|Veröffentlichungsdatum||17. Aug. 2006|
|Eingetragen||17. März 2006|
|Prioritätsdatum||19. März 1999|
|Auch veröffentlicht unter||CA2367912A1, CN1348396A, EP1165235A1, EP1165235B1, US6306578, US6436632, US7666360, US20020015994, US20020192716, US20050059074, US20120094851, WO2000056456A1|
|Veröffentlichungsnummer||11378735, 378735, US 2006/0183171 A1, US 2006/183171 A1, US 20060183171 A1, US 20060183171A1, US 2006183171 A1, US 2006183171A1, US-A1-20060183171, US-A1-2006183171, US2006/0183171A1, US2006/183171A1, US20060183171 A1, US20060183171A1, US2006183171 A1, US2006183171A1|
|Erfinder||Volker Schellenberger, Amy Liu|
|Ursprünglich Bevollmächtigter||Volker Schellenberger, Liu Amy D|
|Zitat exportieren||BiBTeX, EndNote, RefMan|
|Patentzitate (57), Referenziert von (20), Klassifizierungen (26), Juristische Ereignisse (3)|
|Externe Links: USPTO, USPTO-Zuordnung, Espacenet|
This application is a divisional application of copending Ser. No. 10/223,893, filed Aug. 20, 2002, which is a continuation of U.S. Ser. No. 09/970,578 (issued as U.S. Pat. No. 6,436,632), which is a continuation of U.S. Ser. No. 09/528,085 (issued as U.S. Pat. No. 6,306,578), which is a continuation-in-part of U.S. Ser. No. 09/471,852 (abandoned), which is a continuation of U.S. Ser. No. 09/272,122 (issued as U.S. Pat. No. 6,027,873). Each of the patent applications described in this paragraph is hereby incorporated herein by reference.
This invention is related generally to a screening method and, more particularly, to a method employing multi-through hole testing plate for high throughout screening.
Prior testing apparatuses have consisted of a testing plate with a pair of opposing surfaces and plurality of wells. The wells extend in from one of the opposing surfaces, but do not extend through to the other opposing surfaces. The wells are used to hold samples of solution to be analyzed.
Although these testing apparatuses work there are some problems. For example, the wells in these testing apparatuses are difficult to fill. Special delivery systems, such as large pipette systems, are needed to fill each of the wells with samples of solution. These special delivery systems are often expensive and difficult to operate. As a result, the overall cost of the testing procedure is increased.
Another problem with these prior testing apparatuses is with their construction. The bottom of the wells in these testing plates need to be transparent so that light can be transmitted through the samples during testing. However, the rest of the testing plate needs to be constructed of a non-transparent material. The construction of a testing apparatus with these characteristics is difficult and expensive.
Yet another problem with these prior testing apparatuses is with the operator locating a particular well in the testing apparatus. Typically, these testing apparatuses each include large numbers of wells which are equidistantly spaced apart. As a result, locating a particular well within the large number of wells is difficult.
Accordingly, there is a need for an improved testing apparatus for high throughput screening.
A method for holding samples in accordance with one embodiment of the present invention includes several steps. First, a testing plate with a pair of opposing surfaces and a plurality of holes is provided. Each of the holes extends from one of the opposing surfaces to the other one of the opposing surfaces. Next, at least one of the opposing surfaces of the testing plate is immersed in a solution to be analyzed. A portion of the solution enters openings for each of the holes in the immersed opposing surface and any gases in the holes escape though openings for each of the holes in the other opposing surface. Next, the testing plate is removed from the solution. Surface tension holds some of the solution in each of the holes. The opposing surfaces of the testing plate are then held above a supporting surface and the solution held in at least one of the holes is analyzed.
