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Description  |
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to systems and methods for
performing chemical and biological analyses. More particularly, the
present invention relates to the design and use of an analyzer system
which employs analytical substrates evaluated in a base unit, where an
adapter is used as an interface between the substrate and the base unit.
Numerous systems and instruments are available for performing chemical,
clinical, and environmental analyses of chemical and biological specimens.
Conventional systems may employ a variety of detection devices for
monitoring a chemical or physical change which is related to the
composition or other characteristic of the specimen being tested. Such
instruments include spectrophotometers, fluorometers, light detectors,
radioactive counters, magnetometers, galvanometers, reflectometers,
ultrasonic detectors, temperature detectors, pressure detectors,
mephlometers, electrophoretic detectors, PCR systems, LCR systems, and the
like. Such 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 stand-alone analyzer. Such
analyzers may be adapted to receive a sample directly but will more
usually be designed to receive a sample placed on a sample-receiving
substrate, such as a dipstick, cuvette, analytical rotor or the like.
Usually, the sample-receiving substrate will be made for a single use
(i.e. will be disposable), and the analyzer will include the circuitry,
optics, sample manipulation, and other structure necessary for performing
the assay on the substrate. As a result, most analyzers are intended to
work only with a single type of sample-receiving substrate and are not
readily adaptable to be used with other substrates.
Recently, a new class sample-receiving substrate has been developed,
referred to as "microfluidic" systems. Microfluidic substrates have
networks of chambers connected by channels which have mesoscale
dimensions, where at least one dimension is usually between 0.1 .mu.m and
500 .mu.m. Such microfluidic substrates may 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 sophisticated chemical and biological analytical techniques.
Microfluidic analytical technology has a number of advantages, including
the ability to employ very small sample sizes, typically on the order of
nanoliters. The substrates may be produced at a relatively low cost, and
can be formatted to perform numerous specific analytical operations,
including mixing, dispensing, valving, reactions, and detections.
Because of the variety of analytical techniques and potentially complex
sample flow patterns that may be incorporated into particular microfluidic
test substrates, significant demands may be placed on the analytical units
which support the test substrates. The analytical units not only have to
manage the direction and timing of flow through the network of channels
and reservoirs on the substrate, they may also have to provide one or more
physical interactions with the samples at locations distributed around the
substrate, including heating, cooling, exposure to light or other
radiation, detection of light or other emissions, measuring
electrical/electrochemical signals, pH, and the like. The flow control
management may also comprise a variety of interactions, including the
patterned application of voltage, current, or power to the substrate (for
electrokinetic flow control), or the application pressure, acoustic energy
or other mechanical interventions for otherwise inducing flow.
It can thus be seen that a virtually infinite number of specific test
formats may be incorporated into microfluidic test substrates. Because of
such variety and complexity, many if not most of the test substrates will
require specifically configured analyzers in order to perform a particular
test. Indeed, it is possible that particular test substrates employ more
than one analyzer for performing different tests. The need to provide one
dedicated analyzer for every substrate and test, however, will
significantly reduce the flexibility and cost advantages of the
microfluidic systems.
It would therefore be desirable to provide improved analytical systems and
methods which overcome or substantially mitigate at least some of the
problems set forth above. In particular, it would be desirable to provide
analytical systems including base analytical units which can support a
number of different microfluidic or other test substrates having
substantially different flow patterns, chemistries, and other analytical
characteristics. It would be particularly desirable to provide analytical
systems where the cost of modifying a base analytical unit to perform
different tests on different test substrates is significantly reduced.
2. Description of the Background Art
Microfluidic devices for analyzing samples are described in the following
patents and published patent applications: U.S. Pat. Nos. 5,498,392;
5,486,335; and 5,304,487; and WO 96/04547. An analytical system having an
analytical module which connects to an expansion receptacle of a general
purpose computer is described in WO 95/02189. A sample typically present
on an analytical rotor or other sample holder, may be placed in the
receptacle and the computer used to control analysis of the sample in the
module. Chemical analysis systems are described in U.S. Pat. Nos.
5,510,082; 5,501,838; 5,489,414; 5,443,790; 5,344,326; 5,344,349;
5,270,006; 5,219,526; 5,049,359; 5,030,418; and 4,919,887; European
published applications EP 299 521 and EP 6 031; and Japanese published
applications JP 3-101752; JP 3-094158; and JP 49-77693.
