bottom protective layer 362 can be included to seal and protect the top and bottom of substrate 346, as shown in Fig. 3C-1.
- the top protective layer 360 is flexible to allow movement of diaphragm 352 during actuation.
- Diaphragm 338 is attached to the top of substrate 346 and is made out of a thin sheet of flexible material such as plastic, glass, silicon, elastomer, or any other suitable, flexible material.
- the flexibility or stiffness required of diaphragm 338 depends on the desired deflection of the diaphragm. Typically the stiffness is selected to achieve a total upward and downward deflection of approximately five to fifteen microns.
- Any suitable attachment mechanism, such as chemical bonding, can be used to attach diaphragm 338 to substrate 346. The bonding technique utilized should be capable of maintaining the seal while the pump 320 is operating.
- Magnetic member 352 is made out of magnetic material which is attracted and repelled by a magnetic force from magnetic core 354. Magnetic member 352 can be adhesively bonded to diaphragm 338, or electroplated onto the diaphragm 338 during manufacturing.
- Substrate 346 can be made of plastic, silicon, or other suitable material that is capable of substantially retaining the shape of pump chamber 340 during operation.
- An electrically conductive wire is coiled around magnetic core 354 to form solenoid 356. When an electric current passes through solenoid 356, a magnetic field is created in magnetic core 354. The polarity of the current can be alternated to change the direction of force of the magnetic field, thus alternately repelling and attracting magnetic member 352.
- the repelling and attracting forces cause diaphragm 338 to move, changing the volume of chamber 340.
- An increase in volume draws fluid or gas into chamber 340 via channel 342, and a decrease in volume forces the fluid or gas into channel 344.
- the flow rate is thus directly controlled by the frequency of the alternating current to solenoid 356.
- the current through solenoid 356 can have a positive or negative sign that produces a magnetic field in magnetic core 354.
- One end of the magnetic core 354 becomes positively charged, and the other end becomes negatively charged.
- magnetic core 354 When the sign of the current through solenoid 356 is reversed, the charge at the ends of magnetic core 354 also reverse. When the current is shut off, magnetic core 354 loses its magnetism. Further, magnetic member 352 has a positively charged end, and a negatively charged end. Magnetic member 352 is attracted to magnetic core 354 when the ends closest to each other are oppositely charged. Similarly, magnetic member 352 is repelled by magnetic core 354 when the ends closest to each other have the same charge. The strength of the attraction or repulsion depends on the number of windings in solenoid 356, and the strength of the electric current.
- Check valve 348 controls the inflow of fluid or gas into chamber 340, and check valve 350 controls flow out of chamber 340.
- Check valve 348 allows fluid to flow into chamber 340 when the volume of chamber 340 is increased, and prevents backflow of the fluid or gas when the volume of chamber 340 is decreased.
- Flow through channel 344 is controlled by check valve 350, which allows flow into channel 344 when the volume of chamber 340 is decreased, and prevents backflow from channel 344 when the volume of chamber 340 is increased.
- Pump 337 is well-suited for use with a variety of devices, in addition to microfluidic system 104, because the components associated with actuating pump 337, namely, magnetic member 352, magnetic core 354, and coil 356, can be fabricated to a wide range of dimensions, including micro-scale dimensions. Flow rates can be adjusted by varying the frequency and amplitude of the alternating current through solenoid 356. Additionally, an electronic, microprocessor-based control system 366, as known in the art and shown in Fig. 3E, can be implemented to receive sensor input from flow sensors 368 that measure the flow into and/or out of pump 337. For example, a Digital Signal Processor such as model number ADSP-2181 by Analog Devices, Inc. of Norwood, Massachusetts, can be used as the controller.
- a Digital Signal Processor such as model number ADSP-2181 by Analog Devices, Inc. of Norwood, Massachusetts, can be used as the controller.
- Magnetic member 352 is located on diaphragm 338.
- Magnetic core 354 is positioned close enough for its magnetic field to actuate diaphragm 338.
