CN204251600U - Modular Apparatus for Flow-through Hybridization - Google Patents

Abstract

The utility model provides a modular device for hybridization of biological molecules such as nucleic acids and proteins, and a method for manufacturing the same. In one embodiment, the modular device provided by the utility model includes a housing, a base, a membrane, and one or more hybridization regions. In another embodiment, the modular device of the utility model further includes one or more connection ports, a snap-fit body, a label, and/or a module frame. In one embodiment, the modular device of the utility model can be used in combination with other devices or equipment such as a flow-through hybridization device.

Description

Modular Apparatus for Flow-through Hybridization

technical field

The present invention relates to a device and method for conducting nucleic acid and protein hybridization experiments.

Background technique

Hybridization is the most commonly used method in molecular research involving nucleic acids and proteins in biological sciences today. Molecular probes such as oligonucleotides, peptides, antibodies or other molecules are immobilized on a solid surface to capture or react with target molecules in the sample fluid. By designing probes with complementary sequences to target molecules and using appropriate detection systems, hybridization technology can provide a convenient and reliable method for the identification and analysis of molecules such as nucleic acids and proteins. The technique is robust, simple and applicable in many fields. For example, it greatly simplifies the discovery process of new genes or mutated genes associated with certain metabolic pathways, and can also assist in the genetic analysis of specific disease states. Clinically, hybridization technology has been widely used in disease diagnosis.

Traditional hybridization techniques, such as traditional Southern blot, Northern blot, dot blot, slot blot and reverse dot blot, usually require the use of a large number of reagents, probes and samples, and require long incubation and tedious operations program. Furthermore, the effectiveness of traditional hybridization techniques is limited by the surface area of the hybridization support used to immobilize molecular probes. This limitation is especially pronounced when using membranes as hybridization supports. Since membranes are usually porous (usually between 0.1–0.45 μm in diameter), only a small fraction of probes can be immobilized on the membrane surface, and these exposed probes can capture or react with target molecules. Instead, most probes are immobilized and hidden inside the membrane, so only a few can capture target molecules.

A number of methods and devices are available today to improve upon traditional hybridization techniques. Among them, U.S. Patent No. 5,741,647 (Tam) and U.S. Patent No. 6,020,187 (Tam) describe a new technology for rapid nucleic acid hybridization, namely "flow-through hybridization". Devices and methods using this technology have been developed and protected by patents. To put it simply, the diversion hybridization technology uses a direct diversion mechanism to allow the solution to pass through the hybridization carrier (that is, the position of hybridization) from top to bottom, so as to use the hybridization carrier as much as possible. This technology can greatly improve the speed and sensitivity of the hybridization process. speed and efficiency.

Flow-through hybridization significantly reduces hybridization time from hours to minutes compared to traditional hybridization techniques (the entire hybridization assay can be completed within 5-30 minutes depending on the method used to generate the detection signal), and requires only a small amount of Reagents, probes and samples. With proper design, flow-through hybridization devices allow more precise and simple adjustment of hybridization conditions, and are less expensive to manufacture. Therefore, the flow-through hybridization device makes molecular analysis and diagnosis more affordable, efficient and accurate.

Flow-through hybridization devices described in US Pat. No. 5,741,647 (Tam) and US Pat. No. 6,020,187 (Tam) include a hybridization chamber with an internal opening for holding a membrane to which molecular probes have been immobilized. Under the suction of a suitable device or system (such as a vacuum pump), the liquid flows from the upper end of the hybridization chamber, passes through the membrane, enters the internal opening of the hybridization chamber, and finally exits the lower end of the hybridization chamber. The whole hybridization process includes pre-blocking and equilibration of the membrane, immobilization of probes on the membrane, incubation between the membrane and the sample, washing of the membrane to remove unbound molecules or substances, and detection of signals. The entire hybridization process can be completed within one minute at the fastest.