The disclosure of the present application is related to the following
co-pending applications, the full disclosures of which are incorporated
herein by reference, application Ser. Nos. 60/015498 (provisional), filed
on Apr. 16, 1996; 08/671,987, filed on Jun. 28, 1996; 08/671,986, filed on
Jun. 28, 1996; 08/678,436, filed on Jul. 3, 1996; and 08/683,080, filed
Jul. 16, 1996.
SUMMARY OF THE INVENTION
The present invention overcomes at least some of the deficiencies described
above by providing analytical and preparatory systems and methods which
employ an adapter to interface between a sample substrate and an
analytical base unit. The sample substrate is usually a microfluidic
substrate but could be any other sample substrate capable of receiving
test specimen(s) or starting material(s) for processing or providing a
detectable signal, where the base unit manages sample flow, reagent flow,
and other aspects of the analytical and/or preparatory technique(s)
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 quite different
configurations and to manage numerous specific analytical and preparatory
techniques on the substrates with little or no reconfiguration of the base
unit itself.
The methods and apparatus will find use with both analytical and
preparatory techniques. By "analytical," it is meant that the assay or
process is intended primarily to detect and/or quantitate an analyte or
analytes in a test specimen. By "preparatory," it is meant that the
process is intended primarily to produce one or more products from one or
more starting materials or reagents. The remaining description relates
mainly to the analytical methods and devices, but for the most part, all
technology described will be equally useful for preparing materials for
other subsequent uses.
In a first aspect, the present invention provides an analytical system
comprising a base unit having an attachment region with a base interface
array including at least one interface component therein. An adapter that
is configured to be removably attached to the attachment region of the
base unit and has an adapter-base interface array which also includes an
interface component. The adapter-base interface array mates with the base
interface array when the adapter is attached to the base unit, and at
least some of the interface components in each of the arrays will couple
or mate with each other. The adapter further includes a sample substrate
attachment region having an adapter-sample substrate interface array
therein. The adapter-sample substrate interface array will usually also
include at least one interface component (but in some cases could act
primarily to position interface component(s) on the base units relative to
interface component(s) on the sample substrate). A sample substrate is
configured to be removably attached to the sample substrate attachment
region of the adapter and itself includes a sample substrate interface
array which usually includes at least one interface component. The
interface component(s) in the sample substrate interface array will mate
with corresponding interface component(s) in the adapter-sample substrate
interface array and/or in the base interface array when the sample
substrate is attached to the sample substrate attachment region.
By providing suitable interface components in each of the interface arrays,
power and/or signal connections may be made between the base unit and the
sample substrate in a virtually infinite number of patterns. In some
cases, the base unit will provide only power and signal connections to the
adapter, while the adapter will provide a relatively complex
adapter-sample substrate interface array for managing flow, other
operational parameters, and detection on the sample substrate. In other
cases, however, the base interface array on the base unit may be more
complex, including for example light sources, detectors, and/or high
voltage power, and the adapter will be less sophisticated, often acting
primarily to position the sample substrate relative to interface
components on the base unit, channeling voltages, and allowing direct
communication between the base unit and the sample substrate.
Exemplary interface components include electrical power sources, analog
signal connectors, digital signal connectors, energy transmission sources,
energy emission detectors, other detectors and sensors, and the like.
Energy transmission sources may be light sources, acoustic energy sources,
heat sources, cooling sources, pressure sources, and the like. Energy
emission detectors include light detectors, fluorometers, UV detectors,
radioactivity detectors, heat detectors (thermometers), flow detectors,
and the like. Other detectors and sensors may be provided for measuring
pH, electrical potential, current, and the like. It will be appreciated
that the interface components will often be provided in pairs where a
component in one array is coupled or linked to a corresponding component
in the mating array in order to provide for the transfer of power, signal,
or other information. The interface components, however, need not have
such paired components, and often energy transmission sources or emission
detectors will be provided without a corresponding interface component in
the mating interface array.
