Dual manifold system and method for fluid transfer

Details Dual manifold system and method for fluid transfer Dual manifold system and method for fluid transfer

2000-12-15

2003-05-27

Warden, Jill (Department: 1743)

Chemistry: analytical and immunological testing

Including sample preparation

Volumetric liquid transfer

C436S174000, C422S105000, C073S864170, C073S863320, C073S864000, C073S864010, C073S864020, C073S864110

Reexamination Certificate

active

06569687

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to an apparatus and method for fabricating microarrays of biological samples on a support substrate, and more particularly to a dual manifold system for the rapid, parallel transfer of reagents to test substrates for large-scale screening assays.
BACKGROUND OF THE INVENTION
In clinical chemistry, it is frequently necessary to carry out the metered application of an analytical liquid to a target. One case which is particularly relevant to the present invention is the application of the analytical liquid to an analysis element such as a chip-based biological sensor in which biological materials are integrated with microelectronic devices. In recent years, rapid technological advances have enabled the use of micro-scale chemical/biochemical reactions for performing various types of analyses. For instance, DNA microarrays such as genosensors allow thousands of samples to be assessed simultaneously on a microelectronic test chip that is less than one-quarter of an inch in length per side. Typical test sites on such a chip are on the order of about 100 microns (&mgr;m) in diameter. Conventional applications of chip-based biological sensors include mutation diagnosis, organism identification and gene expression profiling. More recent applications, such as parallel screening of chemical compounds for drug discovery and protein arrays for functional analysis, will soon be routine.
Known fluid handling systems for dispensing, or “micro-spotting”, arrays of biological materials on a target substrate commonly comprise pick-and-place equipment. Generally, pick-and-place dispense systems include a dispense head adapted for transferring volumes of fluid from a fluid source to a target substrate. The time required to pick up, transfer and deposit a given volume of liquid significantly limits the efficiency of pick-and-place systems for micro-spotting. This lack of efficiency is even more pronounced where the target substrate contains hundreds, or even thousands, of test sites. Efforts have been made to improve the efficiency of pick and place systems for micro-spotting. For instance, systems have been adapted for picking up, transferring and depositing multiple sample volumes simultaneously. However, the time required for dispense head movement remains a significant limitation of such systems.
Furthermore, the multiple degrees of freedom associated with the movement of individual system components, such as the dispense head, significantly limits the positional accuracy of samples deposited on a target substrate. In instances where the equipment is adapted for contact dispensing (i.e., where the dispense elements of the system physically contact the target substrate to effect transfer of the fluid to the target substrate) such limitations may be magnified. In particular, dispense tip deformation can lead to irregular sample spacing and, in some instances, cross-contamination of adjacent test sites.
Due in part to the aforementioned limitations, the positional accuracy and liquid transfer volume capability of conventional pick-and-place dispensing systems can not meet the requirements of many evolving applications. Constructing microarrays having a higher degree of miniaturization will require an increase in test site array density. Realizing such an increase in density will require a reduction in sample spot size and spot pitch (i.e., the center-to-center distance between adjacent deposits). In order to achieve such miniaturization, a fluid handling system capable of accurately and efficiently depositing chemical and biochemical reagent droplets having volumes on the order of picoliters is required.
Technology for dispensing liquid volumes on the order of picoliters exists, but has been primarily limited to the field of ink-jet printing. Many drop-on-demand ink-jet ideas and systems were invented, developed, and produced commercially in the 1970s and 1980s. A detailed and comprehensive summary of state-of-the-art drop-on-demand ink-jet printing technologies, including the fabrication of ink-jet valves and printheads, is provided in a published article by Hue P. Le, entitled Progress and Trends in Ink-jet Printing (Journal of Imaging Science and Technology, Volume 42, Number 1, pp. 49-62)(1998).
There is an established need for an apparatus and method for accurately and efficiently transferring and depositing, or printing, microarrays of reagent samples having volumes on the order of picoliters on a test substrate. It would be desirable to have a microarray printing apparatus for performing large-scale chemical/biochemical screening assays, wherein the system incorporates known drop-on-demand ink-jet printing technology and is particularly suited for dispensing chemical and/or biochemical reagents.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a liquid transfer apparatus capable of accurately and efficiently transferring liquid reagents from an array of reservoirs to an array of sites on a target substrate
It is another object of this invention to provide a liquid transfer apparatus capable of accurately and efficiently depositing volumes of liquid reagents in the range of about (10)
−12
to about (10)
−6
liters.
It is another object of this invention to provide a liquid transfer apparatus capable of effecting such reagent transfer with minimal movement of the apparatus during operation.
It is another object of this invention to provide a liquid transfer apparatus employing non-contact dispensing.
It is another object of this invention to provide a liquid transfer apparatus and method adapted for the automated printing, or micro-spotting, of multiple analytical chips in succession for performing large-scale screening assays.
These and other objects are achieved with the assembly and method of the present invention. Briefly, according to the invention, a dual-manifold assembly generally includes an aspiration manifold
10
, a dispense manifold
20
, and fluid transfer elements
80
for the parallel transfer of fluids therebetween. Although the apparatus and method are adaptable for use transferring a variety of liquids to a variety of target substrates, in the preferred embodiment of the invention the apparatus is particularly suited for transferring chemical or biochemical reagents from an array of microtiter plate wells to an array of test sites on a chip-based biological sensor.
The aspiration manifold
10
is positioned above a source plate
50
, such as a microtiter plate, and is adapted for simultaneously aspirating liquid, such as a chemical reagent, from an array of reservoirs
52
. In the preferred embodiment of the present invention, the aspiration manifold includes an array of aspiration manifold subassemblies extending through a base plate
17
and adapted for being received by an array of reagent-filled wells
52
. When the aspiration manifold is seated onto the microtiter plate
50
, each subassembly seals a single well such that fluid communication to and from the well is limited to a pair of conduits
12
,
14
extending into the well. In operation, each well is pressurized by a pressure source
40
through conduit
12
which urges the liquid
54
through conduit
14
toward dispense manifold
20
. In an alternate embodiment of the invention, the aspiration manifold has a gasket element
23
for sealing against the periphery of the microtiter plate
50
during operation, precluding the need to pressurize the wells individually. In this alternate embodiment, pressurization of the wells
52
is accomplished through a single pressure conduit
12
extending through base plate
17
.
In the preferred embodiment of the invention, a plurality of aspiration conduits communicate with the dispense manifold side of the assembly through a modular connector
90
. Generally, the modular connector includes a male component
94
which releasably engages a female component
92
. Preferably, the aspiration conduits
14
terminate at component
94
which has integral tips
95
adapted for receipt by female

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