HK1021954A - Analytical system and method - Google Patents

Description

Analysis system and method

This application is filed 1996, 8/2/and is continued through the section of U.S. patent application No. 08/691632, the disclosure of which is incorporated herein by reference.

Background

1. Field of the invention

The present invention relates generally to systems and methods for performing chemical and biological assays. In particular, the present invention relates to the design and use of an analyzer system employing an analysis substrate to be evaluated in a base unit, wherein an adapter is used as an interface between the substrate and the base unit.

Chemical, clinical and environmental analysis of chemical and biological samples can be performed using a variety of systems and instruments. Conventional systems may employ various detection devices to monitor chemical or physical changes to the composition or other properties of the sample being measured. These instruments include spectrum analyzers, fluorometers, light detectors, radioactivity counters, magnetometers, galvanometers, reflectometers, ultrasonic detectors, temperature detectors, pressure detectors, toxic gas detectors, electrophoresis detectors, PCR systems, LCR systems, and the like. These instruments are often combined with electronic support systems such as microprocessors, timers, video displays, LCD displays, input devices, output devices, and the like, in a single analysis device. These analytical devices may be adapted to receive a sample directly, but are more often designed to receive a sample placed on a sample receiving substrate, such as a dipstick, cuvette, analytical rotor, etc. Sample-receiving substrates are typically manufactured for single use (i.e., disposable), while analytical devices include circuitry, optics, sample manipulation, and other structures necessary for conducting assays on the substrate. As a result, most analytical devices tend to work with only a single type of sample-receiving substrate and are not suitable for use with other substrates.

A new sample-receiving substrate known as a "microfluidic" system has been developed in recent years. Microfluidic substrates have a network of several chambers connected by trenches of medium size, at least one of which is typically between 0.1 μm and 500 μm. These microfluidic substrates can be fabricated using photolithographic techniques similar to those employed in the semiconductor industry, and the resulting devices can be used to perform a variety of complex chemical and biological analysis techniques. Microfluidic analytical processes have many advantages, including the ability to use very small sample sizes, typically on the order of nanoliters. The substrates can be produced at low cost and can be formatted to perform a variety of specific analytical tasks, including mixing, formulating, valving, reacting, and detecting.

Due to the variety of analytical techniques and the potentially complex sample flow patterns that may be incorporated into a particular microfluidic test substrate, particular demands may be placed on the analytical devices supporting the test substrate. Not only must the analytical device manage the direction and timing of flow through the network of channels and reservoirs on the substrate, it must also provide one or more physical effects at locations distributed around the substrate, including heating, cooling, exposure to light or other radiation, detection of light or other illumination, measurement of electrical/electrochemical signals and ph, etc. Flow control management may also consist of various actions including patterned application of voltage, current or power to the substrate (for electrokinetic flow control), or application of pressure, sonic energy or other mechanical action for additional induced flow.

It follows that a virtually unlimited number of specific test formats can be incorporated into a microfluidic test substrate. Because of this diversity and complexity, many, if not most, test substrates will require specially designed analytical equipment to perform a particular test. In practice, it is possible that a particular test substrate is tested differently using more than one analytical device. However, the need to provide a dedicated analysis device for each substrate and test would greatly reduce the flexibility and cost advantages of microfluidic systems.

It is therefore desirable to provide improved analysis systems and methods that overcome or greatly mitigate at least some aspects of the above-described problems. In particular, it would be desirable to provide an analytical system that includes a substrate analysis unit that can support a number of different microfluidic or other test substrates having widely differing flow patterns, chemistries, and other analytical characteristics. It is particularly desirable to provide an analysis system that can greatly reduce the cost of modifying a substrate analysis unit to perform different tests on different test substrates.

2. Description of the background Art

Microfluidic devices for analyzing samples are described in the following patents and published patent applications: U.S. patent nos. 5498392; 5486335, respectively; 5304487 and WO 96/04547. In WO95/02189 an analysis system with an analysis module connected to an expansion socket of a general-purpose computer is described. A sample is typically mounted on an analysis rotor or other sample support device, which may be placed in the receptacle, and the computer is used to control the analysis of the sample in the module. Chemical analysis systems are described in U.S. patent nos. 5510082; 5501838, respectively; 5489414; 5443790, respectively; 5344326, respectively; 5344349, respectively; 5270006, respectively; 5219526, respectively; 5049359, respectively; 5030418 and 4919887; european published patent applications EP299521 and EP 6031; japanese published patent applications JP 3-101752; JP3-094158 and JP 49-77693.

The disclosure of this application is related to the following co-pending applications, the disclosures of which are incorporated herein by reference: U.S. patent application No. 60/015498 (provisional) filed 4, 16 1996; U.S. patent application No. 08/671987 filed on 28/6/1996; U.S. patent application No. 08/671986 filed on 28/6/1996; U.S. patent application No. 08/678436 filed on 3/7/1996; U.S. patent application No. 08/683080 filed on 16/7/1996.

Summary of the invention

The present invention overcomes at least some of the above-mentioned disadvantages by providing an analysis and preparation system that employs an adapter as an interface between a sample substrate and an analysis substrate unit. The sample substrate is typically a microfluidic substrate, but may be any other sample substrate capable of receiving a test piece or starting material to process or provide a detectable signal, wherein the substrate unit manages sample flow, reagent flow, and other analytical and/or preparative techniques performed on the substrate. The adapter allows a single type of base unit, i.e., a base unit having a particular configuration, to interface with a large number of test and other substrates having different configurations and to manage many specific analysis and preparation techniques on the substrates with little or no re-layout of the base unit itself.

