U.S. patent application number 09/976132 was filed with the patent office on 2002-12-19 for analytical system and method.
This patent application is currently assigned to Caliper Technologies Corp.. Invention is credited to Chow, Calvin Y.H..
Application Number | 20020192112 09/976132 |
Document ID | / |
Family ID | 24777319 |
Filed Date | 2002-12-19 |
United States Patent
Application |
20020192112 |
Kind Code |
A1 |
Chow, Calvin Y.H. |
December 19, 2002 |
ANALYTICAL SYSTEM AND METHOD
Abstract
An analytical or preparatory system comprised as a base unit, an
adapter, and a substrate. The adapter is attached to an attachment
region on the base unit, and the substrate is attached to an
attachment region on the adapter. The adapter permits the base unit
to be interfaced with a wide variety of different substrates to
perform chemical and biological analytical analyses and preparatory
procedures.
Inventors: |
Chow, Calvin Y.H.; (Portola
Valley, CA) |
Correspondence
Address: |
CALIPER TECHNOLOGIES CORP
605 FAIRCHILD DRIVE
MOUNTAIN VIEW
CA
94043
US
|
Assignee: |
Caliper Technologies Corp.
605 Fairchild Drive
Mountain View
CA
94043
|
Family ID: |
24777319 |
Appl. No.: |
09/976132 |
Filed: |
October 12, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09976132 |
Oct 12, 2001 |
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09531189 |
Mar 21, 2000 |
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6399025 |
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09531189 |
Mar 21, 2000 |
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09243670 |
Feb 2, 1999 |
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6071478 |
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09243670 |
Feb 2, 1999 |
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08911310 |
Aug 14, 1997 |
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5955028 |
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08911310 |
Aug 14, 1997 |
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08691632 |
Aug 2, 1996 |
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6399023 |
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Current U.S.
Class: |
422/63 ; 422/504;
422/537; 422/81 |
Current CPC
Class: |
Y10T 436/25 20150115;
B01L 9/527 20130101; B01L 2200/143 20130101; B01L 2300/0645
20130101; B01L 2200/027 20130101; B01L 2300/0654 20130101; Y10T
436/11 20150115; G01N 2035/00326 20130101; B01L 3/502715 20130101;
B01L 3/50273 20130101; Y10T 436/2575 20150115; B01L 2400/0415
20130101 |
Class at
Publication: |
422/63 ; 422/81;
422/103 |
International
Class: |
G01N 033/00 |
Claims
What is claimed is:
1. A system for manipulating materials comprising: a base unit
having an attachment region with a base interface array including
at least one interface component therein; an adapter configured to
be removably attached to the attachment region and having an
adapter-base interface array including at least one interface
component disposed to mate with a corresponding interface component
in the base interface array when the adapter is attached to the
attachment region, a substrate attachment region, and an
adapter-substrate interface array having at least one interface
component therein; and a substrate configured to be removably
attached to the substrate attachment region of the adapter and
having a substrate interface array including at least one interface
component disposed to mate with a corresponding interface component
in the adapter-substrate interface array when the substrate is
attached to the substrate attachment region.
Description
[0001] This application is a continuation of application Ser. No.
09/243,670, filed Feb. 2, 1999, which is a continuation of
application Ser. No. 08/911,310, filed Aug. 14, 1997, now U.S. Pat.
No. 5,955,028, which is a continuation-in-part of application Ser.
No. 08/691,632, filed on Aug. 2, 1996, the full disclosures of
which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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.
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 2. Description of the Background Art
[0010] 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.
[0011] 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 No. 60/015,498
(provisional), filed on Apr. 16, 1996; application Ser. No.
08/671,987, filed on Jun. 28, 1996; application Ser. No.
08/671,986, filed on Jun. 28, 1996; application Ser. No.
08/678,436, filed on Jul. 3, 1996; and application Ser. No.
08/683,080, filed Jul. 16, 1996.
SUMMARY OF THE INVENTION
[0012] 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.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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
[0025] FIG. 1 illustrates a first embodiment of an analytical
system incorporating the features of the present invention.
