Refrigeration – Processes – Treating an article
Reexamination Certificate
2001-02-01
2002-03-12
Tapolcai, William E. (Department: 3744)
Refrigeration
Processes
Treating an article
C062S074000
Reexamination Certificate
active
06354091
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an apparatus and a method for the formation of frozen reagent beads, and more particularly, to an apparatus and method for the freeze forming of such beads comprised of a reagent used to carry out the analysis of a biological agent.
In the analysis of certain biological samples, it is common to use dry beads of specific reagents of a small precisely measured quantity. Such dried beads are commonly used in the analysis of blood assays but are also used with at variety of other analyses for other biological fluids and the reagent composition of the beads can also widely vary depending upon the particular analysis to be performed. As such, therefore, there is a need to produce dry reagent beads of a variety of compositions that are of a uniform size and predetermined characteristics by an apparatus or by using a method that is reliable and that can produce a large quantity of such beads at a rapid rate.
One of the methods of creating such dry chemical reagent beads is to use a freezing technique where the liquid reagent, in the desired amount and composition, is progressively dropped into a liquid cryogen, such as liquid nitrogen, where the liquid drop is fairly rapidly frozen into a reagent bead in a spherical configuration of the predetermined precise quantity. The frozen beads are thereafter harvested in a batch process and further processed by being lyophilized to form the ultimate product that is a dry bead of the desired reagent that dissolves quickly when in contact with the sample to be analyzed.
Thus, it is important to be able to rapidly create a large quantity on a continual basis of the frozen reagent beads such that the overall formation of such spherical beads, can be carried out efficiently and rapidly to produce the reagent beads of a constant, known quantity and contents.
In the production of the reagent bead, therefore, the liquid reagent is produced in the desired final concentration of constituents in liquid form and that liquid is dispensed in the form of drops that fall downwardly by means of gravity into a quantity of the liquid nitrogen. The liquid drop is thus frozen and eventually the frozen droplets fall to the bottom of the liquid nitrogen container. As the one drop is dispensed from the apparatus into the liquid nitrogen, the apparatus readies another drop that thus follows the prior drop after a predetermined elapsed time. The accumulated frozen beads of the particular reagent composition collect in the bottom of the container holding the liquid nitrogen and are periodically harvested, by a batch process, from the bottom of the container holding the liquid nitrogen and the process continued.
There is, therefore, a need for the aforesaid process to produce a large quantity of the final reagent beads in as rapid a period of time as is practical. At the present, the overall freezing process poses a problem to increasing the speed of the overall operation in that there is a physical limitation on the current process relating to the freezing process itself. As the spherical liquid drop is dispensed into the liquid nitrogen, the temperature of the liquid drop is relatively hot as compared with the temperature of the liquid nitrogen and thus, the initial contact between the liquid drop and the liquid nitrogen causes the liquid nitrogen to boil violently and generate a large quantity of nitrogen gas under the drop as it rests upon the surface of the liquid nitrogen.
In effect, the liquid drop floats upon the gaseous nitrogen and is supported so as to not be directly in contact with the much colder liquid nitrogen. That boundary layer of nitrogen gas isolates the liquid nitrogen from direct contact with the liquid drop of reagent and that boundary layer of the nitrogen gas is a poor thermal conductor, thus having a deleterious effect on the rate of freezing of the reagent drop. Obviously, in attempting to increase the rapidity of the overall freezing process, any parameter or effect that reduces the freezing rate is disadvantageous to the overall aim of the apparatus.
Accordingly, the freezing process itself is delayed by the boundary layer that impedes the rapid cooling and freezing of the drop of liquid reagent and thus imposes a severe limitation on the overall throughput of product since any subsequent drop cannot be dispensed until the prior drop has frozen and dropped to the bottom of the liquid nitrogen, otherwise, two drops may fuse together and create an extra large or double sized bead of the reagent and can introduce an inaccuracy with the use of that oversized reagent bead in carrying out a later analysis. However, due to the formation of the boiled nitrogen gas, the drop floats on the surface of the liquid cryogenic until it finally freezes and sinks to the bottom of the cryogen. The time for such freezing and dropping can vary and is dependent upon the size and density of the drop, however, a typical time can be in the order of about six seconds.
Therefore, there is a timewise constraint on the overall freezing process, and left alone, would pose a serious hindrance to any effort at speeding up the present freezing process that depends highly upon the freezing rate of the liquid drop of reagent. It should be noted that the formation of periodic double drops cannot fully and successfully be alleviated through the use of passing all of the frozen reagent beads through a sieve material to try to capture the larger, oversized beads as the particular orientation of the beads as they pass through such a sieve can render the use of a sieve unreliable and thus still not fully solve the problem, that is, even a double bead can, at times, be in the proper orientation so as to pass through a sieve that is sized for a single bead. In addition it is believed to be a better course of action to solve the problem in the first place rather than resort to a remedial effort to minimize the problem of the formation of double sized beads, and thus, a solution to the initial problem would be preferable.
One currently known apparatus for the formation of the frozen reagent beads is shown and described in U.S. Pat. No. 5,275,016 of Chatterjee et al, where an apparatus is provided that has a rotating carousel on which is situated a plurality of trays containing the cryogenic liquid. In the Chatterjee et al patent, therefore, the carousel is rotated so as to position the trays beneath a liquid dispensing means where the drops of reagent are deposited in the liquid filled trays and the carousel continuously rotates. The difficulty with a rotating carousel, however, is that the throughput is also limited by the physical dimensions of the overall apparatus, thus, as one attempts to increase the throughput to achieve a higher production rate of frozen drops of reagent, the diameter of the rotating carousel has to increase outwardly at a drastic rate and cause the overall apparatus to become exceedingly large in order to produce any appreciable increase in the rate of production. This is an inefficient use of the space available to the user with the employment of a rotating carousel that creates a limitation on the rate of production of the frozen reagent drops of the Chatterjee et al apparatus. Too, with a rotary carousel, the linear speed of the carousel varies depending upon the radial position of the drops that fall into the carousel.
In addition, in the Chatterjee et al apparatus, it is stressed that the continuous rotational movement of the carousel, as opposed to a stop and go or intermittent movement, is intended to create a smooth movement so as to prevent agitation of the cryogenic liquid. However, as has been previously discussed, there is a layer of nitrogen gas that forms directly under the liquid drop of reagent as it is in the freezing process resting on the surface of the liquid cryogen and which forms a boundary layer that impedes the freezing process. As such, and to the contrary of the Chatterjee et al smooth movement, it would be preferable to create some agitation or movement of the cryogenic l
Ali Mohammad M.
Klauber & Jackson
Spectral Diagnostics Inc.
Tapolcai William E.
LandOfFree
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