To make the analysis more cost-effective and affordable, the hybridization area (eg, the membrane) can be divided into multiple hybridization chambers, allowing one or more samples to be tested simultaneously during a single hybridization. Using this method, it is possible to simultaneously detect and analyze a certain condition of different samples, different conditions of the same sample, or different conditions of multiple samples. For example, the hybridization area may be divided into "4x1" for simultaneous processing of four samples, or "4x3" for simultaneous processing of twelve samples.

Existing designs typically add a prefabricated shell with spacing to the surface of the membrane to subdivide the hybridization area. To assemble the membrane and housing, usually by hot melt technology, the plastic (ie membrane and housing) is subjected to high temperature and pressure, and the plastic molecules of the membrane and housing are connected to each other. When the plastic cools down, the plastic becomes rigid, completely connecting the membrane and the housing. Depending on the frame design of the housing, membranes with consistent properties (eg, membranes immobilized with molecular probes of the same type) can be divided into smaller hybridization chambers for testing individual samples. Because the shell and membrane are not elastic, a semi-rigid material such as ethylene/vinyl acetate copolymer (EVA) foam is usually placed between the shell and the membrane to seal the gap between the shell and the membrane.

However, these existing designs have at least the following problems: i) Since only one type of membrane (i.e., a membrane immobilized with the same type of molecular probes) can be assembled at a time, only one type of membrane can be performed in each hybridization process. testing, thus limiting the flexibility of testing; ii) EVA foam is not elastic enough to completely seal the gap, and thus cannot tightly and completely connect the membrane and the shell. Liquid may leak (i.e., cross-contaminate) between different hybridization chambers, thereby greatly reducing the accuracy of the assay; iii) Due to the high aspect ratio of the device, the two ends of the assembled membrane and shell may be dissociated after thermal melting become twisted or bent, thereby impairing the efficiency of vacuum suction and even affecting hybridization performance. Leakage between hybridization chambers may also occur. In order to reduce the chance of leakage and increase the efficiency of vacuum suction, an additional load (which can be part of the hybridization device) is sometimes applied to the top of the housing, which will press the housing down to reduce the gap between the housing and the membrane .

Contents of the invention

In order to solve the above-mentioned problems in the existing designs, the present invention provides a hybridization device comprising independent modular hybridization elements. This hybridization device allows for more flexible design of hybridization experiments, as well as increased accuracy and efficiency of hybridization assays.

The present invention provides modular devices for hybridization of biomolecules such as nucleic acids and proteins, and methods for their manufacture.

In one embodiment, the present invention provides a modular device for flow-through hybridization and a method of manufacturing the same.

In one embodiment, the present invention provides a modular device comprising a housing, a base, and a membrane. In another embodiment, a modular device of the invention comprises one or more hybridization regions.

In one embodiment, the modular device of the present invention also has snap fits and/or markings on its housing.

In one embodiment, the modular device of the present invention also has one or more snap fits and/or markings on its housing.

In one embodiment, the modular devices of the present invention can be arranged in different arrays for hybridization.

In one embodiment, the modular apparatus of the present invention further includes a modular frame.

In one embodiment, the modular device of the present invention can be used in combination with other hybridization devices or devices, such as conventional hybridization devices and flow-through hybridization devices. In another embodiment, a modular rack can be used to support individual modular devices on a hybridization device.

In order to solve the above-mentioned problems in the existing designs, the present invention provides an improved device that operates in a modular form and is equipped with different features, which can perform hybridization (eg, flow-through hybridization) more flexibly, accurately and efficiently.

1-11 are schematic representations of various embodiments of the apparatus of the present invention. It is to be noted that the different features of the device, such as the housing and the base, can take an appropriate form or shape depending on the needs of the hybridization assay and the device used with it.

Figures 1A-1C illustrate a modular device comprising a housing (10), a base (20) and a hybridization zone (30). As shown in Figure 1A, the housing (10) is a device having a hollow opening. The membrane (31) is sandwiched between the bottom of the housing (10) and the base (20). The membrane (31) and the inner wall of the housing (10) constitute the hybridization zone (30). Reagents and samples are introduced into the hybridization zone (30) through the upper opening of the housing (10). Molecular probes for hybridization are arrayed on the membrane (31), and the hybridization process takes place on the membrane (31). In one embodiment, the membrane is affixed to the bottom of the housing (10) by suitable techniques, such as heat melting, ultrasonic welding or using adhesive glue.