The base unit, adapter and sample substrate will be configured so that they
may be physically joined to each other to form the analytical system. For
example, the attachment region in the base unit may be a cavity, well,
slot, or other receptacle which receives the adapter, where the dimensions
of the receptacle are selected to mate with the adapter. Similarly, the
attachment region on the adapter may comprise a receptacle, well, slot, or
other space intended to receive the sample substrate and position the
substrate properly relative to the adapter and or base unit. The sample
substrate will preferably employ mesoscale fluid channels and reservoirs,
i.e. where the channels have at least one dimension in the range from 0.1
.mu.m to 500 .mu.m, usually from 1 .mu.m to 100 .mu.m. The present
invention, however, is not limited to the particular manner in which the
base unit, adapter, and substrate are attached and/or to the particular
dimensions of the flow channels on one sample substrate.
Although described thus far as a three-tiered system, it should be
understood that the additional components or "tiers" could be utilized.
For example, additional carriers or adapters could be utilized for
providing additional interface(s), such as a carrier for the sample
substrate, where the carrier would be mounted within or attached to the
adapter which is received on the base unit. Similarly, the attachment
region in the base unit which receives the adapter may comprise a discrete
component which is itself removably or permanently affixed to the base
unit. Formation of the attachment region using a discrete component is
advantageous since it facilitates standardization of the system. For
example, the adapter-attachment region component could be manufactured
separately, optionally at a single location, and/or otherwise prepared to
strict specifications, both of which would help assure that the base units
which incorporate such standardized attachment regions will be compatible
with all corresponding adapters. The standardized adapter-attachment
region could also be adapted to interconnect with other components of the
base unit, such as heaters, cooling blocks, pin connections, and the like,
thus facilitating interface with these elements. Thus, systems having four
or more tiers fall within the scope of the present invention.
In a second aspect of the present invention, the analytical system
comprises a base unit and a sample substrate, generally as described
above. An adapter is configured to be removably attached to the attachment
region of the base unit and includes an attachment region to removably
receive the sample substrate. The adapter holds the sample substrate in a
fixed position relative to the base unit and provides either (i) a
connection path from an interface component in the base interface array to
the substrate or (ii) a connection path from an interface component in the
sample substrate array to the base unit. In this aspect of the present
invention, the adapter can act primarily to position a sample substrate
relative to the interface array in the base unit. For example, if the base
unit interface array includes a light source and/or light detector, the
adapter can properly position the sample substrate relative to the light
source/detector in order to perform a desired measurement. The adapter
could optionally but not necessarily provide further interface
capabilities between the sample substrate and the base unit.
In yet another aspect of the present invention, adapters are provided for
use in combination with base units and sample substrates, as described
above. The adapter comprises an adapter body having an adapter-base
interface array including at least one of power and signal connector(s)
disposed to mate with corresponding connector(s) in the base interface
array when the adapter is attached to the attachment region on the base
unit. The adapter further includes a sample substrate attachment region
having an adapter-sample substrate interface array including at least flow
biasing connectors disposed to mate with corresponding regions in the
sample substrate interface array when the sample substrate is attached to
the attachment region of the adapter. The flow biasing connectors will
commonly be electrodes for electrokinetic flow control in mesoscale and
other microfluidic sample substrates, but could also be acoustic,
pressure, or mechanical flow-producing components. The adapter-sample
substrate interface array will frequently include interface components in
addition to the flow biasing connectors, such as radiation emission and
detection components positioned to interface with particular regions of
the sample substrates.
The base unit may be self-contained, i.e. it may include all digital and/or
analog circuitry as well as user input/output interfaces which are
necessary for controlling an assay and producing assay results from the
system. Often, however, it will be preferable to interface the base unit
with a general purpose or conventional computer, where the computer can
provide some or all of the control analysis, and/or reporting function(s)
as well as some or all of the user interface. Usually, the computer will
be a standard personal computer or workstation which operates on a
standard operating system, such as DOS, Windows.RTM. 95, Windows.RTM. NT,
UNIX, Macintosh, and the like. The computer will be able to provide a
number of standard user input devices, such as a keyboard, hard disk,
floppy disk, CD reader, as well as user outputs, such as screens,
printers, floppy disks, writable CD output, and the like. Use of the
computer is particularly advantageous since it can significantly reduce
the cost of the base unit and allow significant upgrading of the computer
component of the system while using the same base unit. Despite these
advantages, in some instances it may be desirable to incorporate the
interface and digital circuitry of a computer into the base unit of the
present invention, allowing all of the capabilities of a conventional
digital computer, but with perhaps less flexibility.