- Magnetic core 354 with solenoid 356 can be positioned above magnetic member 352 or below chamber 340, depending on the strength of the magnetic field developed by the magnetic core. Instead of a single electromagnet, two magnets placed on opposite sides of the magnetic member 352 can also be used in a push-pull configuration to maximize deflection.
- magnetic core 354, solenoid 356, and current source 364 can be built into a structure surrounding substrate 346, diaphragm 338, and magnetic member 352.
- Other types of devices for creating magnetic fields for actuating the magnetic member 352 can also be utilized with the present invention, instead of, or in addition to an electromagnet.
- permanent magnets with opposing charges can be mounted on a structure that moves toward and away from the magnetic member 352 at a periodic, variable rate, thereby actuating diaphragm 338.
- the magnet having a like charge to the magnetic member 352 would be used to repel the magnetic member 352, while the magnet having the opposite charge would be used to attract the magnetic member 352.
- Other alternatives known in the art for attracting and repelling a magnetic member 352 can also be utilized.
- check valves 348 and 350 are passive flaps etched or molded in the substrate 346.
- check valves 348, 350 are a substantially straight flap having a length that is longer than the width of channels 342, 344. The flap is angularly positioned across the width of the channel, with the end that is closer to the start of the flow being anchored to a sidewall of the channels 342, 344, while the other end of the flap is free-floating.
- This type of construction can be achieved by cutting or etching around the substrate material to leave it attached to one sidewall, while cutting or etching through the material to free it from the other sidewall. If an injection molding process is used, the mold is continuous between the sidewall and the flap to leave it attached to the sidewall, while a space is left between the other end of the flap and the sidewall.
- the force of a substance, such as a fluid or gas, being pumped through channels 342, 344 tries to align the flap with the direction of the flow.
- the substance passes through channel 342 as the free-floating end of the flap moves away from the sidewall with the direction of the flow caused by the vacuum that is created when diaphragm 338 is raised.
- the vacuum created by upward movement of diaphragm 338 also forces the free end of check valve 350 into the sidewall of channel 344, thereby preventing backflow from channel 344.
- biosensor device 102 would include one or more bi-directional valves. Further, the operation of both unidirectional and bidirectional valves could be controlled by the force of the flow created by actuating diaphragm 338, or electronically using logic in valve controller 164 (Fig. 1 A) to open and close valves 348, 350, in Fig. 3C-2.
- one or more channels can feed into pump chamber 340.
- one or more channels can be used to transport a substance out of pump chamber 340.
- Figs. 3D-1 and 3D-2 show a cross-sectional side view and a top view, respectively, of a pump-valve structure 320 that is suitable for use as pumps 206,212, 215, 218, 226, 228, 234, 236 and 250 in microfluidic system 104 (Fig. 1).
- Pump-valve structure 320 includes diaphragm 338, and pump chamber 340 with one or more ports, such as ports 348, 350.
- the volume of a pump chamber 340 changes when diaphragm 338 is deflected.
- Diaphragm 338 acts as a seal over port 350 when not deflected.
- Ports 348, 350 are openings that allow a substance to flow into and out of chamber 340, depending on the position of the diaphragm.
- pump chamber 340 contains a liquid or gaseous substance
- the substance can be transferred into another chamber or reservoir (not shown) via channels 342, 344 by alternately flexing diaphragm 338 in opposite directions.
- the diaphragm 338 is actuated electro-magnetically with magnetic member 352 being alternately attracted and repelled by magnetic core 354 and alternating current in solenoid 356.
- diaphragm 338 is flexed so that it does not contact gasket 358, then the substance can flow into or out of chamber 340 through port 350.
- the top substrate 346 of pump-valve structure 320 includes pump chamber 340, gasket 358, and ports 348 and 350.
- the bottom substrate 347 can include channels 344 and 342 that connect reservoirs, and ports 357 and 367 for loading reagents and other substances into chamber 340 or other reservoirs, as required.
- ports can also be provided through diaphragm 338 and top substrate 346.
