Solid supports for analytical measuring processes

Details Solid supports for analytical measuring processes Solid supports for analytical measuring processes

1999-01-14

2004-05-18

Alfandary-Alexander, Lyle (Department: 1743)

Chemical apparatus and process disinfecting, deodorizing, preser

Control element responsive to a sensed operating condition

C422S067000, C422S105000, C435S288400, C435S305200

Reexamination Certificate

active

06737024

ABSTRACT:

The invention relates to solid supports for analytical measurement methods which are essentially composed of an inert solid support material on which hydrophilic measurement zones which may be provided with a surface loading are separated from one another by at least one hydrophobic coating, where the number of measurement points applied per cm
2
of the support is greater than or equal to 10. The invention furthermore relates to a process for producing the supports, and to the use of the supports in diagnostic methods, in research looking for active substances, in combinatorial chemistry, in crop protection, in toxicology or in environmental protection.
A main task of research looking for active substances in crop protection or in medicine is to identify novel lead structures and to develop active substances derived from these structures.
In classical research looking for active substances, the biological effect of novel compounds has been tested in random screening on the whole organism, for example the plant or the microorganism. Employed for this purpose were complex in vitro and in vivo test methods with which only a few hundred substances could be tested each year.
In this case the biological testing was the limiting factor with respect to the synthetic chemistry.
The provision of molecular test systems by molecular and cell biology has led to a drastic change in the situation. These molecular test systems, such as receptor binding assays, enzyme assays or cell-cell interaction assays, can, as a rule, readily be carried out in microtiter plates in reaction volumes of from 50 to 250 &mgr;l and can easily be automated. Automation and miniaturization of these test systems permits the sample throughput to be high. This development makes it possible to test large numbers of different chemicals for possible use as lead structure in research looking for active substances.
A modern automated test system allows 100,000 or more chemicals to be tested for their biological effect each year in mass screening. Microtiter plate assays are very often used because, as a rule, they entail low costs, are very reliable and have little susceptibility to faults.
In order to be able fully to exploit the efficiency of these test systems, novel solid-phase syntheses have been and are still being developed in combinatorial chemistry.
Combinatorial chemistry makes it possible to synthesize a wide variety of different chemical compounds, called substance libraries. This is particularly true when combinatorial chemistry makes use of automated solid-phase synthesis (see, for example, review articles I. [sic] Med. Chem. 37 (1994) 1233 and 1385). Solid-phase synthesis has the advantage that a large number of compounds can be synthesized, and that by-products and excess reactants can easily be removed, so that elaborate purification of the products is unnecessary.
The large number of synthesized compounds in combinatorial chemistry means that the efficiency of modern automated test systems can be fully exploited with regard to chemical diversity. Since, however, in contrast to classical active substance synthesis, the chemicals to be investigated are not available in any desired amount on synthesis by means of combinatorial chemistry, only a restricted number of test systems can be examined because of the amounts of chemicals required in the test systems.
Another disadvantage of present test systems, for example in research looking for active substances, in diagnostic methods, in environmental protection or crop protection, is that the reagents required for many test systems, such as enzymes, antibodies, receptors, fluorescent dyes, radioactively or otherwise labeled ligands, cytokines, activators, inhibitors or other reagents, are costly, difficult to prepare and/or not available in a quantity sufficient for the automated tests.
DE-A 44 35 727 describes an approach for reducing the reagents required for a test.
The disadvantage of this process is that the support for the measurements must first be produced in an elaborate multistage process.
Another disadvantage is that the reactions which can be carried out with this support material are confined to reactions linked to solid phases, such as reactant binding between antibodies, antigens, haptens or nucleic acids. It is not possible with this method to carry out reactions in solution.
It is an object of the present invention to develop a novel analytical measurement method which can be carried out without the stated disadvantages and provide it for research looking for active substances, diagnostic methods, environmental protection, crop protection, toxicology or combinatorial chemistry.
We have found that this object is achieved by using the solid support described at the outset for the measurement method.
It has been found that the surface tension which hinders further miniaturization of the present microtiter plate technique to ever smaller reaction cavities (=wells), because thereby forces such as adhesion of the reaction liquid to the surface of the microtiter plates or the capillary forces are of increasing importance, and thus make it impossible to fill the reaction cavities and thus carry out a measurement, in very small microtiter plate wells, can be utilized advantageously for the supports according to the invention.
Hydrophilic measurement zones on the support mean areas on the support on which or in which the measurement is carried out after application of the reaction liquid and thus of the reactants (see number
2
in
FIGS. 1
,
3
and
4
). They thus correspond to the wells in microtiter plates and are referred to hereinafter as “measurement zones or measurement points”.
The hydrophilic measurement zones on the support are advantageously surrounded by a hydrophobic zone (see number
1
in
FIGS. 1
to
4
). This hydrophobic zone can be composed of at least one hydrophobic coating which covers the support completely or only partly with discontinuities. These discontinuities (see number
5
in
FIGS. 1
to
4
) are advantageously hydrophilic.
FIGS. 1
to
4
serve to illustrate the supports according to the invention by way of example.
The measurement zones, and the hydrophobic zones which separate them from one another (see number
1
in
FIGS. 1
to
4
), can be applied, for example, by microlithography, photoetching, microprinting or a micropunch technique or can be sprayed on using a mask technique. Photochemical processes which can be used to make the surfaces of plates or rolls specifically hydrophobic at particular points and hydrophilic at other points are known from the techniques for producing printing plates. It is possible with this technique to produce, for example, a grid of several thousand regularly arranged hydrophilic measurement zones (see number
2
in
FIGS. 1
,
3
and
4
), surrounded by hydrophobic margins (see number
1
in
FIGS. 1
to
4
), in a simple manner on a support, eg. on a glass or metal plate. This may entail firstly one or more hydrophobic coatings being applied to the support, and subsequently the measurement zones being applied to the required points or, conversely, initially the hydrophilic measurement zones and then the hydrophobic zones, or both simultaneously, being applied. It is also possible to apply a plurality of hydrophilic measurement zones to the same point.
FIG. 2
depicts by way of example a support according to the invention having the size of a microtiter plate.
The measurement zones can have any desired shape, with circular measurement zones being preferred.
The hydrophobic coating or coatings may be applied coherently to the support or else be provided with discontinuities of any design. They may also be in the form of separate zones around the measurement zones, with hydrophobic rings separating the hydrophilic measurement zones from one another being preferred.
The hydrophobic coating or coatings are intended to prevent the measurement zones spreading into one another and thus to make accurate measurement of individual reaction mixtures possible.
It is possible i

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