[0026] FIG. 2 illustrates a second embodiment of an analytical
system incorporating the features of the present invention.
[0027] FIG. 3 is a block diagram illustrating the information flow
between various components of the system of the present
invention.
[0028] FIG. 4 illustrates an exemplary analytical system
incorporating the components of the system of the present
invention.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
[0029] 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,
galvanometry, reflectrometry, ultrasonic detection, mephlometry,
electrophoretic measurement, temperature measurement, pressure
measurement, potentiometric measurement, amperometric measurement,
and the like. In the exemplary and preferred embodiments below,
sample manipulation and detection are performed in microfluidic
substrates where the sample is manipulated between and among very
small volume reservoirs and flow channels formed in the substrate.
Usually, all flow and test conditions on the substrate will be
controlled through the base unit and the adapter, as described in
more detail below.
[0030] The base unit of the present invention will typically
comprise an enclosure or frame which may be intended for mounting,
e.g. on the floor, on a counter, in a rack, or in any other
conventional manner, or which may be portable or hand-held. The
base unit will usually include at least power and/or signal
transmission circuits, and will usually include signal processing
capability for helping to analyze and/or store data received from
the adapter as described in more detail below. The base unit will
usually further include a microprocessor for helping manage both
its substrate management and data collection duties. Optionally,
information displays in the form of video monitors, alphanumeric
displays, printers, LED displays, and the like, may be provided on
or in the frame, often together with data entry devices, such as
keyboards, touch screens, and the like. In the exemplary
embodiments, however, the base unit includes only a plug connector
for interfacing with an external computer, where the computer
provides the necessary input and output devices. In such cases, the
base unit will often, but not necessarily, include an internal
microprocessor for controlling or helping to control the internal
operations of the base unit and adapter. Alternatively, a
microprocessor could be provided in the adapter, with the base unit
providing only interface functions between the adapter and the
computer. In other cases, all control functions will be managed
through the separate computer with the base unit and adapter
providing only distribution and interface functions. Again, it
should be appreciated that availability of both the base unit and
the adapter provides for a very wide range of specific designs with
different functions being selectively distributed between the
adapter and the base unit for particular assays and sample
substrate designs.
[0031] The base unit will include an attachment region for
removably securing the adapter. The attachment region on the base
unit has a base interface array including at least one, and usually
multiple, interface component(s) intended to provide power and/or
information communication with the adapter. The interface
component(s) comprise a wide variety of devices as described in
more detail below. The attachment region may be any feature or
structure on the enclosure or frame of the base unit which can
removably attach the adapter. The attachment region will usually be
constructed so that the adapter can be connected in a unique
configuration only so that the base interface array will be
uniquely configured relative to the adapter. The attachment region
may have a wide variety of forms, such as receptacles, wells,
slots, trays (similar to a CD tray), or the like. Often, the
attachment region will define a receptacle having dimensions which
correspond to the outer peripheral dimensions of the adapter so
that the adapter may be held in a desired orientation relative to
the base unit. Alternatively, or in addition, pegs, pins, latches,
or other attachment elements may be provided to hold the adapter on
the base unit in a desired orientation.
[0032] The adapter will also comprise an enclosure or frame,
although the enclosure or frame will usually be significantly
smaller than that of the base unit. The enclosure or frame will be
adapted to be received on or in the attachment region of the base
unit, as generally discussed above, and will itself include an
attachment region for removably securing the sample substrate. The
attachment region on the adapter may take any of the forms
discussed above for the attachment region on the base unit, and it
will usually be necessary for the attachment region to immobilize
the sample substrate in a particular orientation relative to the
adapter.
[0033] The adapter will include an adapter-base interface array
which meets with or couples to the base interface array when the
adapter is mounted in the attachment region on the base unit. The
adapter-base interface array will include at least one interface
component which mates with a corresponding interface component
within the base interface array, usually to provide for power
and/or signal connection between the base unit and the adapter. The
interface component(s) may provide for a wide variety of additional
interconnections, and will be described in greater detail
below.