Fig. 1 B shows the bottom of a modular device, the base (20) is a flat and resilient member, the base (20) surrounds the border at the bottom of the housing (10) and the bottom of the membrane (31, not shown in Fig. 1B). The boundary, thereby strengthening the connection between the shell (10) and the membrane (31), achieves a sealing effect. In one embodiment shown in Figure 1C, the bottom of the housing (10) has a housing recess (11) into which the base (20) can fit and surround both the housing (10) and the membrane (31).

The shell (10) can be made of plastics such as polycarbonate (PC) and polypropylene (PP) or other materials. The base (20) can be made of plastic, silicon rubber or other elastic materials.

In one embodiment, after the housing (10) and membrane (31) are assembled, a material such as silicone rubber is placed on the side of the membrane (31) facing away from the hybridization area (30). Silicone rubber surrounds both the casing (10) and the membrane (31), thereby forming the base (20) and sealing the gap between the casing (10) and the membrane (31).

In one embodiment, the housing (10), membrane (31) and base (20) are assembled by compression molding. In another embodiment, adhesive glue can be coated on the bottom of the housing (10), or the housing groove (11) at the bottom of the housing (10), to stick the base (20) to the membrane (31) and the housing (10) , further ensuring that the gap between the housing (10) and the membrane (31) is sealed. the

The present invention modularizes the hybridization device and adds a base on the hybridization device. Compared with the design using EVA foam plastic before, it has the following advantages: i) the hybridization area of the hybridization device is divided into multiple sub-districts, and in the same hybridization device Incorporating different types of membranes to allow for more flexible hybridization design; ii) previously designed devices are larger in size, in contrast, the aspect ratio of the modular device of the present invention is small, which will cause the membrane or shell that thermal melting may cause The possibility of twisting is minimized; iii) Silicone rubber is more elastic than EVA foam, which can enhance the sealing effect between the shell and the membrane; iv) Hybridization is usually performed under a certain pressure environment, especially when using vacuum suction At times, a high-stress environment develops. Silicone rubber, and optionally adhesive, reinforce the connection between the membrane and the housing, allowing the membrane to withstand high pressures. In addition to enhancing the sealing effect between the housing and the membrane, the present invention can also enhance the sealing effect between the modular device and the hybridization device used with it. Due to the enhanced sealing effect, the efficiency of the vacuum suction is also improved, and the seepage between the various hybridization areas is also reduced. It also saves the trouble of putting extra load on the case.

With proper design of the housing (10), the hybridization region can be compartmentalized into multiple hybridization regions. The modular device shown in Figures 2A-B comprises a housing (10), a base (20), three hybridization regions (30) and snap-fit bodies (40, 40'). Depending on the design of individual hybridization experiments, the modular apparatus can be designed in different formats, such as 1x1, 2x1, 3x1, 2x2 or 2x3 formats. In one embodiment, the modular device has one, two, three, four or more hybridization zones (30).

The membranes (31) embedded in the modular device can have different characteristics or be of different types, such as thickness, pore size, type and number of molecular probes immobilized, or other characteristics. In one embodiment, the same type of membrane is embedded into the modular device, thereby constructing multiple hybridization regions for the same type of analysis. In another embodiment, a specific type of membrane is placed in each hybridization zone of the modular device, thereby constructing multiple hybridization zones for multiple different types of assays. In one embodiment, two or more hybridization zones are placed with the same type of membrane. In another embodiment, the modular device is a virtual modular device in which the membrane is not immobilized with any molecular probes.

Any membrane capable of immobilizing nucleic acids or proteins may be used, depending on the needs of the individual hybridization assay. These membranes include, but are not limited to, Digestive Fiber, Nylon and Nytran ^™ . Molecular probes can be immobilized on the membrane either before or after assembly of the modular device.

