Fluent material handling – with receiver or receiver coacting mea – Processes
Reexamination Certificate
2001-05-21
2004-04-20
Huson, Gregory L. (Department: 3751)
Fluent material handling, with receiver or receiver coacting mea
Processes
C141S279000, C422S105000, C436S180000, C118S243000, C118S263000, C427S256000
Reexamination Certificate
active
06722395
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to the deposit upon substrates of small quantities of fluid in a precise manner and in arrays of desired density and consistency. The invention is useful, for instance, in carrying out reactions, in providing accurate overlays of deposits, and, in particular, in preparing microscope slides and membranes with biological materials.
The invention also relates to array products produced by the novel deposit techniques and to methods of analysis that employ the deposit techniques.
In the field of biochemistry it is desirable to accurately and efficiently deposit tens, hundreds, thousands and tens of thousands of samples of differing compositions on reaction or examination areas. Improvement in the speed of deposition, the precision of the size, shape, quantity and location of the deposits and the control over density of the deposits can lead to important advantages.
In particular, well developed biological analytical technology, and 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 complementariTy. 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 or slide-like member that occupies an area 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 and substrates 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 bioassay 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
One purpose of the invention 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 375 or 300 &mgr;m diameter, and in important cases much smaller than that, and at correspondingly high densities (as used in this application, the term fluid “drop” refers to a very small quantity of fluid, and not to any particular shape of the fluid volume). The fluids and the resultant dots permissibly exhibit a wide range of properties such as viscosity, evaporative characteristics, surface tension, wettability, surfactant characteristic, dynamic contact angle and free surface energy. These and numerous other objectives are achieved by a number of broad features and preferred embodiments which are individually novel and important and which in many cases cooperate to achieve highly effective results.
According to one aspect of the invention, an apparatus for depositing fluid dots on a receiving surface in an array suitable e.g., for microscopic analysis reaction and the like, is provided, comprising a deposit device and a fluid source which are cooperatively related to enable the deposit device to precisely size a drop of fluid of small diameter on a drop-carrying surface of the device, transport mechanism for positioning the device at a precisely referenced lateral position over the receiving surface and drive mechanism for moving the deposit device, relatively, in deposition motion toward and away from the surface, the apparatus adapted, by repeated action, to deposit the drops of fluid precisely in a desired array, preferably the apparatus being computer controlled.
Preferred embodiments have one or more of the following features.
The drop-carrying surface has a diameter less than 375 micron, preferably less than 300 micron, preferably between about 15 or 50 micron and 250 micron.
The drop-carrying surface is bound by a sharp rim that defines the perimeter of the drop of fluid.
The deposit device is a pin or pin-like structure having an end surface that carries the fluid drop, preferably the pin or pin-like structure having sides that intersect with the end surface to define a sharp peripheral drop-defining rim.
Another broad aspect of the invention is an apparatus for depositing fluid drops on a receiving surface per se, comprising a deposit device and a fluid source which are cooperatively related to provide to a drop-carrying surface of the deposit device a precisely sized drop of fluid, the deposit device being a pin or pin-like structure having an end surface that serves as the drop-carrying surface, the pin or pin-like structure having sides that intersect with the end surface to define a sharp peripheral drop-defining ri
Flowers Peter T.
Honkanen Peter
Mace Myles L.
Montagu Jean I.
Overbeck James W.
deVore Peter
Huson Gregory L.
McGarrigle Philip L.
Sherr Alan B.
Zitkovsky Ivan D.
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