Optics: measuring and testing – Sample – specimen – or standard holder or support
Reexamination Certificate
2001-03-08
2003-11-04
Evans, F. L. (Department: 2877)
Optics: measuring and testing
Sample, specimen, or standard holder or support
C359S398000, C422S105000, C435S288400, C435S288700
Reexamination Certificate
active
06643010
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to providing a microchannel chip device which will be able to perform a large number of bio molecule tests simultaneously, as well as producing a uniform test environment for each biomolecule test and eliminate the statistical test to test variations.
BACKGROUND OF THE INVENTION
It is known in fluid dynamics that, due to the viscosity of the biological sample containing fluid, which is usually water, the dynamic pressure to pass this fluid through and into the multiple channel glass panel increases as the microchannel diameter is reduced and the glass plate thickness increases. Threshold values are such that, below 10&mgr; in channel diameter, increase in vacuum pressure is required to force water through the microchannels, and also structural integrity of the glass sample then becomes problematic. However, on the other side, by increasing channel diameter beyond 10&mgr; and reducing the thickness of the glass plate, vacuum pressure is still required but to a lesser extent, while undesirable artifacts are generated in particular increased diffuse halos around the top access mouth of the channels. These undesirable artifact halos considerably deteriorate both the image quality and the sensitivity of the test.
It is noted that fluid dynamics in a microchannel are not the same as those in diametrally larger tubes, e.g. a water filled coffee mug. Indeed, because of the larger inner diameter of a coffee mug, when a water filled coffee mug is tilted from an upright condition to a laterally inclined position, the top surface menisk of the volume of water will not concurrently tilt and thus will remain parallel to the ground in both instances, although the longitudinal axis of the mug is no longer vertical in its tilted condition. On the other end, due to surface tension properties and viscosity of the water and due to the micrometer grade diameter of the microscopic (micro-) channel, when a microchannel is tilted from an upright condition to a laterally inclined condition, the menisk will not stay parallel to the ground as it did in larger diameter cylinder such as a coffee mug, but will tilt with the tilted microchannel so that the perpendicular axis to the top surface menisk of the water volume inside the tilted microchannel will remain coaxial to the longitudinal axis of the tilted microchannel.
Existing devices for binding a target molecule comprise a substrate having a multiplicity of discrete tubes extending transversely therethrough. These tubes extend orthogonally to the top surface of the substrate. A first binding reagent is immobilized on the walls of a first group of tubes, while a second binding reagent is immobilized on the walls of a second group of the tubes. Such device is for use in the identification or characterization of nucleic acid sequences through nucleic acid probe hybridization with samples containing an uncharacterized polynucleic acid, e.g. recombinant DNA, polymerase chain reaction fragments, etc . . . as well as other biomolecules.
In these known tubes, their diameter ranges between about 0.03 to 10&mgr;. The reason for the top threshold diameter value is that if your have upright tubes or channels, any diameter larger than about 10&mgr; will enlarge optical halo artifacts at the top access mouth of the tubes, and accordingly will bring, much reduced sensitivity.
During the 1990s, microfabrication technology has enabled miniaturization and automation of manufacturing processes in numerous industries. The impact of microfabrication technology in biomedical research can be seen in the growing presence of microprocessor controlled analytical instrumentation and robotics in the laboratory engaged in high throughput genome mapping and sequencing (see the current “Human Genome Project”, with its first phase just completed). Optical detection of fluorescent labelled receptors is employed inter alia in detection for sequencing. Detection can be achieved through use of a charge coupled device array, or confocal laser imaging technology such as DNA scope (TM).
Capillary tube glass arrays are already in use as high surface area nanoporous support structures to tether DNA targets or probes for hybridization. Such capillary tube glass wafers contain a regular geometric array of parallel holes or tubes as small as 33 nanometers in diameter, or as large as several micrometers in diameter. These holes or tubes serve as sample wells for placement of a substantially homogeneous sample of a biomolecule within each hybridization site. The orifices are fabricated using excimer laser machining.
However, such prior art microscopic detection devices usually require charged coupling devices, and cannot scan the full sample area. This is because, since you have vertical micro-channels, the diameter thereof larger than 10&mgr; will produce much larger optical halo artifacts and will bring about much diminished microscopic sensitivity. This is why the claimed microchannel diameter in the Beattie patent is limited to a range from 0.03 to 10&mgr;.
Methods are also known in the art for delivering sub-nanoliter microdroplets of fluids to a surface at submicron precision. A microjet system or a microspotter, capable of delivering subnanoliter DNA solution to the wafer surface, can thus be employed.
Moreover, in the field of biotechnology, there is an increasing use of biochips for detection of macromolecules such as DNA and proteins. Amongst the various numbers of biochips the flow-through bio-chip is preferred, because of the advantage in terms of speed of the reaction and sensitivity associated with it. Mostly these biochips are made from cylindroid and cross-sectionally polygonal channels that are extended through the length of the panel chip. The diameter of these channels may vary from a few to several hundred micrometers, but usually about 25&mgr;.
Most of the testing solutions such as serum, are not homogeneous in nature and contain impurities as the entire cell or cell particles. Some are very viscous in nature and have difficulties passing through small pores of micrometer size. Serum contains fibrin, which is the long strands of wire mesh adapted to entrap the cells. These fibrin strands may be present in serum even after separation. Other impurities like leukocytes with a diameter of 35&mgr; and thickness of a few micrometers, may clog the cylindrical pore. If the pore is in the shape of a slot with a length of e.g. 40&mgr; and a width of 3&mgr;, it thus has opening area of 120 square &mgr; which can easily accommodate the passage of white blood cells (WBC) through the panel chip. Cylindrical pores with a diameter of 40&mgr; have opening area of (20×20×3.141592&mgr;) or approximately 1,256&mgr;
2
, being ten times bigger than the slot form.
Indeed, the bigger the diameter of cylindrical channels, the worst image deterioration occurs in scanning. The opening area and dead space may be interchangeable terms. Usually, opening area is the area of open space (or empty space) that extends through the chip from the surface or the surface area which separates these channels. The inner surfaces of these pores are areas in which most binding occurs. A cylindrical pore with diameter of 2&mgr; and a constant thickness K has opening area of (1×1×3.141592) or approximately 3 square micrometers with inner surface area of (2×K×3.141592) i.e. approximately 6K or 6. Since both panel chips have the same thickness, so the K would remain the same. If one increases the diameter of a cylindrical pore to 200&mgr;, the opening area would be (100×100×3.141592) i.e. approximately 30,000 square micrometers, and inner surface would be (200×3.141592) i.e. approximately 600&mgr;
2
. From these calculations it is understood that 100 folds increase in diameter of cylindrical pore shape from 2 to 200&mgr;, has resulted in a 10,000 times increase in opening area (from 3 to 30,000) which is considered to be useless area where no binding occurs, and 100 times for inner surface area (from 6 to 600) where the bind
Evans F. L.
Royce Technologies LLC
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