Fluent material handling – with receiver or receiver coacting mea – Processes
Reexamination Certificate
1998-07-24
2001-08-07
Huson, Gregory L. (Department: 3751)
Fluent material handling, with receiver or receiver coacting mea
Processes
C422S105000, C436S180000, C118S243000, C118S263000, C427S256000
Reexamination Certificate
active
06269846
ABSTRACT:
FIELD OF INVENTION
Well developed biological analytical technology, as well as recently developed “Lab on a Chip” or “Gene Chip” techniques require creation of dense arrays of fluorescently labeled micro-organisms and DNA assays in a two dimensional field. It is desirable to place the arrays on a conventional microscope slide, and to create many such slides simultaneously in a manufacturing process.
In important applications, single stranded DNA or PNA or other biological elements in the form of fragments carrying known information are distributed onto the surface of a planar field array containing up to possibly 100,000 objects per microscope slide. The objects of the array represent discriminating sequence information. Different laboratories have targeted the objects of the array to have various spot sizes over a range of the order of 25 to 250 &mgr;m in diameter, depending primarily upon the total number of objects anticipated in the array. The objects of the array are probed with fluorescently labeled fragments of potential complementarily. When a match occurs between these fragments and hybridization occurs, a positive is scored by observing fluorescence at the site of hybridization. By manipulating the deposition of complementary strands or fragments into the array and scoring “hits”, many levels of information can be inferred.
For gene chip technology to proceed to complete fruition, as well as to improve the application of previous analytical techniques, economical instruments have been needed that can rapidly and accurately create the dense array of objects over a large field portion of a glass microscope slide that occupies approximately 22 mm wide and 50 mm long of a slide that is nominally 25 mm×75 mm.
In the deposition upon a microscope slide of discrete, minute quantities of a large variety of fluid materials, the volume deposited at a discrete spot typically may be from a few pico liter to a fraction of a micro liter, depending upon the application. The biological material carried in this fluid can range from a few strands of short oligonucleotides in a water solution to a high concentration of long strands of complex proteins. The properties of these fluids vary enormously. Some are akin to water while others are far more viscous, resembling a light oil or honey. The range of fluids that may be employed also exhibits wide differences in evaporative characteristics and in other properties.
Such large range of property variations in fluids of interest has caused great difficulties for any single type of process to operate over a wide range.
Certain processes employing photolithographic techniques have offered excellent positional accuracy of the objects and high dot density but have great limitations due to cost and due to the limited range of biological and chemical techniques that are applicable. These techniques typically construct short segments of DNA or other molecules by adding single bases, one at a time.
Certain other processes for forming arrays of dots of biological material have utilized piezo micro cylinders to aspirate and jet small volumes of fluid containing the material while others have used processes akin to a fountain pen, comprising a “quill” deposition tool. An assemblage of quills suck up a desired amount of fluid and by tapping a quill upon the receiving substrate, the meniscus holding the fluid in the gap of the quill breaks, due to inertia of the fluid within the suddenly stopped tool, so that a drop of fluid is effectively propelled from inside the quill to the impacted surface.
The development of such techniques has occurred against the background of the quite old technique for forming much larger deposits, of transferring a portion of fluid by a pin or a set of pins that are e.g. dipped in a fixed reservoir containing fluid to be transferred and moving the pins into position to contact a usually soft substrate to form relatively large spots. Some of these instruments are known as “replicators”. An example of a product produced by such prior pins would be a 22 cm×22 cm bioassy plate carrying 0.6 mm diameter spots located on a grid 1 mm on center. This spot density is approximately
3
orders of magnitude too low from that needed for current “Gene Chip” applications, and the previously known techniques are impractical for present purposes for a number of other reasons as well.
SUMMARY OF THE INVENTION
Our purpose is to provide a technology adapted to the deposition of very small drops of fluids, e.g. drops that form spots of less than about 300 &mgr;m diameter, and in important cases much smaller than that, and at high density, the fluids and the resultant spots permissibly exhibiting a wide range of properties such as viscosity, evaporative characteristics, surface tension, wettability, surfactant characteristic, dynamic contact angle and free surface energy. The present invention employs features presented in U.S. patent application Ser. No. 09/006,344, filed Jan. 13, 1998, entitled “Depositing Fluid Specimens on Substrates” and in our further applications referred to above, as well as additional technology, to be described below.
A. Features Described in our Prior Applications
In our U.S. applications Ser. No. 09/006,344 and U.S. Ser. No. 09/079,324 we describe apparatus for deposit of fluid samples in a dense array of mutually isolated dots, comprising a deposit pin or other deposit device, a fluid source for repeatedly providing a dot of fluid on the end of the deposit pin or device, mechanism for moving the pin or device relatively over an array of spaced apart deposit locations of a receiving substrate, mechanism for repeatedly moving the pin or device, relatively, toward and away from the receiving substrate to deposit respective dots at respective deposit locations on the substrate, a cleaning system, and a control system adapted to control relative movement of the deposit pin or device between a resupply relationship to the source, a depositing relationship to the substrate over the array of spaced apart deposit locations on the substrate, and a cleaning relationship to the cleaning system mechanism.
In preferred embodiments the deposit device has a tip of diameter of about 0.3 mm or less, and is so constructed and constrained in space that the tip is compliant axially while being precisely located laterally relative to the receiving substrate. (By “compliant” is meant that the tip has a range of movement in the absence of a substrate, but stops wherever the substrate may lie within the range, the tip readily stopping when it encounters the substrate, without exertion of significant force or impact energy by the tip on the substrate).
Also in our prior application we have shown a moveable deposit device associated with a local fluid storage device that is separate from but generally moveable with the deposit device over the array of deposit locations, the fluid storage device being constructed and arranged to locally resupply the deposit device during its deposit sequence.
In certain cases shown, the local storage device is constructed and arranged to be replenished from a remotely located relatively large reservoir, the reservoir being constructed to store a multiplicity of isolated fluid volumes, the apparatus constructed to move the local supply device to a selected fluid volume of the reservoir for replenishment.
In these arrangements the deposit device can quickly pick up a drop of fluid from its companion mobile supply without excessive movement, and then can deposit the drop fully as an accurately located, small dot deposit, without influence by the fluid supply.
In our prior applications, for use in certain cases, we employ a mobile supply member in which a pin or other device is dipped. In other advantageous cases a member defines a generally annular fluid retention surface and a deposit pin or other deposit device is constructed to move within the annular retention surface from retracted to extended positions. In the retracted position the deposit portion of the deposit device is retracted from the lower
Flowers Peter T.
Honkanen Peter
Mace Myles L.
Montagu Jean I.
Overbeck James W.
deVore Peter
Genetic Microsystems, Inc.
Huson Gregory L.
McGarrigle Philip L.
Sherr Alan B.
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