A method for identifying the location at least one sample of a solution in accordance with another embodiment of the present invention includes several steps. First, a testing plate with a pair of opposing surfaces and a plurality of holes is provided. Each of the holes in the testing plate extend from one of the opposing surfaces to the other one of the opposing surfaces. The holes in the plate are arranged in groups. Each of the groups comprises at least two rows and two columns of holes. Once a testing plate has been provided, solution is loaded into the holes and is then analyzed. Based on this analysis, the solution in at least one hole is identified for further study. The location of the identified hole is marked based upon the group in which the hole is found.
A method for screening a sample in accordance with another embodiment of the present invention includes several steps. First, a solution of the sample is prepared for screening. Next, a testing plate with a pair of opposing surfaces and a plurality of holes is provided. Each of the holes extends from one of the opposing surfaces to the other one of the opposing surfaces in the testing plate. Next, at least one of the opposing surfaces of the testing plate is immersed in a solution. A portion of the solution enters openings for each of the holes in the immersed opposing surface of the testing plate. Once the solution has enter into the holes, the testing plate is removed from the solution and the surface tension holds at least some of the solution in the holes. Next, the solution in one or more of the holes is analyzed.
An apparatus for holding samples of a solution with cells for analysis in accordance with another embodiment of the present invention includes a testing plate with a pair of opposing surfaces and a plurality of through holes. Each of the holes extends from an opening in one of the opposing surfaces in the testing plate to an opening in the other one of the opposing surfaces and is sized to hold a plurality of the cells. A portion of at least one of the opposing surfaces of the testing plate where the holes are located is recessed so that the openings in the testing plate are spaced in from the opposing surface.
An apparatus for holding samples for analysis in accordance with yet another embodiment of the present invention also includes a testing plate with a pair of opposing surfaces and a plurality of holes. Each of the holes extends from one of the opposing surfaces to the other one of the opposing surfaces. The holes are arranged in groups on the testing plate, where each of the groups comprises at least two rows and two columns of holes.
The method and apparatus for holding samples for analysis in accordance with the present invention provides a number of advantages. For example, the present invention simplifies testing procedures. The samples of solution to be analyzed can be loaded into the testing plate by simply dipping or flooding one of the surfaces of the testing plate into the solution. As a result, the present invention does not require the use of a separate delivery systems for loading solution into the wells on the testing plate.
The present invention also simplifies the construction of the testing apparatus. The testing apparatus merely needs one of the opposing surfaces of the testing apparatus to be spaced away by additional spacers or machined to create a recessed portion and then a plurality of holes need to be drilled through the plate in the recessed portion. Unlike prior testing apparatuses, the present invention does not require any special construction techniques to male the bottom of the wells transparent because the holes extend all of the way through the plate.
The present invention also permits an operator to more easily identify a particular hole filled with a sample for further analysis. Instead of spacing the holes equidistantly over the testing plate, the present invention arranges the holes in groups of at least two columns and two rows of holes and arranges the groups in sets of at least two or more. The groups are spaces further apart then the holes within each group and sets of groups are spaced further apart then the groups are spaced apart. As a result, an operator can more easily identify a particular hole based upon which set, group, row, and column the hole is located in on the testing plate.
A testing apparatus 10 in accordance with one embodiment of the present invention is illustrated in
The testing plate 12 includes the pair of opposing surfaces 14 and 16. In this particular embodiment, the opposing surfaces 14 and 16 are substantially planar, except where the recessed portions 20 and 22 are located, although the surfaces 14 and 16 could have other relationships with respect to each other. Each of the opposing surfaces 14 and 16 includes one of the recessed portions 20 and 22 which are machined into the testing plate 12, although other techniques for forming the recessed portions 20 and 22, such as by molding or adding spaces, can be used. When either of the opposing surfaces 14 and 16 of the testing plate 12 rests on a supporting surface 28, the recessed portion 14 or 16 along with the plurality of holes 18 located in the recessed portion 14 or 16 are spaced away from the supporting surface 28. If openings 30 and 32 to the holes 18 contacted the supporting surface 28, then any solutions in the holes 18 would drain out of the holes 18. In this particular embodiment, a ridge 34 if formed in each of the opposing surfaces 14 and 16 by the recessed portions 20 and 22 which extends around the outer circumference of the testing plate 12. Although the holes 18 are spaced from the support surface 28 by a recessed portion 20 or 22 formed in the testing plate 12, the holes 18 can be spaced from the supporting surface 28 with other types of supporting structures, such as a bracket attached to the testing plate which supports the testing plate 12 and holes 18 above the supporting surface 28.