- sample(s) and reagents can be introduced using a syringe and then sealing ports 357, 367 by bonding layers 360, 362 to the top and/or bottom sides, respectively. Other methods and mechanisms known in the art for sealing ports 357, 367 can also be utilized.
- Microfluidic system 104 with pump-valve structure(s) 320 can also be fabricated out of one or more layers of molded or embossed polymers, hi one embodiment, pump chambers, gaskets and ports can be embossed in substrate 346.
- a flexible layer can be chemically bonded to the top of substrate 346, to form diaphragm 338 and seal the pump chamber 340, and also to seal port 350 when undeflected.
- One or more magnetic members 352 can be positioned on top of top substrate 338.
- a top protective layer 360 can be included to seal and protect the top substrate 346, as shown in Fig. 3D-1.
- the top protective layer 360 is flexible to allow movement of diaphragm 338 during actuation and is therefore typically much thinner in thickness, for example, 10 to 40 microns, than the diaphragm.
- the bottom substrate 347 is similarly embossed with channels, reservoirs and ports.
- a bottom protective layer 362 can be included to seal the ports 348 and 350.
- the top substrate 346 and bottom substrate 347 can be chemically bonded to one another to complete the device.
- Diaphragm 338 is attached to the top of substrate 346 and is made out of a thin sheet of flexible material such as plastic, glass, silicon, elastomer, or any other suitable, flexible material.
- the flexibility or stiffness required of diaphragm 338 depends on the desired deflection of the diaphragm. For example, a stiffness factor can be selected to achieve a total upward and downward deflection of approximately five to fifteen microns.
- Any suitable attachment mechanism such as chemical bonding with or without an intermediate glue layer, can be used to attach diaphragm 338 to substrate 346 around the periphery of chamber 340.
- the bonding technique utilized should be capable of substantially maintaining the seal between diaphragm 338 and substrate 346 while the pump-valve structure 320 is operating. The bonding technique should avoid bonding the diaphragm 338 to the gasket 358 which can prevent motion of the diaphragm 338.
- Magnetic member 352 is made out of magnetic material, which is attracted and repelled by a magnetic force from solenoid 356.
- the magnet can be a permanent magnet, a ferromagnetic material such as iron, or any other suitable magnet.
- Magnetic member 352 can be adhesive-bonded to diaphragm 338, or electroplated onto the diaphragm 338.
- other techniques for selective deposition or growth of magnetic material on the substrate can also be employed.
- iron powder can be mixed with a thermosetting or ultraviolet adhesive and stencil-printed on to the substrate before final cure.
- Substrate 346 can be made of plastic, silicon, or other suitable material that is capable of substantially retaining the shape of pump chamber 340 and gasket 358 during operation.
- substrate 347 can be made of plastic, silicon, or other suitable material that is capable of substantially retaining the shape of channels 344, 347 and ports 357, 367.
- an electrically conductive wire is coiled around magnetic core 354 to form solenoid 356.
- the strength of the magnetic force that can be achieved with solenoid 356 depends on the size of the magnetic core 354, the amount of wire coiled around the magnetic core 354, and the amount of current applied to the wire. The parameters can be varied to achieve the forces required for various embodiments of biosensor device 102.
- an electric current passes through solenoid 356, a magnetic field is created in magnetic core 354.
- the polarity of the current can be alternated to change the direction of force of the magnetic field, thus alternately repelling and attracting magnetic member 352.
- the repelling and attracting forces cause diaphragm 338 to move, thereby changing the volume of chamber 340.
- a periodic excitation voltage e.g., a square wave
- solenoid 356, such as provided by current source 364 causes diaphragm 338 to oscillate, producing a pumping action.
- the solenoid can also be a simple coil with no physical core, i.e., air core. Typically air core solenoids produce less force as compared to magnetic core solenoids.
- an increase in volume draws a substance into chamber 340, and a decrease in volume forces the substance out of chamber 340.
- the actuation frequency and diaphragm flexibility can be selected to cause a substance to enter chamber 340 through port 350 and exit chamber 340 through port 348.