The methods and apparatus of the present invention can be used with analytical and preparative techniques. By "analyzing" is meant that the assay or process is substantially intended to perform a detection and/or quantitative analysis in a test piece. By "preparing" is meant that the process is substantially inclined to produce one or more products from one or more starting materials or reagents. The following description relates primarily to analytical methods and apparatus, but for the most part all of the techniques described are equally useful for preparing materials for other subsequent uses.

In a first aspect, the present invention provides an analytical system including a substrate unit having a mounting region with a substrate interface structure including at least one interface piece therein. An adapter is configured to be removably mounted to the mounting area of the base unit and has an adapter-to-base interface structure that also includes an interface member. When the adapter is mounted on the base unit, the adapter-to-base interface structures mate with the base interface structures, and at least some of the interface members in each structure will interconnect or mate. The adapter also includes a sample substrate mounting area having an adapter-sample substrate interface structure therein. The adapter-sample substrate interface structure also typically includes at least one interface member (although in some cases the interface member may be substantially disposed on the base unit relative to the interface member on the sample substrate). A sample substrate is designed to be removably mounted to the sample substrate mounting area of the adapter and itself includes a sample substrate interface structure that typically includes at least one interface member. When the sample substrate is mounted in the sample substrate mounting region, the interface piece in the sample substrate interface structure will mate with a corresponding interface piece in the adapter-sample substrate interface structure and/or the base plate interface structure.

By providing appropriate interface members in each interface structure, power and/or signal connections can be made in a virtually indefinite number of patterns between the base unit and the sample substrate. In some cases, the base unit will only provide power and signal connections to the adapter, while the adapter will provide a relatively complex adapter-sample substrate interface for managing flow, other various operating parameters, and detection of sample substrates. In other cases, however, the substrate interface structure on the substrate unit may be more complex, including, for example, light sources, detectors, and/or high voltage power supplies, while the adapter is simpler, often to position the sample substrate on the substrate unit relative to the interface, to multiplex the voltages, and to allow direct communication between the substrate unit and the sample substrate.

Exemplary interfaces include power supplies, analog signal connectors, digital signal connectors, energy delivery sources, energy emission detectors, other detectors and sensors, and the like. The energy transfer source may be a light source, an acoustic energy source, a heat source, a cooling source, a pressure source, or the like. Energy emission detectors include photodetectors, fluorometers, UV detectors, radioactivity detectors, thermal detectors (calorimeters), flow detectors, and the like. Other detectors and sensors may be provided to measure ph, potential, current, etc. It will be appreciated that where an interface member in one configuration is connected or engaged with a corresponding interface member in a mating configuration to transfer power, signals or other information, the interface members are often provided in pairs. However, the interface members do not all require pairs, and the energy delivery source or emission detector is often provided without a corresponding interface member in the mating interface member.

The base unit, adapter and sample substrate will be designed such that they can be physically joined to each other to form an analysis system. For example, the mounting area in the substrate unit may be a cavity, well, slot, or other receptacle that receives the adapter. Similarly. The mounting area on the adapter may include a receptacle, well, slot, or other space that tends to receive a sample substrate and properly position the substrate relative to the adapter and/or base unit. The sample substrate preferably employs fluid channels and reservoirs of intermediate size, i.e., wherein the channels have at least one dimension in the range of 0.1 μm to 500 μm, typically 1 μm to 100 μm. However, the invention is not limited to the particular manner in which the base unit, adapter and substrate are mounted and/or the particular dimensions of the flow channels on a sample substrate.

While the above description is directed to a three layer system, it should be understood that additional components or "layers" may be employed. For example, additional carriers or adapters may be employed to provide additional interfaces, such as carriers for sample substrates, wherein the carriers are mounted within or connected to the adapters received on the base unit. Similarly, the mounting area in the base unit that receives the adapter may include a separate component that is itself removably or permanently secured to the base unit. The use of discrete components to form the mounting area is advantageous because it facilitates standardization of the system. For example, the adapter-mounting region component can be separately, optionally manufactured, and/or prepared to exacting specifications at a single location, both of which help ensure that a base unit associated with such a standardized mounting region can mate with all of the corresponding adapters. Standardized adapter-mounting areas can also be adapted for interconnection with other components of the base unit, such as heaters, cooling devices, plug connections, etc., thus facilitating interconnection with these devices. Thus, systems having four or more layers are within the scope of the present invention.

In a second aspect of the invention, an assay system comprises a base unit and a sample substrate, generally as described above. An adapter is configured to be removably mounted to the mounting area of the base unit and includes a mounting area for removably receiving the sample substrate. The adapter holds the sample substrate in a fixed position relative to the base unit and provides (i) a connection path from an interface member in the base interface structure to the substrate; or (ii) a connection path from the interface member in the sample substrate structure to the base plate unit. According to this aspect of the invention, the adapter is capable of substantially positioning a sample substrate in the substrate unit relative to the interface structure. For example, if the substrate unit interface structure includes a light source and/or light detector, the adapter may properly position the sample substrate relative to the light source/detector to perform a desired measurement. The adapter may optionally, but not necessarily, provide further interface capabilities between the sample substrate and the base unit.