Multiple samples of the same type of analysis can be performed simultaneously using a modular device configured with the same type of membrane. On the other hand, modular devices configured with different types of membranes and/or probes allow multiple hybridization assays to be performed simultaneously. This design facilitates simultaneous analysis of multiple phenotypes, genotypes or multiple samples. The modular device of the present invention can be used with any biological sample. A biological sample can be any material from the same individual or from different individuals, such as blood, serum, plasma, saliva, semen, lymph or other bodily fluids.

The modular device of the present invention can be added with additional components or features according to different experimental purposes.

The modular device of the present invention also includes a snap-fit system for stacking individual modular devices. As shown in Figures 1 and 2, the snap-fit body (40 or 40') is embedded along the longitudinal wall of the housing (10).

Using an appropriate and complementary pair or pairs of fasteners (40, 40'), it is possible to ensure that each modular device is aligned in a specific orientation, thereby regulating the orientation of the membrane on the hybridization device. This ensures that hybridization patterns are viewed in the correct orientation and that hybridization results are interpreted correctly.

Figures 3A-C show a plurality of modular devices provided with complementary snap fits (40, 40') located on the outer longitudinal wall of the housing (10). Figures 4A-C show a modular device with three hybridization zones (30) and complementary snap fits (40, 40') on the outer longitudinal wall of the housing (10). In another embodiment, the fastening body (40) is located on the outer lateral wall of the casing (10). In another embodiment, the fastening body (40) is located on both the longitudinal wall and the transverse wall of the casing (10).

The snap-fit bodies (40, 40') may be of any type and shape capable of stacking or snap-fitting modular devices. In one embodiment, the snap-fit bodies (40, 40') of the modular device are "push-pull" (Fig. 3A, 4A), "slide-in" (Fig. 3B, 4B) or "snap-on" fastening systems . In another embodiment, the fastening bodies (40, 40') are circular, elliptical, rectangular, hexagonal or star-shaped.

In one embodiment, one or more snap fits (40, 40') are embedded along the outer longitudinal wall of the housing (10) (Figs. 3A and 4A). In another embodiment, one or more snap fits (40, 40') are embedded in the distal or proximal end of the outer longitudinal wall of the housing (10) (Figs. 3B and 4B).

In one embodiment shown in Fig. 3A and 3B, the snap-fit body (40) of the same type or shape is embedded in the same side longitudinal wall of the casing (10), and the snap-fit body (40') with complementary type or shape is embedded in the casing ( 10) the other side vertical wall. In another embodiment, as shown in FIG. 3C , different types or shapes of fastening bodies ( 40 ) are embedded in the longitudinal wall of the same side of the housing ( 10 ).

As shown in FIGS. 5A and 5D , the inner wall of the housing ( 10 ) of the modular device of the present invention is further equipped with a plurality of marks ( 50 ). Figure 5E is a top view of the modular device with reference (50). With the help of the marker (50), the present invention ensures that the user can quickly and easily find and identify the position of the hybridization signal (such as a spot), thereby helping to interpret the hybridization result.

Any type of indicia (50), such as graphics, lines, numbers and letters, etc. can be used in the modular device of the present invention. Indicia (50) may be raised, debossed or colored. The marker (50) may be in the shape as shown in Figures 5A-5D or in any other shape. The positions of the markers (50) and the distance between each marker (50) can be adjusted according to the design of the modular device and/or the hybridization device, or the actual needs of the hybridization analysis. In one embodiment, the markings (50) are located on the same side of the inner wall of the housing (10). In another embodiment, the markings (50) are located on two or more sides of the inner wall of the housing (10), wherein the markings (50) can be of the same type, or of different types.