A plurality of through holes 18 are located in the testing plate 12. The holes 18 extend from openings 30 in the recessed portion 20 of one of the opposing surfaces 14 to openings 32 in the recessed portion 22 of the other opposing surface 16. In this particular embodiment, the holes 18 have a substantially cylindrical shape, although the holes 18 could have other shapes, such as a hexagonal cross-sectional shape or a cone shape. In this particular embodiment, each of the holes 18 has a diameter of about one millimeter and can hold about hold about 5.5 microliters of solutions S and cells C, although the diameter, volume and number of cells C each hole 18 can hold can vary as needed or desired. The solution S along with cells C in the solution S are held in the holes 18 by surface tension as shown in
One of the advantages of the present invention is that the testing plate 12 is easy to manufacture. A plate having opposing surfaces can have an appropriate number of holes drilled there through. The plate can include one or more recessed portions 20, 22, and the through holes can pass through the recessed portion of the plate 12. Since the holes 18 extend all of the way through, there is no need for a transparent bottom in each hole 18. Light transmitted into the holes 18 will pass through during testing. With prior wells, the testing apparatus also needed to be non-transparent, but since the wells did not extend through the apparatus, the bottom of the wells needed to be made of a transparent material to permit light to pass through the sample for optical analysis. Constructing these prior testing apparatuses was difficult and expensive.
By arranging the holes 18 in sets 26 and groups 24, it is much easier for an operator to identify a particular hole 18 in the testing plate 12 and retrieve a particular sample. The sets 26 of holes 18 help the operator identify the general area of the hole 18 and then the groups 24 help the operator to begin to narrow down the location of the hole 18. The column and row of the hole 18 in each group 24 provides the precise location of the hole 18. The spacing between sets 26, groups 24, and rows and columns are different to make it visually easier for an operator to identify a particular hole 18. When the holes 18 are all spaced equidistantly apart, then it is more difficult to identify a particular hole 18 and it is easier for an operator to lose his/her place and select a sample from the wrong hole 18.
Although the holes 18 are arranged in groups 24 and sets 26 in testing apparatuses 10 and 50 to aid human operators, other arrangements for the holes 18 may also be used. For example, when the testing apparatuses are used by robotics, instead of human operators, the holes 18 can also be spaced equidistantly apart as shown in the embodiment of the testing apparatus 60 illustrated in
Instead of a recessed portion in the plate 12, an assembly comprising the plate and evaporation plates can be provided with spacers between the testing plate and the evaporation plates to space the openings of the through holes away from the evaporation plates. The evaporation plates could be provided with recesses portions in addition to, or instead of, spacers between the testing plate and the evaporation plates. Any combination of recessed portions in the testing plate, recessed portions in the evaporation plates, or spacers can be used to provide the spacing between the openings of the through holes and the evaporation plates.
According to an embodiment of the present invention, stackable testing plates are provided which may or may not have evaporation plates in-between testing plates. The stackable testing plates may be provided with recessed portions or evaporation plates with recessed portions can be provided between a stacked testing plate. Any combination of recessed portions in the testing plates, recessed portions in the evaporation plates, or spacers can be used to provide a stack of testing plates wherein each testing plate is spaced from the surface of an adjacent testing plate, evaporation plate, or both.
One example of one application of the present invention will be discussed with reference to testing apparatus 10 shown in
Although one example of preparing the solution S and cells C is disclosed, other methods and techniques for preparing samples to be used with the testing apparatus 10 can be used as is readily understood by one of ordinary skill in the art.