In another aspect of the invention, an adapter is provided for use in combination with a base unit and a sample substrate, as described above. The adapter includes an adapter body having an adapter-substrate interface structure including at least one power and signal connector configured to mate with a corresponding connector in the substrate interface structure when the adapter is mounted in the mounting area of the substrate unit. The adapter also includes a sample substrate mounting region having an adapter-sample substrate interface structure including at least one flow biasing connector configured to mate with a corresponding region in the sample substrate interface structure when the sample substrate is mounted in the mounting region of the adapter. The flow biasing connectors are typically used for electrokinetic flow control in medium and other microfluidic sample substrates, but may also be components that generate acoustic, pressure, or mechanical flow. Adapter-sample substrate interface structures often include, in addition to flow biasing contacts, interface components, such as radiation emission and detection components, that are configured to interface with specific areas of the sample substrate.

The substrate unit may be self-enclosed, i.e., may include all digital and/or analog circuitry and user input/output interfaces necessary to control an assay and produce assay results from the system. However, it is often desirable to connect the base unit to a general purpose or general purpose computer that provides some or all of the control analysis, and/or reporting functions and some or all of the user interface. The computer is typically a standard personal computer or workstation and operates in accordance with a standard operating system such as DOS, Windows  95, Windows  95NT, UNIX, Macintosh, etc. The computer can provide a number of standard user input devices such as a keyboard, hard drive, floppy disk, CD reader; and user output devices such as screens, printers, floppy disks, writable CD output devices, etc. This is particularly advantageous because the use of a computer can greatly reduce the cost of the base unit and greatly increase the rating of the computer components of the system using the same base unit. In addition to these advantages, in some cases it may be preferable to incorporate a computer's interface and digital circuitry into the substrate unit of the present invention, which can take on all of the capabilities of a general purpose digital computer, but may be less flexible.

When the system of the present invention is controlled by digital circuitry, i.e., using a separate general purpose computer connected through the base unit or with digital control circuitry incorporated within the base unit, it is generally preferred to provide at least a portion of the manipulation instructions associated with any particular adapter and/or any particular sample substrate and to verify the format in a computer readable form, i.e., on a general purpose computer storage medium such as a floppy disk, compact disk (CD ROM), tape, flash memory, etc. The medium will store computer readable code that sets forth the required instructions for enabling the computer, which may be a separate or integrated computer, to interface with the base unit and control the assay performed by the base unit on a sample substrate supported by an adapter received on the base unit. The invention itself therefore comprises a computer program in the form of a tangible medium, such as a disk, CD, tape, storage, etc., which can be used in conjunction with the system of the invention. The present invention also includes systems that include an adapter in combination with a tangible medium that stores the computer instructions described above. The invention also includes systems that are a combination of one or more simple substrates as set forth above and a tangible medium as set forth above including computer readable code of instructions as set forth above.

The user may preload the supplied computer program onto a desired medium, typically a floppy disk or cd rom, or alternatively may load the program onto the medium by the user over a network, over telephone lines, or by other communication and transmission means. The program is then incorporated into the medium and provided to the systems and methods of the present invention for use.

In yet another aspect of the invention, a method for providing an analytical system includes providing a base unit having a mounting area including at least one interface piece therein. An adapter is removably mounted to the mounting area of the base unit such that the interface members on the adapter mate with corresponding interface members on the base unit. The adapter includes a sample substrate mounting region having at least one interface member therein, and a sample substrate is removably mounted to the mounting region of the adapter such that the interface member on the sample substrate mates with a corresponding interface member on the adapter. Typically, but not necessarily, the adapter is removably mounted on the base unit by mounting the adapter in a socket of the base unit, and the sample substrate is removably mounted on the adapter by mounting the sample substrate in the socket of the adapter. The sample substrate is preferably a microfluidic device having a plurality of channels connecting a plurality of reservoirs and including a flow biasing region disposed at one of the reservoirs and/or channels. The base unit may then direct and manage the flow in the substrate by providing flow control signals to the adapter. The flow control signal energizes the flow biasing regions on the adapter, thereby energizing corresponding flow biasing regions on the substrate to control flow through the channel and between the reservoirs. For example, flow control may be effected by electrically biasing electrodes on the sample substrate to induce electrokinetic flow control. In addition, the exciting step may include acoustically driving a flow biasing region on the sample substrate. The adapter typically includes a source of electromagnetic radiation and a detector for signal generation and detection in various analytical techniques. Any of the above control steps may be implemented by providing computer readable code to an integral or separate computer that controls the analysis system.

Brief description of the drawings

FIG. 1 illustrates a first embodiment of an analysis system incorporating features of the present invention.

FIG. 2 illustrates a second embodiment of an analysis system incorporating features of the present invention.

FIG. 3 is a block diagram illustrating the flow of information between various components of the system of the present invention.

FIG. 4 illustrates an exemplary analysis system incorporating the system components of the present invention.

Description of the specific embodiments

The analysis system of the present invention includes a base unit, an adapter, and a sample substrate. Each of these system parts will be described in detail below. Typically, the analysis system is designed to house and analyze a wide variety of samples and specimens. For example, the sample may be a biological sample taken from a patient, but may be a variety of other biological, chemical, environmental and other samples that have a component to be characterized or an analyte to be detected. The assay system may be used to perform a variety of specific assay and/or preparation techniques, such as chromatography, PCR, LCR, enzymatic reactions, immunological reactions, and the like. The sample is typically a liquid or liquefied prior to testing and is often subjected to a chemical or biochemical reaction prior to analysis. The assay system can provide various sample processing in addition to chemical or biochemical reactions, such as mixing, compounding, valving, separation, heating, cooling, detection, and the like. The assay system may rely on various existing detection techniques such as spectroscopic analysis, fluorescence analysis, radiometric measurement, magnetometry, amperometric measurement, reflectometry, ultrasonic detection, toxic gas detection, electrophoretic detection, temperature detection, pressure detection, potentiometric detection, amperometric detection, and the like. In the following exemplary preferred embodiments, sample manipulation and detection are both performed in a microfluidic substrate, wherein the sample is manipulated between a reservoir of very small volume formed in the substrate and a flow channel.

