Chemistry: molecular biology and microbiology – Apparatus – Including measuring or testing
Reexamination Certificate
2001-12-18
2004-06-29
Redding, David A. (Department: 1744)
Chemistry: molecular biology and microbiology
Apparatus
Including measuring or testing
C435S288300, C435S091200, C422S098000, C422S109000, C204S403030, C204S403130
Reexamination Certificate
active
06756223
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to the analysis of biomolecular samples. More particularly, the present invention relates to fabrication and integration of thermal management techniques and devices for close proximity monitoring of a bioassay in a bioelectronic analyzer for the analysis of biomolecular samples such as nucleic acids.
BACKGROUND OF THE INVENTION
Molecular biology is an ever expanding field of study. Of great importance within the field of molecular biology is the detection and analysis of RNA, DNA, bacteria, proteins, and the like. Identification of molecular structure has become very important in many industries. In particular, biological molecules such as nucleic acids and proteins are analyzed to form the basis of clinical diagnostic assays. Currently it is predicted that a large market exits for bio-chips (micro-array chips) in the diagnosing and treating of diseases. Envisioned is a day when physicians will have the capabilities to use bio-chips to make an immediate genomic marker based diagnosis in their offices without the need for a lab as an intermediate diagnostic facility.
Currently, the greatest emphasis and market existence for bio-chips is within the field of genetic and pharmaceutical research, where many thousands of genes can be analyzed in parallel. The procedures utilized often involve large numbers of repetitive steps which consume large amounts of time. With the advent of large projects such as the human genome project, faster and less complex techniques are required.
Simpler and quicker analysis of molecules has been provided by the development of devices often referred to as biochips, which include arrays of test sites formed on a substrate platform. Each of the plurality of test sites includes probes therein to bond with target molecules from samples applied to the device. During analyzation, once certain conditions are met (discussed presently), the binding of a biomolecular to a probe is noted, thereby providing for the identification of the specific biomolecular.
DNA chips or microarrays generally consist of thin wafers of glass, silicon, plastic, printed circuit board (PCB), or ceramic having numerous microscopic bits of bio-molecules or porous support medium containing biomolecules, such as immobilized DNA probes sequences arrayed on the surface. These are used to identify specific disease genes and to speed drug discovery efforts. For example, microarray data has been used to identify gene clusters based on co-expression (Eisen, M. B. et al., Proc. Natl. Acad. Sci., 95, p. 14863-8, (1998)), define metrics that measure a gene's involvement in a particular cellular event or biochemical process (Spellman, P. T., et al., Molecular Biology of the Cell, 9, p. 3273-97, (1998)) and predict regulatory elements (Brazma, A., et al., Genome Research, 8, p. 1202-15, (1998)). It is anticipated that in the future increased use of bio-molecule related science will allow for a more personalized practice of medicine, more particularly the design and use of customized treatments and therapies based on a patient's genetic makeup (for review see Health Horizons articles on http://www.msnbc.com
ews/horizons_front.html).
Currently, bio-chips, more specifically DNA chips, are known that are based on a common method of manufacture, namely the etching of silicon computer chips, as currently utilized in the semiconductor industry (O'Donnell-Maloney, Maryanne J. et al., Tibtech, 14, p. 401-407, (1996)). Of all of the uses of bio-chips to study bio-molecules, the study of DNA is the most mature. In one specific instance, a photoactivated DNA probe synthesis process is used to manufacture high density DNA chips (Fodor et al., Science, 251, p. 767-773, (1991)). Typically eighty photolithographic mask levels are used to synthesize DNA probes. Alternative approaches for dispensing reagents on a substrate have been reported in the prior art (e.g. U.S. Pat. No. 6,048,699, issued Apr. 11, 2000; U.S. Pat. No. 6,013,446, issued Nov. 1, 2000). In particular, the use of dispensing techniques to place purified, presynthesized oligonucleotides onto specific locations on a surface to produce a DNA chip is described in Schober, A., et al., BioTechniques, 15(2), p. 324-329, (1993) and U.S. Pat. No. 6,083,762, issued Jul. 4, 2000. The later technique does not require photolithography and requires fewer redundant probes because the purity of the probe sequences is much higher than in the photoactivated probe synthesis process. [E.P. 0910570 A1, issued Apr. 28, 1999; U.S. Pat. No. 6,312,960, issued Nov. 6, 2001].
An alternative means for synthesizing DNA probes is by using tiny micromirrors which allow for the placement of in excess of 300,000 bits of DNA onto a chip in just a few hours. In addition, the use of ink-jet printing is known, using high-speed robotic devices to print DNA on tiny squares of glass, to form an array. (U.S. Pat. No. 6,285,490B1, issued on Sep. 4, 2001). These types of machines are capable of forming as many as 32,000 DNA molecules on a single chip.
Still other methods include the use of fiber-optic bundles to build chips capable of holding 50,000 different DNA fragments on a single chip, and microelectronic chips that utilize electricity to attach DNA molecules to the surface of the chip. Other techniques can comprises the use of RF transponders, (U.S. Pat. No. 5,981,166A1, issued on Nov. 9, 1999), microbeads (Czarnik et al., Modern Drug Discovery, 1(2), p. 49-55 (1998)); U.S. Pat. No. 6,266,459B1, issued Jul. 24, 2001; U.S. Pat. No. 6,261,782B1, issued Jul. 17, 2001).
In the typical application, the biomolecular, or biological, sample that is being tested must be heated while held in the biochip to enhance kinetics prior to analyzation. In most instances, an external separate probe for temperature measurement is utilized to monitor the temperature of the biomolecular sample while the sample and biochip are placed in an oven or in conjunction with an external power source generating heating of the entire biochip or part thereof (e.g. the use of a Peltier heater/cooler requires mass transfer through at least the mass of the substrate of the chip on which said sample is attached that can typically limit the efficiency and duration of the thermal process to about 1 C/s). More particularly, the probe (e.g. resistance temperature device (RTD), pn junction, electrode, Kelvin probe, (e.g. used in atomic force microscopy) (AFM)) is in thermal contact with the biomolecular sample which must be heated to a given temperature and held at that temperature for a given period for analyzation of the sample to take place. Typically, a separate, externally located Peltier cooler/heater is utilized to accomplish this heating of the biomolecular sample and maintenance of the sample at the appropriate temperature. Prior to use, the heater must undergo calibration so that proper temperature sensing is achieved. (or alternative differential measurement). The bio-chip, containing the DNA probes and the biomolecular sample is introduced into a pre-calibrated oven chamber or preferably a calibrated Peltier heater, where the temperature is sensed and adjusted so that proper analyzation can take place. This presents not only an additional analyzation step, but a delay in a “sample in, data out” cycle. Furthermore, there is no control of the thermal profile at the chip level yielding to possible uncontrolled inhomogeneous thermal gradient at the sensor pad of the microarray of the biochip. More recently, Kajiyama et al. (Kajiyama, T., et al, Micro Total Analysis Systems 2000, p. 505-508, (2000) and E.P. No. 1108472A2, published on Jun. 20, 2001) described how to arrange DNA probes based on their melting temperature and hybridization using Si-islands that can be independently controlled by using the simple function of the pn-junction's voltage. Although, Kajiyama is teaching a method for attaching oligonucleotide probes to a silicon nitride surface, the method requires (i) chemically modifying the silicon nitride for generating rea
Burdon Jeremy W.
Roberts Peter C.
Sadler Daniel J.
Zenhausern Frederic
Koch William E.
Redding David A.
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