[0034] The sample substrate attachment region will include an
adapter-sample substrate interface array intended to mate with or
couple to a sample substrate interface array on the sample
substrate when the sample substrate is attached to the attachment
region. The adapter-sample substrate interface array will itself
include at least one interface component which may be any of the
components described in more detail below. Usually, the
adapter-sample substrate interface array will include multiple
interface components which are disposed or distributed in a pattern
selected to mate with at least some corresponding interface
component in the sample substrate array on the sample
substrate.
[0035] The sample substrate may comprise any one of a variety of
known analytical devices or articles intended for receiving a
sample and processing the sample in some manner to provide a
detectable output which can be related to a sample characteristic,
e.g. the presence of an analyte, the composition or nature of a
molecule present in the sample (e.g. protein or nucleic acid
sequence), or the like. The present invention is particularly
intended for use with microfluidic sample substrate of the type
described in U.S. Pat. Nos. 5,498,392; 5,486,355; 5,304,487; and
published PCT application WO 96/04547, the full disclosures of
which are incorporated herein by reference. Suitable microfluidic
substrates are also described in commonly assigned co-pending
pending application Ser. No. 08/761,987, filed Jun. 28, 1996, and
08/845,759, filed Apr. 25, 1997, the full disclosures of which are
incorporated herein by reference.
[0036] A particular advantage of the present invention is that the
adapter can be configured to receive any one of a variety of
specific sample substrate configurations. In that way, the designer
of the sample substrate is free to optimize the size, design, flow
paths, and other features of the sample substrate without undue
regard to the nature of the base unit. Within a wide latitude, most
specific design features of a sample substrate may be accommodated
by appropriately designing an adapter. While this advantage is
available, it is also possible that the design of the sample
substrate take into account specific characteristics and design
features of either or both of the base unit and adapter. It will be
appreciated that the system architecture employing the adapter as
an interface between the sample substrate and the base unit
provides for significant design flexibility.
[0037] The sample substrate will have dimensions and other
characteristics selected to permit removable attachment to the
attachment region, as generally discussed above. Sample substrate
will further include the substrate interface array which includes
at least one interface component disposed to mate with a
corresponding interface component on the adapter-sample substrate
interface array on the adapter. Again, the interface components may
comprise any of a wide variety of particular devices and elements,
as discussed in more detail. The interface components on the
adapter and sample substrate will generally be able to provide for
both flow control management of the sample and other liquid
reagents present in and applied to the sample substrate and will
further provide for interconnection of power and signals between
the adapter and sample substrate.
[0038] As used herein and in the claims, the phrase "interface
component" refers to any one of a wide variety of discrete
components or regions present in the interface arrays on the base
unit, adapter, or sample substrate. Interface components will
generally provide for electrical or other energy transfer, analog
or digital signal transfer, energy transmission, energy emission
detection, and the like.
[0039] Electrical connections, both for power and signal transfer,
will generally comprise conventional connectors in the form of
electrodes, pins, plugs, zero insertion force (ZIF) connectors, and
the like. Such electrical connections will usually require mating
connectors in two of the interface arrays which are brought
together when the system is put together. The electrical connectors
will often be present on a surface or edge of the interface array
so that corresponding components will be engaged against each other
when the adapter is mounted in the base unit or the substrate is
mounted on the adapter. Similarly, surface or edge electrodes in
the adapter-sample substrate interface array may be provided to
mate with corresponding surface or edge electrodes on the sample
substrate. The electrodes on the sample substrate may then be
connected internally in the substrate to the desired reservoirs or
fluid flow channels in order to effect electrokinetic flow control,
as described in the previously incorporated patents and patent
applications. In other cases, however, it will be desirable to
provide interface components in the adapter-sample substrate
interface array which directly contact the fluid to be
electrokinetically controlled. For example, probes or pins may be
provided on the adapter which will penetrate into open wells or
through septums on the sample substrate in order to permit direct
contact and application of electrical potential. A specific example
of such connectors are shown in FIG. 2 below.