All flow and test conditions on the substrate are generally controlled by the base unit and adapter as described below.

The base unit of the present invention typically comprises a housing or frame that is intended to be mounted, for example, on a floor, on a counter, on a stand or in any other conventional manner, or may be portable or hand-held. The base unit typically includes at least power and/or signal transmission circuitry, and typically includes signal processing capabilities to facilitate analysis and/or storage of data received from the adapter as described below. The base unit also typically includes a microprocessor to facilitate management of its substrate management and data collection functions. An information display, optionally in the form of a video monitor, alphanumeric display, printer, LED display, etc., may typically be mounted on or in the frame along with a data entry device such as a keyboard, touch screen, etc. However, in these exemplary embodiments, the base unit includes only a plug connection device for connecting to an external computer, wherein the computer houses the necessary input and output devices. In these cases, the base unit often, but not necessarily, includes an internal microprocessor for controlling or facilitating control of the internal operation of the base unit and adapter. In addition, a microprocessor can be installed in the adapter, and the base plate unit only provides the interface function between the adapter and the computer bracket. In other cases, all control functions are managed by a separate computer, while the base unit and adapters provide only distribution and interface functions. It is again noted that the capabilities of the base unit and the adapter provide a wide range of specific designs with different functions selectively distributed between the adapter and the base unit for specific assays and sample substrate designs.

The base unit includes a mounting area for removably securing the adapter. The mounting area on the base unit has a base interface structure that includes at least one, and typically a plurality of interface members that are intended to provide power and/or information communication with the adapter. The interface consists of a number of devices, as described in detail below. The mounting area may be any feature or structure on the housing or frame of the base unit that can removably mount the adapter. The mounting area is typically designed to couple the adapters in a unique arrangement so that the substrate interface structure is uniquely configured relative to the adapters. The mounting area may have many forms such as a socket, well, slot, disk (similar to a CD disk), etc. The mounting area often defines a receptacle size having dimensions corresponding to the outer perimeter of the adapter to secure the adapter in a desired orientation relative to the base unit. Additionally, pegs, plugs, snaps, or other fasteners may be provided to secure the adapter to the base unit in a desired orientation.

The adapter also includes a housing or frame, although the housing or frame is typically much smaller than the housing or frame of the base unit. As mentioned above, the housing or frame is adapted to be received on or in the mounting region of the base unit, itself and includes a mounting region for removable attachment to a sample substrate. The mounting area on the adapter may take any of the forms described above for the mounting area on the base unit, which typically must hold the sample substrate in a particular orientation relative to the adapter.

The adapter includes an adapter-substrate interface structure that mates with or connects to the substrate interface structure when the adapter is mounted in the mounting area on the substrate unit. The adapter-substrate interface structure includes at least one interface that mates with a corresponding interface within the substrate interface structure, typically for providing power and/or signal connections between the substrate unit and the adapter. The interface may provide a variety of additional interconnections and will be described in detail below.

The sample substrate mounting region includes an adapter-sample substrate interface structure that is intended to mate with or connect to a sample substrate interface structure on a sample substrate when the sample substrate is mounted to the mounting region. The adapter-sample substrate interface structure itself includes at least one interface member that can be any of the elements described in detail below. The adapter-sample substrate interface structure typically includes a plurality of interface members arranged or distributed in a pattern selected to mate with at least some corresponding interface members in the sample substrate structure on the sample substrate.

The sample substrate may comprise any of a number of existing analytical devices or articles for holding and processing samples in a manner for providing a detectable output, which may relate to a sample property, such as an analyte, composition and properties of molecules present in the sample (e.g., proteins or nucleic acids), and the like. The present invention is particularly intended for use with microfluidic sample substrates of the type disclosed in U.S. patent nos. 5498392, 5486355, 5304487 and published PCT application No. WO96/04547, which are incorporated herein by reference. Suitable microfluidic substrates are also described in commonly assigned U.S. patent application Ser. No. 08/761987 filed on 28.6.1996 and U.S. patent application Ser. No. 08/845759 filed on 25.4.1997, the descriptions of which are incorporated herein by reference.

A particular advantage of the present invention is that the adapter can be designed to accommodate any of a variety of specific sample substrate configurations. In this way, the designer of the sample substrate is free to optimize the dimensions, design, flow paths and other features of the sample substrate without having to take into account the nature of the substrate elements excessively. In a broad range, most of the specific design features of the sample substrate can be included by appropriate design of an adapter. While providing this advantage, the design of the sample substrate may also take into account specific features and design characteristics of the base unit and/or adapter. It should be noted that the system configuration using the adapter as an interface between the sample substrate and the base unit provides great design flexibility.

As described above, the sample substrate has dimensions and other characteristics selected to allow it to be removably mounted to the mounting area. The sample substrate also includes a substrate interface structure including at least one interface piece configured to mate with a corresponding interface piece on the adapter-sample substrate interface structure on the adapter. This interface, once again, may comprise any of a number of specific devices and components, as previously described. Interface elements on the adapter and sample substrate generally provide flow control management of the sample and other liquid reagents present and applied on the sample substrate, and further provide power and signal interconnections between the adapter and sample substrate.

The term "interface" as used herein and in the claims refers to any of a number of discrete components or regions in an interface structure present on a substrate unit, adapter or sample substrate. The interface is typically provided for electrical or other energy transmission, energy emission detection, and the like.