- different values for the actuation frequency and diaphragm flexibility can be selected to reverse the direction of flow, causing a substance to enter chamber 340 through port 348 and exit chamber 340 through port 350, as indicated in Fig. 3D-1.
- the pump-valve structure 320 can operate as a pump by two different mechanisms: 1) a "Variable Gap” mechanism, and 2) an “Elastic Chamber” mechanism.
- the diaphragm 338 is a stiff material, for example, a glass layer with a thickness of 250 microns
- the pump operates by the Variable Gap mechanism, as disclosed in Stehr, M. et al., "A New Micropump With Bi-Directional Fluid Transport and Selfblocking Effect", Proceedings of the 1996 IEEE Workshop on Microelectromechanical Systems (MEMS 96), San Diego, California, pp. 485-490 (hereinafter, "the Stehr pump”).
- the pump-valve structure 320 operates by the Elastic Chamber mechanism.
- the direction of flow is from port 348 to port 350, as shown in Fig 3D-1, while in the case of the Elastic Chamber mechanism, the flow is in the opposite direction.
- a diaphragm 338 fabricated with polycarbonate material having a thickness of approximately 200 microns can achieve a pump rate up to 60 microliters per minute.
- Figs. 3D-3 and 3D-4 show a cycle of operation of pump-valve structure 320 by the Variable Gap mechanism.
- a square wave periodic excitation is assumed.
- This mechanism has two steps depicted by Fig. 3D-3 and Fig. 3D-4.
- the supply mode Fig. 3D-3
- the diaphragm 338 is deflected away from substrate 346 and the substance is drawn into pump chamber 340 through ports 348, 350 by the displacement.
- the supply mode Fig. 3D-3
- the diaphragm 338 is deflected away from substrate 346 and the substance is drawn into pump chamber 340 through ports 348, 350 by the displacement.
- the gap between the diaphragm 338 and gasket 358 is very small, so the substance flow through this gap and out of port 350 is negligible.
- This second mechanism includes four steps shown in Figs. 3D-5 to 3D-8.
- the diaphragm 338 is switched within a very short time. Since the diaphragm 338 is elastic, the volume increase caused by motion of the diaphragm 338 is compensated by the deformation of the portion of the diaphragm 338 that is not attached to the magnetic member 352. Given the inertia of the substance being pumped there is negligible flow, for example, less than 5 percent of normal flow, within switching times typically of the order of tens of milliseconds.
- the diaphragm 338 relaxes and draws fluid in through ports 348 and 350 as indicated by the arrows in Fig. 3D-6.
- the diaphragm 338 is switched to its original state. Again the switching time is very small and volume decrease caused by the motion of the diaphragm 338 is compensated by deformation of the diaphragm 338.
- the pump mode as shown in Fig. 3D-8, the relaxation of the diaphragm 338 pushes the substance out through port 348 since port 350 is now closed by the diaphragm 338.
- the pump-valve structures 320 in Fig. 2 can operate in the either the Elastic Chamber mechanism or the Variable Gap mechanism depending on the embodiment.
- the direction of substance flow in either the first or second mechanisms can also be reversed by increasing the frequency of periodic excitation to a level at or beyond the resonant frequency of the diaphragm. This is due to the dynamic effects related to the mechanical resonance of elastic components, which experience a phase shift between the pump chamber pressure and the opening of port 350, causing the pump direction to reverse. Thus direction and rate of flow depends on both frequency of excitation and flexibility of the diaphragm 338. At frequencies at or greater than resonant frequency of diaphragm 338, the direction of flow of the substance reverses from that observed at lower frequencies.
- the pump-valve structure 320 can also operate as a normally-closed valve. In the absence of any excitation the diaphragm 338 forms a tight seal with the gasket 358 and the valve is in the closed state.
- the "tightness" of the seal between diaphragm 338 and gasket 358 also referred to as the pressure head that the closed valve can achieve without significant leakage.
- the tightness of the seal is determined by the flexibility or spring constant of the diaphragm 338. For example, the diaphragm 338 should allow less than 5 percent leakage flow when the valve is closed.