Next, a testing plate 12 with a pair of opposing surfaces 14 and 16 and a plurality of holes 18 which extend from one of the opposing surfaces 14 to the other one of the opposing surfaces 16 is provided. At least one of the opposing surfaces 14 of the testing plate is immersed in the prepared solution S. The solution S enters openings 30 and 32 for each of the holes 18 in testing plate 12 and any gases in the holes 18 may escape through openings 30 and 32 at the opposite end of the holes 18. Alternatively, the testing plate 12 may be flooded with solution S so that the solution S enters through the top opening 30 to each hole 18.
One of the advantages of the present invention is the ease with which solution S can be loaded into each of the holes 18. As illustrated in the description above, all of the holes 18 in the testing plate 12 can be loaded with samples of solution S in a relatively short period of time and without any type of specialized solution delivery system. Prior testing apparatuses with wells required specialized solution delivery system, such as large pipette devices, to be able to load solution into each of the wells. These specialized solution delivery systems are difficult to use and are expensive.
Once the solution S has been drawn into the holes 18, the testing plate 12 is removed from the solution S. Surface tension holds the solution S in each of the holes 18. In this particular embodiment, each hole 18 has a diameter of about one millimeter and holds about 5.5 microliters of solution S and cells C as shown in
Once the testing plate 12 is removed from the solution S, the testing plate 12 can be placed on a supporting surface 28. Since the holes 18 are located in a recessed portion 22 of the testing plate 12, the openings 22 to the holes 18 are spaced from the supporting surface 28 so that any solution S being held by surface tension remains in the holes 18. A pair of evaporation plates 40 and 42 may be attached to the opposing surfaces 14 and 16 of the testing plate 12 to prevent the samples of solution S in the testing plate 12 from evaporating or becoming contaminated.
In this particular example, the testing plate 12 is then optionally incubated at a controlled temperature of about 37.degree. C. and a humidity of about 70%, although the temperature and humidity will vary based upon the particular application. During the incubation, the cells multiply and produce a protein of interest (the cells could produce an enzyme, an antibody, or a metabolite which could be of interest). The ability of the protein, such as an enzyme, to hydrolyze a substrate is analyzed, such as by measurement of fluorogenic or chromogenic groups liberated by the hydrolysis.
Although one example of processing the samples of solution S in the testing plate 12 is disclosed, other methods and techniques for processing and analysis the samples can also be used and are know to those of ordinary skill in the art.
Next, in this particular example the samples of solution S with cells C in the holes 18 (as shown in
Although one example of analyzing the samples of solution S in the testing plate 12 using optics is disclosed, other methods and techniques for analyzing the samples, such as non-optical methods, can also be used. For example, a plate containing samples of solution S with cells C could be blotted onto a membrane and used for performing Western blot analysis or alternatively, the samples S with cells C could be blotted onto substrate containing material whereby modification of the substrate is measured visually. As a result, when non-optical means are used to analyze the samples of solution in the testing plate 12, the testing plate 12 can be made of a transparent material.
Next, in this particular example the operator retrieves the samples of solution S which contain the highest concentration of converted substrate. The holes 18 with the solution S with the highest concentration of converted substrate can be identified and located based upon which set 26 of groups 24, which group 24, and which row and column within each group 24 each identified hole 18 is located. One of the advantages of the present invention is the arrangement of the holes in groups 24 and sets 26 which enables an operator to easily identify a particular hole 18 on the testing plate 12. Once the desired samples are retrieved, the operator can conduct further analysis on those samples in manners well known to those of ordinary skill in the art.