Electrical connection means for power and signal transfer typically include conventional connection means in the form of electrodes, plugs, Zero Insertion Force (ZIF) connectors, and the like. These electrical connections typically require mating contacts of two interface structures that are unified when the systems are summed. The electrical connection means are often present on a surface or edge of the interface structure to enable the respective interface members to engage each other when mounting the adapter on the base unit or mounting the substrate on the adapter. Similarly, surface or edge electrodes may be provided in the adapter-sample substrate interface structure to mate with corresponding surface or edge electrodes on the sample substrate. The electrodes on the sample substrate can then be internally connected to the desired reservoirs or fluid flow channels in the substrate for electrokinetic flow control, as described in the previously cited patents and patent applications. In other cases, however, it may be desirable to provide an interface member in an adapter-sample substrate interface configuration that is adapted to be in direct contact with a fluid to be subjected to an electrical force control. For example, probes or plugs may be provided on adapters that penetrate into open wells or through a membrane on the sample substrate to enable direct contact and application of an electrical potential. Fig. 2 shows a specific example of such a joint.

Energy transmission sources are typically intended to energize a region of a test substrate or to provide energy to an initial fluid flow over a sample substrate. This energy can take a variety of forms, including light, such as visible and invisible light; acoustic energy; heating; cooling; pressure; mechanical energy; electrical energy, etc. In the case of sample detection, the energy transmission source may be light or other radiation that tends to excite a specimen or label to be detected. Heating/cooling may be provided to assist in a particular chemical reaction or to provide conditions. Sound, pressure and mechanical energy may be provided to directly effect fluid flow in the channels of the microfluidic sample substrate. It should be understood that these energy transmission sources need not have corresponding interface members in adjacent interface structures. Instead, energy transfer is typically performed at a region on the sample substrate that is to receive energy.

Energy transmission detectors may be provided, typically on the adapter and/or base unit, to detect energy emitted from the sample substrate. For example, the detection reaction may result in the transmission of energy by fluorescence, luminescence, radiation, or other means that need to be detected and/or quantified for a particular assay. Suitable sensing components may be provided in the adapter and/or base unit, with the adapter relying on proper alignment of the substrate with the detector.

One particular class of interface for the analytical system of the present invention is referred to as a "flow offset joint". Flow-biasing connectors are intended to refer to those interface members that are capable of inducing fluid flow on a sample substrate, particularly a microfluidic substrate having a flow channel and a reservoir network. For microfluidic substrates employing electrokinetic management, the flow-biasing contacts on the adapter are typically electrodes, probes, plugs, etc. distributed within or on the adapter sample substrate interface structure to mate with the flow channels and reservoir network in the sample substrate as previously described and referenced. The electrodes typically have corresponding electrode terminals of electrical connections present on the sample substrate, so that the electrode terminals can be interconnected on the adapter with corresponding electrical connections on the adapter-sample substrate interface structure (or in rare cases on the substrate interface structure of the substrate unit). As noted above, in other cases, the flow biasing connector may be a probe or plug of an adapter configured to directly engage a fluid present on or in the sample substrate. For example, the plug structure may be mounted on a hinged lid or cover of the adapter plate to allow the sample substrate to be mounted on the adapter, and then the cover closed to insert the plug into the open sample well on the substrate. Of course, the sample well need not be open and can be covered by any insertable membrane or diaphragm which is pierced by the plug when the cover is closed. Other flow biasing connectors include an acoustic energy source (piezoelectric transducer) mounted within the adapter-sample substrate interface structure to engage them with the sample substrate at a location that tends to direct fluid flow through the flow channel. Other flow biasing fittings also include a pressure source that can initiate flow by pressurization, a mechanical energy source that can cause mechanical pumping of fluid through the flow channel, or the like.

Referring to fig. 1, a first exemplary analysis system 10 in accordance with the principles of the present invention includes a base unit 12, an adapter 14, and a sample substrate 16. The base unit 12 includes a plug receptacle 20 for mating with a plug 22 on the bottom surface of the adapter 14. A computer jack 24 is provided for mating with a conventional serial or parallel input device of a general purpose computer such as a personal computer, workstation, or the like. The substrate typically includes at least signal processing and conditioning components, such as an analog-to-digital converter for receiving analog data from the adapter 14 and converting the data to digital form for transmission to a computer. In other cases, however, the computer may be adapted to convert the analog signal directly to digital data. The base unit 12 and/or adapter 14 can also be provided with an analog-to-digital converter for controlling power, flow or any other parameter directly from the digital signal from the computer. The adapter 14 may also include an internal microprocessor for further data manipulation. The adapter 14 may also include a power input for direct current and/or low voltage alternating current (which may be provided by a power source in the base unit 12). The plug receptacle 20 is typically provided for an interface for power and signal exchange between the base unit 12 and the adapter 14. Alignment pins 28 are mounted on the upper surface of the base unit 12 to engage alignment holes 30 in the adapter 14. Thus, the entire upper surface of the base unit 12 will provide a mounting area for the adapter 14, while the plug receptacle 20 generally provides an adapter-sample substrate interface structure with individual plugs of the mounting interface.