- diaphragms 338 can be designed to have specific flexibility and hence pressure-heads.
- steady- state i.e., constant
- current flows through the solenoid 356 in a direction that causes the solenoid to attract or pull-up the magnetic member 352 on diaphragm 338
- a gap forms between diaphragm 338 and gasket 358. This allows flow of substance through port 350 and the valve is open.
- the pump-valve structure 320 operates as a normally-closed valve.
- the pump-valve structure 320 is fabricated with a gap between the diaphragm 338 and the gasket 358, it would operate as a normally-open valve with steady-state excitation pulling the diaphragm 338 onto the gasket 358 to make tight seal.
- a piezoelectrically-actuated silicon pump-valve that operates similarly to pump- valve structure 320 in Fig. 3D-1 is disclosed in Stehr, M. et al., "A New Micropump With Bi-Directional Fluid Transport and Selfblocking Effect", Proceedings of the 1996 IEEE Workshop on Microelectromechanical Systems (MEMS 96), San Diego, California, pp. 485-490, (hereinafter, "the Stehr pump”).
- the Stehr pump includes a substrate 346 made of Perspex adhesively bonded to an embossed diaphragm 338 made by micromachining silicon. Diaphragm thickness ranges from 0.020 millimeters to 0.015 millimeters.
- Fig. 3L shows the pump rate of water achieved by actuating a Stehr pump with a square wave voltage having an amplitude of 150 Volts. For actuation frequencies between 1 Hertz and 75 Hertz, the substance is directed from port 348 to port 350. At actuation frequencies higher than 75 Hertz, the pump direction changes.
- the stiffness of the diaphragm 338 and the volume of pump chamber 340 determine the pump rate that can be achieved with pump-valve structure 320. Increasing the stiffness of the diaphragm 338 results in decreasing the change in volume of pump chamber 340 when the diaphragm 338 is deflected, and increasing the critical frequency between forward and reverse pump direction.
- the current through solenoid 356 can have a positive or negative sign that produces a magnetic field in magnetic core 354. One end of the magnetic core 354 becomes positively charged, and the other end becomes negatively charged. When the sign of the current through solenoid 356 is reversed, the charge at the ends of magnetic core 354 also reverse. When the current is shut off, magnetic core 354 loses its magnetism.
- magnetic member 352 has a positively charged end, and a negatively charged end. Magnetic member 352 is attracted to magnetic core 354 when the ends closest to each other are oppositely charged. Similarly, magnetic member 352 is repelled by magnetic core 354 when the ends closest to each other have the same charge. The strength of the attraction or repulsion depends on the number of windings in solenoid 356, and the strength of the electric current.
- solenoid 356 can typically require currents in the range of 100 to 500 milliamps and voltages in the range of 5 to 12 Volts to operate.
- Piezoelectric actuators in contrast, typically require 100's of Volts during operation.
- the lower voltages required for electromagnetic actuation, as compared to piezoelectric actuation, facilitates integration of electromagnetically actuated devices, such as the pump-valve structure 320, with other electronic components. This is because many commonly-available electronic devices operate at similar low voltage levels. Lower voltage is also generally advantageous from a safety and portability point of view.
- Pump-valve structure 320 is well-suited for use with a variety of devices, in addition to microfluidic system 104, because the components associated with actuating pump-valve structure 320, namely, magnetic member 352, magnetic core 354, and coil 356, can be fabricated to a wide range of dimensions, including micro-scale dimensions. Flow rates can be adjusted by varying the frequency and amplitude of the alternating current through solenoid 356. Additionally, an electronic, microprocessor-based control system 366, as known in the art and shown in Fig. 3M, can be implemented to receive sensor input from flow sensors 368 that measure the flow into and/or out of pump-valve structure 320. For example, a Digital Signal Processor such as model number ADSP- 2181 by Analog Devices, Inc.
- Logic associated with confrol system 366 can compare the actual flow rate to the desired flow rate, and provides a drive signal to current source 364 to adjust the frequency and amplitude of the current source 364 accordingly to achieve the desired flow rate from pump-valve structure 320.