[0040] The energy transmission sources will generally be intended
to either energetically excite a region on the test substrate or
provide energy to initiate fluid flow on the sample substrate. The
energy may take a wide variety of forms, including light, such as
visible light and UV light, acoustic energy, heat, cooling,
pressure, mechanical energy, electrical energy, and the like. In
the case of sample detection, the energy transmission source may be
light or other radiation intended to excite a species or label to
be detected. Heating/cooling may be provided to help effect or
condition a particular chemical reaction. Acoustic, pressure, and
mechanical energy may be provided to directly effect fluid flow in
channels of microfluidic sample substrates. It will be appreciated
that such energy transmission sources do not necessarily have
corresponding interface components in an adjacent interface array.
Instead, energy transmission will often be directed generally at
regions on the sample substrate where energy is to be received.
[0041] Energy emission detectors may be provided, usually on the
adapter and/or the base unit, to detect energy emitted from the
sample substrate. For example, detection reactions may result in
the emission of light via fluorescence, luminescence, radiation, or
other energy emissions which need to be detected and/or quantified
in order to perform particular analysis. The appropriate detection
components may be provided in the adapter and/or base unit, and the
adapter relied on to appropriately align the substrate the
detectors.
[0042] A particular class of interface components employed by the
analytical system of the present invention are referred to as "flow
biasing connectors." Flow biasing connectors are intended to
identify those interface components which can effect fluid flow on
sample substrates, particularly on microfluidic substrates having a
network of flow channels and reservoirs. For microfluidic
substrates employing electrokinetic flow management, the flow
biasing connectors on the adapter will usually be electrodes,
probes, pins, or the like distributed within or on the adapter
sample substrate interface array to mate with the network of flow
channels and reservoirs in the sample substrate as generally
described above and in the previously incorporated references. The
electrodes will usually have corresponding electrode terminals
present within the interface array on the sample substrate so that
the electrode terminals may be interconnected to corresponding
electrical connectors on the adapter-sample substrate interface
array on the adapter (or in rare cases on the base interface array
on the base unit). In other cases, as described above, the flow
biasing connectors may be probes or pins on the adapter which are
positioned to directly engage fluids present on or in the sample
substrate. For example, an array of pins may be provided on a
hinged lid or cover on the adapter plate so that the sample
substrate may be positioned on the adapter and the lid cover
thereafter closed in order to penetrate the pins into open sample
wells on the substrate. The sample wells, of course, need not be
open and could be covered with any penetratable membrane or septum
which is pierced by the pins when the cover is closed. Other flow
biasing connectors include acoustic energy sources (piezoelectric
transducers) positioned within the adapter-sample substrate
interface array so that they engage the sample substrate at
positions intended to induce fluid flow through the flow channels.
Other flow biasing connectors include pressure sources which can
initiate flow by pressurization, mechanical energy sources, which
can effect mechanical pumping of liquids through the flow channels,
and the like.
[0043] Referring now to FIG. 1, a first exemplary analytical system
10 constructed in accordance with the principles of the present
invention comprises a base unit 12, an adapter 14, and a sample
substrate 16. The base unit 12 includes a pin socket 20 for mating
with a plug 22 on a bottom surface of the adapter 14. A computer
port 24 is provided for mating with conventional serial or parallel
inputs on general purpose computers, such as personal computers,
work stations, and the like. Usually, the base 12 will include at
least signal processing and conditioning components, such as
analog-to-digital converters for receiving analog data from the
adapter 14 and converting that data to digital form for
transmission to the computer. In other cases, however, the computer
may be adapted to directly convert analog signals to digital data.
The base unit 12 and/or adapter 14 could also be provided with
digital-to-analog converters for controlling power, flow, or any
other parameter directly from digital signals from the computer.
The adapter 14 may also include internal microprocessor(s) for
further data manipulation. The adapter 14 may also include a power
input, for either line AC current and/or low voltage DC current
(which may be provided by a power supply in the base unit 12). The
pin socket 20 will usually provide for interface for both power and
signal exchange between the base unit 12 and the adapter 14.
Locating pins 28 are provided on an upper surface of the base 12 to
engage locating holes 30 on the adapter 14. Thus, the entire upper
surface of the base unit 12 will provide the attachment region for
the adapter 14 while the pin socket 20 will generally provide the
adapter-base interface array with the individual pins providing the
interface components.