The plug 22 includes an adapter-sample substrate interface structure on the adapter 14. The plug 22 provides power and signal connections for the base unit 12, while the adapter further provides a light source and detector 34 and a heating/cooling element 36, both of which mate with specific areas on the sample substrate 16, as described below. The adapter 14 also includes an edge connector 40 that includes a plurality of electrodes 42 that mate with corresponding electrodes 44 on an edge of the sample substrate 16. The sample substrate 16 is removably attached to the adapter 14 by sliding the substrate between a pair of guides 46 formed by L-shaped parallel grooves on the upper surface of the adapter 14. When the sample substrate 16 is fully inserted between the guides 46 by the electrodes 44 received in the edge tabs 40, a reaction site 50 on the sample substrate 16 is aligned with the light source of the detector 34 on the adapter 14, and a thermal treatment zone 52 is aligned with the heater/cooler 36 on the adapter. Thus, the light source detector 34, the heater/cooler 36, and the edge connector 40 all include interface members in the mounting area of the adapter 14.

The sample substrate 16 includes a plurality of sample and reagent wells 60, each of which is connected to an electrode 44 in the interface structure. In this manner, sample flow over the sample substrate can be controlled by the base unit 12 and adapter 14 to control power through the electrodes 42. It will be appreciated that this power may be provided directly through the base unit 12, in which case the adaptor 14 functions merely to distribute the power. In addition, the substrate unit 12 can provide information to the adapter, while the adapter 14 internally generates power that is distributed through the electrodes 42. In either case, the flow of sample between the reservoir and the flow channel network 66 is controlled in a desired manner. A portion of the sample and mixed reagent will flow through the heating/cooling zone 52 where it will be appropriately processed. Again, the amount of heating or cooling provided by the region 36 is provided and controlled by a combination of the substrate unit 12 and the adapter 14, wherein a particular function may be provided by one of these two components. The output signal resulting from the reaction or reactions is actually read by the light source/detector 34 at the reaction area. The output of the light source detector 34 will be returned to the substrate unit 12 through the plug receptacle 20 and the male plug 22. The light source detector will typically generate an analog signal, and the analog signal may be converted to digital in any of the adapter 14, the base unit 12, or an external computer (not shown).

Fig. 2 shows a second exemplary embodiment 100 of the analysis system of the present invention. The analysis system 100 includes a substrate unit 112, an adapter 114, and a substrate 116. The base unit 112 is similar in many respects to the base unit 12 of FIG. 1 and includes alignment pins 128, a plug receptacle 120, and a computer jack 124. However, the substrate unit 112 also includes a light source/detector 134. This is different from the analysis system 10 in which the light source/detector 134 is provided as part of the adapter 14.

The adapter 114 includes a plate 115 having a small hole 117 in its center. When the adapter 114 is mounted on the base unit 112, the aperture 117 will generally be located above the light source/detector 134. The adapter 114 also includes a hinged cover 119 for covering and mounting the sample substrate 116 to the top of the plate 115. When the sample substrate 116 is mounted and the lid 119 is closed, the plurality of probes 121 on the lower surface of the lid will be inserted into the sample and reagent wells 160 on the sample substrate 116. The trap 160 may be fully opened by a penetrable diaphragm or membrane. Thus, the probe 121 is immersed and in direct contact with the liquid present in the well 160. In this manner, an electrical bias can be provided for electrokinetic flow management through the network of channels 166 on the sample substrate 116.

The sample substrate 116 includes a reaction region 150 that is typically at least partially transparent or translucent to allow light energy to pass from the light source detector 134 to the fluid in the region and to allow detected and emitted light energy to exit the region. This incident and emitted light from region 150 passes through aperture 117 in adapter 114 so that it can be directly connected to light source/detector 134. Again, this is different from the analysis system 10 of FIG. 1, where detection is performed directly between the adapter 14 and the sample substrate 16.

It should be understood that the exemplary analysis systems 10 and 100 are intended to be representative of a virtually indefinite number of possible system configurations. The various power, signal, and other functions of the analysis system can be included on any of the adapters, base units, substrates, or external computers in virtually any manner using the adapter 14 or 114 so that any particular analysis technique can be best supported by the system.

Referring to fig. 3, the system 200 of the present invention may be designed in a variety of ways. For example, a base unit 212 may comprise a single integrated instrument that contains all the control and analysis components (in combination with adapter 214 and sample substrate 216) necessary for performing the assay, requiring only connection to a power line or other power source. However, the unit 212 will be connected to a general purpose computer 220, such as a personal computer or workstation, which provides at least a portion of the input/output, control, and computing functions of the system 200. Computer 220 may be connected by any conventional connector, typically using serial or parallel input ports. The computer is programmed with software 222 and may take the form of any conventional computer media. The software includes instructions for all or part of the computer functions. For example, the software may include an operating system for performing all assays using the system of the present invention. Alternatively, the computer may employ a conventional operating system that can control real-time functions as described above. The system test software 222 typically includes system instructions that are generic and used for many assays as well as system instructions that are specific to any particular assay. The instructions may be included on a single disk or other medium, or may be included on multiple disks, which may then be combined in a desired manner for performing a particular assay. Alternatively, the test software may be loaded into the base unit and/or loaded onto a storage medium via a network, the Internet, or as previously described. The system software will include, for example, system initialization, certification formats, calculation instructions, user/patient input instructions, etc.