Although one example of retrieving one or more of the samples of solution S in the testing plate 12 is disclosed, other methods and techniques for retrieving samples can also be used. For example, if robotics are used to located and retrieve a particular sample, a different testing apparatus, such as testing apparatus 60 shown in
According to some embodiments of the present invention, the testing plate is in the form of an assembly or substrate. For example, the plate can comprise a plurality of individual components which together make up an assembly having opposing surfaces and a plurality of through holes extending from one surface to the other. An example of the present invention wherein the testing plate comprises such an assembly is a plate made of a bundle of capillary tubes as shown in
As shown in
As can be seen in
The capillary tubes may be hollow cylindrical in shape or may have other rounded, oval, or polygonal cross-sections. The average diameter of each capillary tube preferably ranges from about 0.001 millimeter to about 1 millimeter, and the length of each tube preferably ranges from about 1 mm to about 1 cm. The dimensions of the capillary tubes are preferably such that each tube has the capacity to hold from about 0.0001 microliter to about 10 microliters of liquid sample, for example, about 5.5 microliters, although the diameters, lengths, and holding capacities of the capillary tubes may vary as needed or desired. According to some embodiments of the present invention, it is not necessary to have a band for holding the capillary tubes together in a bundle as the tubes may instead be fused or otherwise bonded, adhered, or maintained together in a bundle.
The number of capillary tubes of the embodiment in
In embodiments such as the one shown in
The assembly shown in
Contact between a liquid sample and an opposing surface can be made by flooding, immersing, pipetting, dropping, pouring, or otherwise loading or at least partially filling a plurality of the capillary tubes or through holes such that capillary action pulls portions of the liquid sample into the respective capillary tubes or through holes. Upon removal or discontinued contact of the liquid sample with the assembly or plate, the opposing surfaces of the assembly or plate are preferably made free of liquid sample such that the portions of the sample that remain held within the respective capillary tubes are isolated from one another.
Automated filling devices can be used and are preferred if it is important that the respective liquid samples or liquid sample portions are to only contact the inner walls of the through holes and avoid contacting the opposing surfaces of the assembly.
According to embodiments of the present invention, a high throughput screening method is provided. The method can screen for at least one liquid sample that includes a target component or substance to be analyzed. Herein, the target component or substance to be analyzed may be referred to as an “analyte”. The analyte may be, but is not necessarily, a biological sample. The analyte exhibits a detectable property or produces a detectable characteristic in the presence of or upon reaction with a marker compound or the like. For example, the analyte may itself exhibit a fluorescent property. After the liquid sample is at least partially filled into a plurality of the through holes, the portions of the liquid sample that contain the analyte can be detected by determining which of the through holes contains a sample portion that exhibits the fluorescent property.
In another example, the analyte itself does not exhibit a detectable property but may instead cause a marker component to exhibit a detectable property upon reaction with the marker component. According to such an embodiment, the through holes of the testing assembly can be pre-loaded or post-loaded with one or more marker components such that after loading the liquid sample into the plurality of through holes, the sample portions containing an analyte can react with the marker compound and thus enable the marker compound to exhibit a detectable property. In such a case, it is not the analyte itself that exhibits the detectable property, but rather the analyte is detected indirectly as the presence of the analyte causes the detectable property of the marker component which in turn is directly detected. In so doing, the methods of the present invention provide a way to partition and isolate analytes from an original liquid sample.
According to the high throughput screening method, portions of the liquid sample are loaded into a testing assembly having a pair of opposing surfaces and a plurality of through holes, with each of the through holes extending from one of the opposing surfaces to the other of the opposing surfaces. Loading preferably results in at least partially filling a plurality of the through holes with at least portions of the liquid sample, and surface tension holds the respective portions in the respective plurality of through holes. Multiple liquid samples can instead be loaded into respective through holes or into respective pluralities of through holes. The method then involves detecting which of the plurality of sample portions in the through holes exhibit the detectable property.
