Chemistry: analytical and immunological testing – Automated chemical analysis – Utilizing a centrifuge or compartmented rotor
Reexamination Certificate
2000-07-11
2003-07-15
Soderquist, Arlen (Department: 1743)
Chemistry: analytical and immunological testing
Automated chemical analysis
Utilizing a centrifuge or compartmented rotor
C422S064000, C422S072000, C436S086000, C436S089000, C436S165000, C436S174000, C494S013000, C494S014000, C494S084000, C494S016000, C494S019000
Reexamination Certificate
active
06593143
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to analytical chemistry and, more particularly, to centrifuge-based automated sample treatment systems. A major objective of the present invention is to provide rapid and fine temperature control during a series of sample treatments in a centrifuge-induced supergravity field.
The standard of living in modern societies has been greatly enhanced by advances in chemical, biological, and medical sciences. These fields all involve the separation of samples into constituent components that may then be processed to aid in their identification and/or quantification. The centrifuge is an important instance of instrumentation used to separate sample components.
A simple centrifuge has a centrifuge rotor that is spun, e.g., by a motor. Typically, a liquid chemical sample spins with the rotor. The spinning liquid sample components are subjected to a centrifugal force (F=m&ohgr;
2
r) proportional to their mass, their distance from the centrifuge spin axis, and the square of the spin rate. The effect of the centrifugal force is much like the effect of gravity-liquid components are separated according to their relative densities. However, unlike gravity, the centrifugal force is readily controlled, e.g., by controlling the spin rate. Thus, a centrifuge can generate centrifugal forces orders of magnitude greater than gravity at the earth's surface. Generally, the “supergravity” conditions of a centrifuge are much more effective than gravity in separating sample components.
In addition, the supergravity conditions afforded by a centrifuge can be used to overcome liquid surface effects that might otherwise impede sample movement. Accordingly, centrifuges that can control the tilt of a chemical-processing unit relative to the centrifugal force can be used for pouring, mixing, filtering, and facilitating chemical reactions. Furthermore, tilting can be used to control liquid movement among multiple processing stations of a chemical-processing circuit so that a series of processes can be implemented without manual intervention. Thus, a centrifuge with tilt control can automate sample processing conventionally performed manually by chemists.
Independent control of centrifuge spin rate and tilt action is disclosed in U.S. Pat. No. 4,814,282 to Holen et al. Tilt of a chemical-processing circuit is used to transfer liquid from one station to another under the influence of centrifugal force. A tilt-drive assembly, including motor and drive chain, is attached to the centrifuge rotor so that it rotates therewith. Power is delivered to the tilt-drive motor via slip rings, which tend to wear out as they are not generally designed to operate at centrifuge speeds. In this approach, any sensors used to track tilt would also rotate at high speeds, further complicating operation. In addition, centrifuge forces are applied to the tilt motor and the drive train. For example, a 1-pound motor must withstand 1000-pound forces in a readily achievable 1000 G supergravity field. Thus, there are a number of robustness issues that can only be addressed with additional complexity and expense.
These robustness issues are mitigated in the centrifuge disclosed in U.S. Pat. No. 5,089,417 to Wogoman. In the Wogoman centrifuge, a holder for a chemical-processing circuit snaps from a first tilt orientation to a second tilt orientation when the centrifuge exceeds a predetermined rotation rate. Similarly, the first tilt orientation is resumed when the centrifuge spin rate falls below the threshold rate. Thus by increasing and decreasing the centrifuge spin rate, sample movement between reaction stations of the chemical-processing circuit can be controlled. However, this approach provides little flexibility in selecting the centrifuge spin rate or tilt angles relative to the centrifugal force. It would be preferable to control the centrifuge rotation and the tilt actions independently.
U.S. Pat. No. 4,776,832 to Martin et al. avoids the need for physical connections to drive a tilt rotor by using inductive motors. The inductive motors include induction rotors that are physically coupled to holders, e.g., for reaction cells, and stationary stators, which are located beneath the centrifuge rotor (wheel). The stators induce eddy currents in the induction rotors, causing them to rotate. No physical connection is required between the stators and the induction rotors, eliminating the need to deliver power through slip rings. On the other hand, the non-physical coupling of drive and induction rotor does not ensure precise and flexible control of sample-container orientation relative to the supergravity field.
Parent U.S. patent application Ser. No. 09/576,690 discloses a coaxial-drive centrifuge in which part of the drive assembly for the tilt motion is coaxial with the centrifuge axis. This arrangement overcomes the robustness limitations of Holen et al., the flexibility limitations of Wogoman, and the precision limitations of Martin et al. A tilt-drive motor provides complete control over tilt without restricting centrifuge rotation rates. The tilt-drive motor is stationary, so electrical coupling is not required to a rotating element. The coupling between the tilt-drive motor and the chemical-processing circuit is mechanical, so there is no problem of precision in tilt control.
The coaxial-drive centrifuge holds the promise for rapid and fully automated sample processing through a series of treatment steps. For example, a polymerase chain reaction (PCR) technique requires many iterations of a series of steps. PCR is used to copy small fragments of doxyribonucleic acid (DNA); the procedure can be iterated so that the amount of DNA grows exponentially. Thus, a limitless amount of DNA sample can be “amplified” from a single DNA fragment. This can allow, for example, multiple parallel destructive analyses to be performed. PCR techniques have accelerated the study of gene functions and gene mappings (e.g., in the Human Genome Project). Generally, PCR is useful in biology, clinical medice, and forensic science.
One variant of PCR , begins with heating a DNA solution (e.g., to 90° C.) so that individual strands separate. Then the DNA solution is cooled (e.g., to 50-60° C.), allowing oligonucleotide primers to bind to the separated DNA. Then the temperature is raised (e.g., to 70° C.) so that polymerase can copy the DNA rapidly. These three phases, melting, annealing, and extension, can be iterated so that the amount of DNA grows exponentially. Typically, the DNA sample remains in a container that is heated and cooled by using temperature controlled baths. The time for the temperature to transfer through the sample container wall is a limiting factor in the rate at which the PCR reaction can be iterated.
Tilt-capable centrifuges with multi-chamber chemical-processing circuits could be used so that each PCR step can be conducted in a dedicated station. Each station can be kept at the temperature associated with one step, e.g., melting, annealing, and extension. Changes in container orientation between steps can be used to move the sample from station to station to automate the processing.
However, the promise for rapid and fully automated chemical-sample processing faces a challenge in temperature control. Typically, different temperatures are required for different sample treatments. The entire centrifuge can be temperature controlled, but then it is difficult to change temperatures rapidly. At best, slow temperature changes delay processing throughput; at worst, slow temperature changes can be incompatible with certain treatment requirements. Local resistive heaters can provide rapid heating. However, delivering electrical power to a rotating chemical-processing circuit for heat control faces linkage challenges as discussed above with respect to Holen et al.
Moreover, sample temperature should be monitored to provide precise closed-loop control thereof. Once again, electrical connections to rotating elements are preferably avoided. What is needed is a system that provides f
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