It can be seen that the base unit 212 and computer 220 are generally useful for performing many different types of assays, while the adapter 214 and sample substrate 216 are more specifically targeted for a particular assay. One type of adapter 214 may be mated to a plurality of sample substrates 216 that are intended to perform two or more different assays, wherein the system test software 222 enables the adapter 214 and base unit 212 to be properly connected to the sample substrates 216. Thus, the system of the present invention further includes testing software 222 in combination with one or both of an adapter 214, sample substrate 216. This is because a user of a processed monolithic substrate unit 212 or combined substrate unit 212 and computer 220 may later require system test software 222 and adapters 214 that are prone to perform one or more specific assays. The system is designed to receive a sample substrate for analysis of a particular test piece for a desired analyte by then mounting the adapter 214 on the base unit and the software 222 on the computer 220/base unit 212. In addition, when an adapter 214 is adapted for two or more assays, the user may later obtain a combination of test software 222 and sample substrate 216 that enables a new assay to be performed on a previous combination of computer 220, base unit 212, and adapter 214. In some cases, the user is also provided with a combination of the adapter 214, sample substrate 216, and system test software 222.

Referring now to FIG. 4, a layout of an exemplary system 300 is shown. The system 300 includes a base unit 312, an adapter 314, and a sample substrate 316. In addition, a universal adapter 320 is provided as a separate component for removable or permanent mounting to the base unit 312. The universal adapter 320 defines a mounting area on the base unit 312 for receiving the adapter 314. The substrate unit 312 provides system functions such as a light source/detector 322 and a heater plate 324. The universal adapter 320 is mounted on a support surface 326 of the base unit 312 above the heater plate 324. The base unit 312 is then ready to removably receive an adapter plate 314, which in turn is ready to receive a sample substrate 316. The various interfaces between the system components may be connected to the system of fig. 1 and 2 in any of the above-described patterns, and the use of a universal adapter 320 is advantageous because it facilitates standardization of the interface between the base unit 312 and the adapter 314. A single base unit 312 (or base unit design) may also be connected to a wider range of adapters 314 by using different grades or types of universal adapters, each of which may exhibit different functional characteristics and interconnection patterns.

Although the foregoing invention has been described by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.

Claims (42)

1. A system for manipulating a material, comprising:

a substrate unit having a mounting area with a substrate interface structure, wherein the substrate interface structure includes at least one interface member;

an adapter configured to be removably mounted to the mounting area and having an adapter-substrate interface structure, the adapter-substrate interface structure including at least one interface member configured to mate with a corresponding interface member in the substrate interface structure when the adapter is mounted to the mounting area, and an adapter-substrate interface structure having at least one interface member therein; and

a substrate configured to be removably attached to the substrate mounting area of the adapter and having a substrate interface structure including at least one interface member configured to mate with a corresponding interface member in the adapter-substrate interface structure when the substrate is attached to the substrate mounting area.

2. The analytical system of claim 1, wherein the substrate interface structure comprises at least one interface member selected from the group consisting of a power source, an analog signal connector, a digital signal connector, an energy transmission source, an electrical/electrochemical signal detector, a ph detector, and an energy emission detector.

3. The analytical system of claim 1, wherein the adapter-substrate structure comprises at least one interface member selected from the group consisting of a power source, an analog signal connector, a digital signal connector, an energy transmission source, a ph detector, an energy emission detector, and an electrical/electrochemical signal detector.

4. The analytical system of claim 1 or 2, wherein the energy transmission source is selected from the group consisting of a light source, an acoustic energy source, a heat source, a cooling source, and a pressure source.

5. The analytical system of claim 1, wherein the substrate unit comprises a digital processor.

6. The analytical system of claim 1, wherein the substrate interface structure comprises at least power supply electrodes configured to mate with power supply electrodes on an adapter-substrate interface structure of an adapter, and at least electrical signal electrodes configured to mate with electrical signal electrodes on an adapter-substrate interface structure of an adapter, the power supply electrodes providing electrical power to the adapter, and the signal electrodes providing data transmission between the substrate unit and the adapter.

7. The analytical system of claim 1, wherein the mounting region on the base unit comprises a socket formed in a surface of the base unit.

8. The analytical system of claim 7, wherein the receptacle has a peripheral dimension that mates with the adapter.

9. The analytical system of claim 7, further comprising a snap on base unit for securing the adapter within the receptacle.

10. The analytical system of claim 1, wherein the mounting area on the base unit comprises a discrete component mounted on the base unit.

11. The analytical system of claim 1, wherein the substrate has a top side, a bottom side, and an interior region therebetween, the interior region having a plurality of intermediate channels connected to the plurality of reservoirs, the flow biasing element comprising electrode terminals exposed at an outer surface of the substrate and/or access points on the substrate that allow passage of probes.

12. The analytical system of claim 9, wherein the substrate has openings over at least some of the reservoirs to enable direct passage of probes in the adapter-substrate interface structure.

13. The analytical system of claim 11, wherein the adapter-substrate interface structure comprises a plurality of electrodes arranged in a pattern to mate with electrode terminals exposed on the substrate.

14. The analytical system of claim 3, wherein the adapter-substrate interface structure comprises at least one additional interface member.

15. The analytical system of claim 14, wherein the additional interface comprises a source of electromagnetic radiation, and wherein the substrate comprises a region transparent to the electromagnetic radiation, the transparent region being aligned with the source of electromagnetic radiation when the substrate is mounted in the substrate mounting region on the adapter.

16. The analytical system of claim 15, further comprising an electromagnetic radiation detector disposed in the adapter-substrate interface structure to receive radiation emitted by the transmission region when the substrate is mounted in the mounting region.

17. The analytical system of claim 1, wherein the mounting region on the adapter comprises a receptacle formed on a surface of the adapter, the receptacle having a peripheral dimension corresponding to a peripheral dimension of the substrate.

18. The analytical system of claim 17, further comprising a snap on adapter for securing the substrate within the receptacle.