In one embodiment, the indicia (50) is a logo with a gradient of colors. During the hybridization process, the color of the signal on the membrane can be compared with the gradient color of the marker (50) to monitor the development of the signal and adjust the hybridization program according to the desired signal profile. For example, if the signal has reached a satisfactory intensity or color, the hybridization analysis can be stopped, saving time and reagents. Conversely, if the signal is too weak for analysis, the signal development steps can be prolonged or more reagents used to generate the signal can be added to the device.

In the embodiment shown in Figure 5D, the marker (50) used in the present invention also includes a set of calibrator (51) showing intensity or chromaticity, and the calibrator shows a specific sample (such as a positive sample or a certain amount of nucleic acid containing sample) intensity or chroma. In one embodiment, the calibrator (51) is located on the upper edge of the housing (10). By comparing the chromaticity or intensity of the signals on the membrane (31) and the calibrator (51), the hybridization signal can be quickly quantified or the hybridization result can be interpreted, which is helpful for subsequent analysis of the test results.

Figure 6A shows a modular device configured with snap fits (40, 40') and markers (50). Figure 6B shows four modular devices arranged in a line, wherein the modular device includes a housing (10), a base (20), snap-fitting bodies (40, 40') and markers (50). Fig. 6C is an exploded view of the modular device, wherein the modular device includes a housing (10), a base (20), a fastening body (40, 40') and a mark (50).

Depending on the hybridization device to be used in combination, the housing (10) may also include two connection ports (12) along the longitudinal axis for assembling the modular device to the hybridization device. The modular device shown in Figure 7A comprises a housing (10) with two connection ports (12), a base (20), a membrane (31) and a marker (50). Fig. 7B is another modular device, wherein the housing (10) is equipped with two connection ports (12) and is divided into three hybridization areas.

Figure 8 shows a device consisting of 16 modular devices arranged in a 4x4 format that can process 16 samples or perform 16 analyzes simultaneously.

Depending on the hybridization devices to be combined, or the requirements of individual hybridization assays, the modular devices can be arranged in any suitable array format. For example, modular units can be arranged in 4x1, 2x2, 3x2, 4x2, 4x4 or any other format.

Furthermore, each modular device can be configured with a different number of hybridization zones (30) with the same or different types of membranes (31). As shown in Figure 8, each modular device contains a hybridization zone (30), and these modular devices can be equipped with the same type or different types of membranes (31). As another example shown in Figure 9, the modular device contains one or three hybridization regions and is assembled in a 4x4 array. Depending on the hybridization device to be combined, the modular device can also be equipped with a connection port (12).

In one embodiment, a single modular device consists of a single housing (10), membrane (31) and base (20), as discussed above with respect to Figure 1 . In another embodiment, as shown in Figures 8 and 9, a prefabricated floor (21) may be used to support and align two or more modular units. In one embodiment shown in Figure 8, multiple modular units are pre-arranged in a 4x4 array and subsequently assembled with a prefabricated base plate (21). As another embodiment shown in Figure 9, individual modular units can be embedded one after the other into a prefabricated floor (21).

In another embodiment, a modular rack (60) may be used on the hybridization device to ensure that one or more modular devices are arranged in the correct order and orientation, depending on the design of the hybridization device and the modular device to be combined. As shown in FIG. 10A , adapters ( 61 ) are provided at both ends of the modular rack ( 60 ) for fastening the modular rack ( 60 ) and positioning the modular rack ( 60 ) on the hybridization device. There is also one or more grooves (62) at the bottom of the module frame (60), into which the connecting port (11) of the modular device can be placed.

The modular rack (60) can be prefabricated in different formats and can be combined with multiple modular devices having different numbers of hybridization zones. In one embodiment shown in Figure 10A, a modular rack (60) is combined with a plurality of modular devices having a hybridization zone. In another embodiment shown in Figure 10A, a modular rack (60) is combined with a plurality of modular devices having three hybridization regions. The modular racks (60) and the modular devices do not have to be in the same array format. For example, a modular device having a 3x1 format can be placed into a modular rack (60) having a 4x1 array format. As shown in Figure 11, a modular rack (60) in the form of a 4x1 array can be combined with a modular device in the form of a 1x1 or 3x1.