[0044] A plug 22 comprises the adapter-base interface array on the
adapter 14. The plug 22 provides for both power and signal
connections to the base unit 12 and the adapter further provides an
optical source and detector 34 and a heating/cooling element 36,
both of which mate to particular regions on the sample substrate
16, as described further below. The adapter 14 further includes an
edge connector 40 which includes a number of electrodes 42 which
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
which are formed by parallel L-shaped channels on the upper surface
of the adapter 14. When the sample substrate 16 is fully inserted
between the guides 46 with the electrodes 44 received in the edge
connector 40, a reaction site 50 on the sample substrate 16 is
aligned with the optical source of detector 34 on the adapter 14
and a thermal treatment region 52 is aligned with the heater/cooler
36 on the adapter. Thus, the optical source detector 34,
heater/cooler 36, and edge connector 40 comprise interface
components in the attachment region of the adapter 14.
[0045] The sample substrate 16 comprises a plurality of sample and
reagent wells 60, each of which is coupled to an electrode 44 in
the interface array. In this way, sample flow on the sample
substrate can be controlled through the base unit 12 and the
adapter 14 to control power through the electrodes 42. It will be
appreciated that the power may be provided directly by the base
unit 12, in which case the adapter 14 acts merely to distribute the
power. Alternatively, the base unit 12 may provide information to
the adapter, and the adapter 14 generate the power internally which
is distributed through the electrodes 42. In either case, sample
flow among the reservoirs and a flow channel network 66 is
controlled in a desired manner. A portion of the sample and mixed
reagents will flow through the heating/cooling region 52, where it
will be appropriately treated. Again, the amount of heat or cooling
supplied by region 36 is provided and controlled by a combination
of the base unit 12 and adapter 14, where specific functions may be
provided by either of those two components. An output signal
resulting from one or more reactions is eventually read at the
reaction region 50 by the optical source/detector 34. Output of the
optical detector 34 will be passed back to the base unit 12 through
the pin socket 20 and male plug 22. The optical detector will
usually produce an analog signal, and such analog signal may be
converted to digital in any of the adapter 14, base unit 12, or
external computer (not shown).
[0046] A second exemplary embodiment 100 of the analytical system
of the present invention is illustrated in FIG. 2. The analytical
system 100 includes a base unit 112, an adapter 114, and a sample
substrate 116. The base unit 112, is similar in many respects to
base unit 12 in FIG. 1, and includes locating pins 128, a pin
socket 120, and a computer port 124. Base unit 112, however,
further comprises an optical source/detector 134. This is different
than the analytical system 10, where the optical source/detector 34
was provided as part of the adapter 14.
[0047] The adapter 114 comprises a plate 115 having an aperture 117
in its center. When the adapter 114 is mounted on the base unit
112, the aperture 117 will lie generally over the optical
source/detector 134. Adapter 114 further includes a hinged cover
119 which is used to cover and position the sample substrate 116 on
top of the plate 115. When the sample substrate 116 is positioned,
and the hinge cover 119 closed, a plurality of probes 121 on a
lower surface of the cover will penetrate into sample and reagent
wells 160 on the sample substrate 116. The wells 160 may be
completely open or may be covered by a penetratable membrane or
septum. The probes 121 will thus be immersed and in direct contact
with the liquids present in the wells 160. In that way, electrical
biasing can be provided in order to effect electrokinetic flow
management through the channel network 166 on the sample substrate
116.
[0048] The sample substrate 116 includes a reaction zone 150 which
will usually be at least partly transparent or translucent to
permit light from the optical source detector 134 to reach the
fluid in the region and to permit emitted or detected light to
leave the region. Such incident and emitted light from region 150
will pass through the aperture 117 in the adapter 114 so that it
may be directly coupled to the optical source/detector 134. Again,
this is a difference with the analytical system 10 of FIG. 1 where
detection was performed directly between the adapter 14 and the
sample substrate 16.