19. The analytical system of claim 1, further comprising a tangible medium storing computer readable code containing instructions that enable a computer to interface with the base unit and control an assay performed by the base unit based on conditions on a substrate supported by an adapter received on the base unit.

20. An analysis system, comprising:

a substrate unit having a mounting area with a substrate interface structure, wherein the substrate interface structure includes at least one interface member;

a substrate having an interface structure, said interface structure including at least one interface element; and

an adapter configured to be removably attached to the mounting area of the base unit and having a mounting area for removably receiving the substrate, the adapter holding the substrate in a fixed position relative to the base unit and providing at least one of (i) a connection path from an interface in the base interface structure to the substrate, or (ii) a connection path from an interface in the base structure to the base unit.

21. The analytical system of claim 20, wherein the adapter comprises an energy distribution network, the interface element in the substrate interface structure is an energy source, and the substrate structure comprises a plurality of energy connectors coupled to the energy distribution network in the adapter.

22. The analytical system of claim 20, wherein the base interface structure comprises an energy emission detector and the substrate structure comprises an energy transmission region, and wherein the adapter aligns the energy emission detector with the energy transmission region when the adapter is mounted to the mounting region of the base unit and the substrate is mounted to the mounting region of the adapter.

23. An adapter for combination with a base unit having a mounting area with a base interface structure and a substrate having a substrate interface structure, the adapter comprising:

an adapter body having an adapter-substrate unit interface structure, said adapter-substrate unit interface structure including at least one of power and signal contacts configured to mate with corresponding contacts in the substrate interface structure when said adapter is mounted on said substrate unit at a mounting area; a substrate mounting region having an adapter-substrate interface structure, the adapter-substrate interface structure including at least flow biasing tabs configured to mate with corresponding regions in the substrate interface structure when the substrate is mounted in the mounting region of the adapter.

24. The adapter of claim 23, wherein said adapter-substrate interface structure comprises at least one additional interface member selected from the group consisting of a power source, an analog signal connector, a digital signal connector, an energy transmission source, an electrical/electrochemical signal detector, a ph detector, and an energy emission detector.

25. The adapter of claim 24 wherein said additional interface comprises a source of electromagnetic radiation, said substrate including a region transparent to said electromagnetic radiation, said transparent region being aligned with said source of electromagnetic radiation when said substrate is mounted in a substrate mounting region on the adapter.

26. An adapter as recited in claim 25, further comprising an electromagnetic radiation detector disposed within the adapter-substrate interface structure to receive radiation emitted by the transparent region when the substrate is mounted in the mounting region.

27. The adapter of claim 23 wherein said mounting area on said adapter comprises a receptacle formed on a surface of said adapter, said receptacle having a peripheral dimension corresponding to a peripheral dimension of said substrate.

28. The adapter of claim 27, further comprising a snap on adapter for securing said substrate within said socket.

29. A system, comprising:

an adapter as in claim 23; and

a tangible medium storing computer readable code containing instructions that enable a computer to interface with the base unit and control an assay performed by the base unit based on a condition on a substrate supported by an adapter received on the base unit.

30. A system for combining with a computer, a base unit having an adapter mounting area, and an adapter, the system comprising:

a substrate capable of receiving an analyte and adapted to be mounted to the adapter; and

the computer readable code includes instructions that enable the computer to interface with the base unit and control an assay performed by the base unit based on a condition on a substrate supported by an adapter received on the base unit.

31. A computer program product for use in combination with a computer, a base unit having an adapter receiving area, an adapter having a substrate receiving area, and a substrate capable of receiving a material to be processed, the computer program product comprising a tangible medium storing computer readable code containing instructions that enable the computer to interface with the base unit and control an assay performed by the base unit based on a condition on the substrate supported by the adapter received on the base unit.

32. A method for designing an analytical system, the method comprising:

providing a substrate unit having a mounting area, the mounting area including at least one interface member;

removably mounting an adapter to a mounting area of said base unit to mate a port on said adapter with a corresponding port on said base unit, said adapter including a substrate mounting area including at least one port therein; and

a substrate is removably mounted to the substrate mounting area on the adapter such that the interface members on the substrate mate with the corresponding interface members on the adapter.

33. The method of claim 32, wherein said adapter is removably attached to said base unit by placing said adapter within a receptacle in said base unit.

34. The method of claim 32, wherein said substrate is removably attached to said adapter by placing said substrate in a receptacle in said adapter.

35. The method of claim 32, wherein the substrate has a plurality of channels connected to a plurality of reservoirs and flow biasing regions disposed at least some of the reservoirs or channels.

36. The method of claim 35, further comprising:

directing a flow control signal from the base unit to the adapter; and

activating the flow biasing regions of the adapter in response to the flow control signal, thereby activating corresponding flow biasing regions on the substrate. To control flow through the channels and between the reservoirs.

37. The method of claim 36, wherein the energizing step comprises electrically biasing the flow biasing region.

38. The method of claim 36, wherein the energizing step comprises acoustically driving the flow biasing region.

39. The method of claim 36, wherein the directing and energizing steps comprise providing computer readable instructions to a computer coupled to the base unit.

40. The method of claim 32, wherein the adapter further comprises at least one electromagnetic radiation source, the method further comprising directing an electromagnetic radiation source control signal from the base unit to the base unit.

41. The method of claim 41, wherein the adapter further comprises an electromagnetic radiation source detector, the method further comprising generating a signal in the adapter based on radiation emitted from the substrate and directing the signal to the adapter.

42. The method of claim 40, wherein the signal generating step and the signal directing step comprise providing computer readable instructions to a computer coupled to the base unit.