- magnetic member 352 is located on diaphragm 338.
- Magnetic core 354 is positioned close enough for its magnetic field to actuate diaphragm 338.
- Magnetic core 354 with solenoid 356 can be positioned above magnetic member 352 or below chamber 340, depending on the strength of the magnetic field developed by the magnetic core.
- two magnets placed on opposite sides of the magnetic member 352 can also be used in a push-pull configuration to maximize deflection.
- magnetic core 354, solenoid 356, and current source 364 can be built into a structure surrounding substrate 346, diaphragm 338, and magnetic member 352.
- magnetic core 354 can be replaced with an air core.
- permanent magnets with opposing charges can be mounted on a structure that moves toward and away from the magnetic member 352 at a periodic, variable rate, thereby actuating diaphragm 338.
- the magnet having a like charge to the magnetic member 352 would be used to repel the magnetic member 352, while the magnet having the opposite charge would be used to attract the magnetic member 352.
- Other alternatives known in the art for attracting and repelling a magnetic member 352 can also be utilized.
- microfluidic system 104 would include one or more bi-directional valves. Further, the operation of both unidirectional and bi-directional valves could be controlled by the by actuating diaphragm 338, or electronically using logic in valve controller 164 (Fig. 1A). Depending on the embodiment, one or more channels, such as channel 342 in Fig. 3D-2, can feed into pump chamber 340. Likewise, one or more channels, such as channel 344, can be used to transport a substance out of pump chamber 340.
- microfluidic system 104 would include one or more bi-directional pump-valve structures 320.
- Fig. 3F shows a diagram of a typical piezoelectric micropump 380 found in the art that is suitable for use with the present invention in addition to, or instead of, pump 320 (Fig. 3C-1).
- Pump 380 includes a pump chamber 382 which is capped by heat-resistant glass layer 388 which also forms the diaphragm.
- Piezoelectric element 390 is bonded to diaphragm 388.
- Applying a voltage from voltage source 386 to the piezoelectric element 390 induces either an upward or downward deflection depending upon the polarity of the applied voltage. This changes the volume of the pump chamber 382, causing it to draw fluid through an inlet valve, and to pump fluid through an outlet valve, on opposite strokes of the cycle.
- Applying a periodic excitation voltage causes diaphragm 388 to oscillate, producing a pumping action.
- the flow rate is thus directly controlled by the frequency of the electrical drive signal to the piezoelectric element 390.
- Substrate 392 can be fabricated from polymer or silicon material.
- the glass layer 384 is bonded onto substrate 392 using a suitable bonding method, such as anodic or epoxy bonding, to prevent leakage.
- a suitable bonding method such as anodic or epoxy bonding
- Polyimides and thermal laminants can also be used for bonding and have the advantage of a lower bonding temperature.
- One way to mix very small amounts of two or more substances in microfluidic system 104 is to feed the flow streams into one channel as they are directed to a reservoir or pump chamber.
- An alternative way includes injecting one substance into another using micro-nozzles.
- Mixer 394 includes a mixing chamber 396 with nozzles 398 on one side.
- the mixing chamber 396 is filled with one or more substances, and another substance is injected through the nozzles 398, thereby generating a plurality of micro-plumes.
- the plumes effectively mix the substances without requiring any additional processing.
- Mixing time depends on injection flow rate, size of nozzles, distance between each nozzle and size of the mixing chamber. Nozzles with orifices as small as one (1) micrometer can be provided using known fabrication processes.
- Information from biosensor device 102 can be accessed by authorized users when biosensor device 102 is connected to an information network.
- One embodiment of components and connections between components in information network 410 that can be used with the present invention is shown in Fig.4. Users access information and interface with information network 410 through workstations 412. Workstations 412 execute application programs for presenting information from, and entering data and selections as input to interface with information network 410. Workstations 412 also execute one or more application programs to establish a connection with server 416 through network 420.
- network 420 includes networking equipment that is suitable to support the communication link being utilized.