When the system of the present invention is controlled via digital
circuitry, i.e. using a separate conventional computer interfaced with the
base unit or using digital control circuitry incorporated within the base
unit, it will usually be desirable to provide at least a portion of the
operating instructions associated with any particular adapter and/or any
particular sample substrate and assay format in a computer-readable form,
i.e. on a conventional computer storage medium, such as a floppy disk, a
compact disk (CD ROM), tape, flash memory, or the like. The medium will
store computer readable code setting forth the desired instructions, where
the instructions will enable the computer (which may be a separate or
integral computer) to interface with the base unit and to control an assay
performed by the base unit upon the sample present on a sample substrate
held by an adapter received on the base unit. The present invention thus
comprises the computer program itself in the form of a tangible medium,
e.g. disk, CD, tape, memory, etc., which may be used in combination with
the system of the present invention. The present invention further
comprises systems which include an adapter as set forth above in
combination with the tangible medium storing the computer instructions
described above. The present invention still further comprises systems
which are combinations of one or more sample substrates as generally set
forth above, together with a tangible medium setting forth computer
readable code comprising instructions as set forth above.
The computer program may be provided to the user pre-loaded onto the
desired medium, usually a floppy disk or a CD ROM, or may alternatively be
downloaded onto the medium by the user from a central location via a
network, over phone lines, or via other available communication and
transmission means. The program will then be incorporated onto the medium
and be available for use in the systems and methods of the present
invention.
In a still further aspect in the present invention, a method for
configuring an analytical system comprises providing a base unit having an
attachment region including at least one interface component therein. An
adapter is removably attached to the attachment region of the base unit so
that an interface component on the adapter mates with a corresponding
interface component on the base unit. The adapter includes a sample
substrate attachment region having at least one interface component
therein, and a sample substrate is removably attached to the sample
substrate attachment region on the adapter so that an interface component
on the sample substrate mates with a corresponding interface component on
the adapter. Usually, but not necessarily, the adapter is removably
attached to the base unit by placing the adapter within a receptacle on
the base unit, and the sample substrate is removably attached to the
adapter by placing the sample substrate within a receptacle on the
adapter. The sample substrate will preferably be a microfluidic device
having a plurality of channels connecting a plurality of reservoirs and
including flow biasing regions positioned at one of the reservoirs and/or
channels. The base unit may then direct or manage flow in the substrate by
providing flow control signals to the adapter. The flow control signals
energize flow biasing regions on the adapter whereby corresponding flow
biasing regions on the substrate are energized to control flow through the
channels and among the reservoirs. For example, the flow control may be
effected by electrically biasing electrodes on the sample substrate to
cause electrokinetic flow control. Alternatively, the energizing step may
comprise acoustically driving the flow biasing regions on the sample
substrate. Usually, the adapter will include electromagnetic radiation
sources and detectors for signal generation and detection in a variety of
analytical techniques. Any of the above control steps may be implemented
by providing computer readable code to an integral or separate computer
which controls the analytical system.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a first embodiment of an analytical system incorporating
the features of the present invention.
FIG. 2 illustrates a second embodiment of an analytical system
incorporating the features of the present invention.
FIG. 3 is a block diagram illustrating the information flow between various
components of the system of the present invention.
FIG. 4 illustrates an exemplary analytical system incorporating the
components of the system of the present invention.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Analytical systems according to the present invention comprise a base unit,
an adapter, and a sample substrate. Each of these parts of the system will
be described in detail below. In general, the analytical systems will be
configured to receive and analyze a wide variety of samples and specimens.
For example, samples may be biological specimens from a patient, but they
may also be a wide variety of other biological, chemical, environmental,
and other specimens having a component to be characterized or analyte to
be detected. The analytical systems may be used to implement numerous
specific analytical and/or preparative techniques, such as chromatography,
PCR, LCR, enzymatic reactions, immunologic reactions, and the like.
Samples will usually be liquid or be liquified prior to testing, and will
frequently undergo a chemical or biochemical reaction prior to analysis.
The analytical systems may provide for a variety of manipulations of the
sample in addition to chemical and biological reactions, such as mixing,
dispensing, valving, separation, heating, cooling, detection, and the
like. The analytical systems may rely on numerous known detection
techniques such as spectrophotometry, fluorometry, radiometry,
magnatometry, ga | | |