According to embodiments of the present invention, the high throughput screening assembly preferably comprises at least about 100 through holes, more preferably at least about 500 through holes, and according to some embodiments of the present invention, up to about 1,000,000 through holes. High throughput screening methods can be used in conjunction with these devices to test over 100,000,000 samples or sample portions per assembly per day. The analyte to be screened may be, for example, a biological cell, a mixture of biological cells, a mutant cell, a secretable protein, an enzyme, a microorganism, a mixture of microorganisms, a contaminant, or combinations thereof. The analyte can be a population of random mutants of one or more organisms. If the analyte is a mixture of biological cells it could be a random sample isolated from a natural environment. The detectable property may be, for example, a fluorescence or adsorption property. Prior to filling the high throughput assembly, the liquid sample may be diluted with a suitable diluent to obtain a concentration of the analyte in the liquid sample such that when the sample is filled into the plurality of through holes, at least one of the analytes is introduced into from about one-quarter to about one-half of the plurality of through holes.
In some cases, it is possible to identify an organism with desirable properties even if the organism is introduced into a plurality of through holes as a mixture with other organisms. Under such conditions, the mixture of other organisms, e.g., mixture of biological cells, may be diluted prior to filling such that several organisms or cells will be introduced into each through hole. Using such a dilution technique, it is possible to detect the presence of an analyte. For example, it is possible to detect one particular mutant from a collection of many biological cells and mutants thereof despite having many cells from the mixture present in each through hole. Thus, for example, if a sample contains 1,000,000 cells and only one of them is a target mutant cell, referred to as the “analyte”, and a testing plate having 10,000 through holes is employed, the sample can be diluted such that the 1,000,000 cells fill the through holes with sample portions wherein each portion contains about 100 cells. In cases where the detectable characteristic of the analyte is detectable despite the presence of many other cells within the same through hole, it is possible to isolate the analyte from 99.99% of the sample in a single assay.
The testing plates used in accordance with the present invention, including the plates of
According to some embodiments of the present invention, to facilitate the capillary reaction, it may be desirable to provide a hydrophilic material immediately adjacent the opening to each through hole on an opposing surface while maintaining or providing the remaining area of the opposing surface hydrophobic or non-hydrophilic. Either or both opposing surfaces of the testing plate can be made of or treated with hydrophobic, hydrophilic, or both materials as discussed above although if the through holes are to be loaded by an immersion technique, it is preferred that the opposing surface which will come in contact with the liquid sample is treated with or formed of a hydrophobic material except in areas immediately adjacent and preferably surrounding the through hole openings in the opposing surface.
Exemplary high throughput screening methods that can be used with the assemblies and other plates of the present invention include absorbance transcription assays, fluorescent transcription assays, fluorescent secreted enzyme assays, and microorganism screening assays. These and other suitable assays that can benefit from the plates and methods of the present invention are described, for example, in: Arndt et al., A rapid genetic screening system for identifying gene-specific suppression constructs for use in human cells, Nucleic Acids Res., 28(6): E15 (2000); Rolls et al., A visual screen of a GFP-fusion library identifies a new type of nuclear envelope membrane protein, J. Cell Biol, 146(1): 29-44 (1999); Sieweke, Detection of transcription factor partners with a yeast one hybrid screen, Methods Mol. Biol., 130: 59-77 (2000); and WO 97/37036, all of which are herein incorporated in their entireties by reference.
Having thus described the basic concept of the invention, it will be rather apparent to those skilled in the art that the foregoing detailed disclosure is intended to be presented by way of example only, and is not limiting. Various alternations, improvements, and modifications will occur and are intended to those skilled in the art, though not expressly stated herein. These alterations, improvements, and modifications are intended to be suggested hereby, and are within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims and equivalents thereto.
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|Internationale Klassifikation||B01L3/00, C40B60/14, G01N33/53, B01J19/00, G01N35/00, G01N35/10|
|Unternehmensklassifikation||B01L3/5085, B01J2219/00662, B01J2219/00524, B01L3/50857, B01J2219/00707, B01L3/5025, B01J2219/0052, B01J2219/00317, B01J2219/00659, B01J2219/00286, G01N2035/00237, G01N35/1065, B01J19/0046, B01J2219/00319, C40B60/14|
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