- workstations 412 can be one of a variety of stationary and/or portable devices that are capable of receiving input from a user and transmitting data to the user.
- the devices can include visual display, audio output, tactile input capability, and/or audio input/output capability.
- Such devices can include, for example, biosensor system 100, desktop, notebook, laptop, and palmtop devices, television set-top boxes and interactive or web-enabled televisions, telephones, and other stationary or portable devices that include information processing, storage, and networking components.
- each workstation 412 can be one of many workstations connected to information network 410 as well as to other types of networks such as a local area network (LAN), a wide area network (WAN), or other information network.
- LAN local area network
- WAN wide area network
- Server 416 is implemented on one or more computer systems, as are known in the art and commercially available. Such computer systems can provide load balancing, task management, and backup capacity in the event of failure of one or more computer systems in server 416, to improve the availability of server 416. Server 416 can also be implemented on a distributed network of storage and processor units, as known in the art, wherein the modules and databases associated with the present invention reside on workstations 412, thereby eliminating the need for server 416.
- Server 416 includes database 422 and system processes 424.
- Database 422 can reside within server 416, or it can reside on another server system that is accessible to server 416.
- Database 422 contains information regarding users as well as results from tests performed using biosensor device 102. Consequently, to protect the confidentiality of such information, a security system can be implemented that prevents unauthorized users from gaining access to database 422. Users can be authorized to transmit and/or receive information from database 422.
- User interface 114 (Fig. 1) can allow the user to download and/or retrieve results from one or more tests to database 422.
- System processes 424 include program instructions for performing analysis of data from biosensor device 102 and other information provided by the user.
- the type of analysis performed is based on the type of data being analyzed, and the type of information to be provided to the user.
- biosensor system 100 is generating and sharing information for medical diagnosis.
- a user can introduce a sample to be analyzed, such as a drop of blood or other bodily fluid, into microfluidic system 104.
- a sample to be analyzed such as a drop of blood or other bodily fluid
- microfluidic system 104 includes the components, and the type and amount of reagents required to perform one or more assays on the sample.
- Biosensor system 100 can screen for known pathogens for infectious diseases and/or markers for genetic disorders. After the sample is analyzed, the presence of a pathogen or a disease marker (gene/protein) above a specific level can be indicated.
- Data from each assay can be transmitted to server 416 directly from biosensor system 100 or via workstation 412.
- the data is stored in server 416 using a personal, secured account that is generated for each user.
- a subscriber, such as a physician and/or other authorized individual, can be granted remote access to the user's account via information network 420.
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2002236852A AU2002236852A1 (en) | 2001-01-22 | 2002-01-22 | Automated microfabrication-based biodetector |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/767,009 US20020098122A1 (en) | 2001-01-22 | 2001-01-22 | Active disposable microfluidic system with externally actuated micropump |
US09/766,740 | 2001-01-22 | ||
US09/766,742 | 2001-01-22 | ||
US09/767,009 | 2001-01-22 | ||
US09/766,740 US20020098097A1 (en) | 2001-01-22 | 2001-01-22 | Magnetically-actuated micropump |
US09/766,742 US6878755B2 (en) | 2001-01-22 | 2001-01-22 | Automated microfabrication-based biodetector |
US92141201A | 2001-07-31 | 2001-07-31 | |
US09/921,412 | 2001-07-31 |
Publications (3)
Publication Number | Publication Date |
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WO2002057744A2 true WO2002057744A2 (en) | 2002-07-25 |