[0049] It should be appreciated that the exemplary analytical
systems 10 and 100 are intended to be representative of a virtually
infinite number of possible system configurations. Use of an
adapter 14 or 114 permits the various power, signal, and other
functions of the analytical system to be included in any one of the
adapter, base unit, substrate, or external computer in virtually
any manner so that any particular analytical technique can be
optimally supported by the system.
[0050] Referring now to FIG. 3, a system 200 according to the
present invention can be configured in a wide variety of ways. For
example, a base unit 212 may comprise a single monolithic
instrument containing all control and analysis components necessary
for performing an assay (in combination with adapter 214 and sample
substrate 216), needing only to be connected to line current or
other power source. The base unit 212, however, will be connected
to a general purpose computer 220, e.g. a personal computer or work
station, which provides at least a portion of the input/output,
control, and computational functions of the system 200. The
computer 220 may be connected by any conventional connectors,
typically using serial or parallel input ports. The computer will
be programmed using software 222, which may be in the form of any
conventional computer medium. The software will comprise
instructions for all or a portion of the computer functions. For
example, the software may comprise the operating system utilized in
performing all assays using the system of the present invention.
Alternatively, the computer may utilized a conventional operating
system capable of controlling real time functions, as set forth
above. The system test software 222 will usually include system
instructions which are general and apply to many assays as well as
system instructions which are specific for any particular assay.
The instructions may be included in a single disk or other medium,
or may be included in multiple disks which may then be combined in
a desired manner for performing a particular assay. Alternatively,
the test software may be downloaded into the base unit and/or onto
a storage medium via a network, the internet, or otherwise as set
forth above. The system software will include functions such as
system initialization, assay format, computational instructions,
user/patient input instructions, and the like.
[0051] Thus, it can be seen, that the base unit 212 and computer
220 will generally be useful for performing many different types of
assays, while the adapter 214 and sample substrate 216 will be more
specifically directed at particular assay(s). One type of adapter
214 may be compatible with multiple sample substrates 216 intended
for performing two or more different assays, where the system test
software 222 can enable the adapter 214 and base unit 212 to
properly interface with the sample substrate 216. Systems according
to the present invention will thus further comprise the combination
of test hardware 222 with either an adapter 214, sample
substrate(s) 216, or both. That is, a user already possessing a
monolithic base unit 212 or combination base unit 212 and computer
220, may later acquire the combination of system test software 222
and adapter 214 intended to perform a particular assay or assays.
By then mounting the adapter 214 on the base unit and loading the
software 222 onto the computer 220/base unit 212, the system will
be configured to receive sample substrates to analyze particular
test specimens for the desired analyte. Alternatively, when an
adapter 214 is suitable for two or more assays, the user may later
acquire the combination of test software 222 and sample
substrate(s) 216 which enable the preexisting combination of
computer 220, base unit 212, and adapter 214 to perform a new
assay. In some cases, the combination of adapter 214, sample
substrate(s) 216, and system test software 222 will also be
provided to the user.
[0052] Referring now to FIG. 4, an exemplary system 300
configuration is illustrated. The system 300 comprises a base unit
312, an adapter 314, and a sample substrate 316. Additionally, a
universal adapter 320 is provided as a discrete component for
removable or permanent mounting onto the base unit 312. The
universal adapter 320 defines the attachment region on the base
unit 312 for receiving the adapter 314. Base unit 312 provides
system functions, such as an optical source/detector 322 and a
heater plate 324. The universal adapter 320 is mounted over the
heater plate 324 onto a support surface 326 of the base unit 312.
The base unit 312 is then ready to removably receive adapter
plate(s) 314 which in turn is ready to receive sample substrates
316. The various interfaces among the system components may follow
any of the patterns described above in connection with the systems
of FIGS. 1 and 2. Use of the universal adapter 320 is advantageous
since it facilitates standardization of the interface between the
base unit 312 and the adapter 314. Also, a single base unit 312 (or
base unit design) can be interfaced with an even wider range of
adapters 314 by employing different classes or types of universal
adapters, each of which can display alternative functionalities and
interconnection patterns.
[0053] Although the foregoing invention has been described in some
detail 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.
* * * * *