WO2002057744A3 WO2002057744A3 (en) | 2002-09-19 |
WO2002057744A9 WO2002057744A9 (en) | 2002-12-19 |
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ID=27505707
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/002005 WO2002057744A2 (en) | 2001-01-22 | 2002-01-22 | Automated microfabrication-based biodetector |
Country Status (2)
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AU (1) | AU2002236852A1 (en) |
WO (1) | WO2002057744A2 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007067063A1 (en) * | 2005-12-07 | 2007-06-14 | International Research Institute Of Stavanger As | A device for a borehole arrangement |
FR2947813A1 (en) * | 2009-07-07 | 2011-01-14 | Centre Nat Rech Scient | SYNTHETIC JET GENERATING MICROSYSTEM, MANUFACTURING METHOD AND CORRESPONDING FLOW CONTROL DEVICE. |
US7998731B2 (en) | 2003-03-17 | 2011-08-16 | General Dynamics Advanced Information Systems, Inc. | Portable sampling device for airborne biological particles |
DE102010015161A1 (en) | 2010-04-16 | 2011-10-20 | Technische Universität Dresden | Microfluidic system and method of its operation |
WO2012159672A1 (en) * | 2011-05-25 | 2012-11-29 | Hach Lange Gmbh | Fluid analysis device |
EP3527826A1 (en) * | 2018-02-16 | 2019-08-21 | ams AG | Pumping structure, particle detector and method for pumping |
Citations (3)
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US5948684A (en) * | 1997-03-31 | 1999-09-07 | University Of Washington | Simultaneous analyte determination and reference balancing in reference T-sensor devices |
US6048734A (en) * | 1995-09-15 | 2000-04-11 | The Regents Of The University Of Michigan | Thermal microvalves in a fluid flow method |
US6109717A (en) * | 1997-05-13 | 2000-08-29 | Sarnoff Corporation | Multi-element fluid delivery apparatus and methods |
-
2002
- 2002-01-22 AU AU2002236852A patent/AU2002236852A1/en not_active Abandoned
- 2002-01-22 WO PCT/US2002/002005 patent/WO2002057744A2/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US6048734A (en) * | 1995-09-15 | 2000-04-11 | The Regents Of The University Of Michigan | Thermal microvalves in a fluid flow method |
US5948684A (en) * | 1997-03-31 | 1999-09-07 | University Of Washington | Simultaneous analyte determination and reference balancing in reference T-sensor devices |
US6109717A (en) * | 1997-05-13 | 2000-08-29 | Sarnoff Corporation | Multi-element fluid delivery apparatus and methods |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7998731B2 (en) | 2003-03-17 | 2011-08-16 | General Dynamics Advanced Information Systems, Inc. | Portable sampling device for airborne biological particles |
WO2007067063A1 (en) * | 2005-12-07 | 2007-06-14 | International Research Institute Of Stavanger As | A device for a borehole arrangement |
GB2445702A (en) * | 2005-12-07 | 2008-07-16 | Internat Res Inst Of Stavanger | A device for a borehole arrangement |
FR2947813A1 (en) * | 2009-07-07 | 2011-01-14 | Centre Nat Rech Scient | SYNTHETIC JET GENERATING MICROSYSTEM, MANUFACTURING METHOD AND CORRESPONDING FLOW CONTROL DEVICE. |
WO2011004124A3 (en) * | 2009-07-07 | 2011-02-24 | Centre National De La Recherche Scientifique (C.N.R.S) | Microsystem for generating a synthetic jet, corresponding manufacturing method and device for flow control |
DE102010015161A1 (en) | 2010-04-16 | 2011-10-20 | Technische Universität Dresden | Microfluidic system and method of its operation |
WO2011127908A1 (en) | 2010-04-16 | 2011-10-20 | Technische Universität Dresden | Microfluidic system and method for the operation thereof |
WO2012159672A1 (en) * | 2011-05-25 | 2012-11-29 | Hach Lange Gmbh | Fluid analysis device |
EP3527826A1 (en) * | 2018-02-16 | 2019-08-21 | ams AG | Pumping structure, particle detector and method for pumping |
WO2019158377A1 (en) * | 2018-02-16 | 2019-08-22 | Ams Ag | Pumping structure, particle detector and method for pumping |
US11732705B2 (en) | 2018-02-16 | 2023-08-22 | Ams Ag | Pumping structure, particle detector and method for pumping |
Also Published As
Publication number | Publication date |
---|---|
AU2002236852A1 (en) | 2002-07-30 |
WO2002057744A3 (en) | 2002-09-19 |
WO2002057744A9 (en) | 2002-12-19 |
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