In another embodiment, the module rack is a pair of positioners (63) for supporting a modular device without a connection port (12). As shown in Figure 12, the four modular devices are sandwiched between a pair of positioners (63), thereby securing the modular devices on the hybridization device.

Figures 13A and 13B are top and perspective views, respectively, of the positioner (63) in Figure 12 . In one embodiment, the locator (63) also includes one or more vertical slots (64), which are recessed markings, to assist in aligning the modular unit.

The modular device of the present invention can be used in conjunction with the methods, apparatus and apparatus described in US Patent No. 5,741,647, US Patent No. 6,020,187, and PCT Application WO/2011/139750, or with any method capable of hybridization or flow-through hybridization ﹑In combination with devices and equipment. In one embodiment, the flow-through hybridization device is the FT-PRO flow-through hybridization system (DiagCor Bioscience Incorporation Limited).

With proper hybridization device design, conditions or conditions such as vacuum aspiration, heat, time, or other constraints in hybridization assays can be independently controlled within individual modular devices. This allows flexible control of hybridization analysis according to the actual needs of individual samples or assays, or based on real-time observation of signals.

On the other hand, operating the modular devices independently allows reagents to be added to each modular device simultaneously, rather than individually into the hybridization device as in most previous designs. Therefore, the time of each hybridization step (such as sample loading, washing, color development, etc.) can be kept consistent in each modular device, thereby increasing the accuracy of the analysis.

The invention provides a modular device for hybridization comprising the following parts:

i) a housing with one or more hollow openings, each opening corresponding to a hybridization area, the hybridization area is used to contain substances or liquids for hybridization; and

ii) A membrane attached to the bottom of the housing, said membrane being located between the housing and a base attached to the bottom of the housing.

In one embodiment, the housing described in the present invention also has a groove at the bottom to accommodate the base.

In one embodiment, the housing described herein further includes one or both of the following features:

i) at least one outer wall of the enclosure is fitted with one or more snap fits; and

ii) at least one side of the inner wall of the housing is provided with one or more markings.

In one embodiment, the snap fits of the outer wall of the housing are of the same type or of different types.

In one embodiment, the marks described in the present invention can be graphics, lines, numbers or letters. In another embodiment, the indicia described herein are raised, recessed or colored. In one embodiment, the mark described in the present invention further includes a logo showing a gradient color or a specific color.

The invention provides a set of devices comprising a modular device of the invention, wherein two or more modular devices are arranged in an array for hybridization, wherein the modular devices have the same number or different numbers of hybridization regions, each of which The membrane in the hybridization zone is immobilized with probes of the same type or different types for hybridization.

In one embodiment, the set of devices described above further comprises one or more positioners for positioning the modular devices.

In one embodiment, the housing of the modular device described herein further comprises one or both of the following features:

i) positioning the modular device to a port on the hybridization device; and

ii) at least one side of the inner wall of the housing is provided with one or more markings.

In one embodiment, the markings of the above-mentioned modular devices are figures, lines, numbers or letters. In another embodiment, the markings are raised, recessed or colored. In one embodiment, the mark also includes a logo that can display a gradient color or a specific color.

The invention also provides a device set comprising a base plate and a modular device as described herein, wherein two or more modular devices are arranged in an array and placed on a base plate having a plurality of hollow openings.

In one embodiment, the above-mentioned modular device has the same or different number of hybridization regions, the membranes in each hybridization region are immobilized with the same or different types of probes for hybridization.

In one embodiment, the present invention provides a hybridization device comprising a modular rack capable of supporting two or more modular devices and a modular device.

In one embodiment, the modular devices in the hybridization device have the same number or different numbers of hybridization regions, and the membranes in each hybridization region are immobilized with the same type or different types of probes for hybridization.

The devices described herein may be used in conjunction with hybridization devices or any other device or device capable of performing hybridization.

The invention can be better understood by reference to the following experimental details. However, those skilled in the art should understand that the examples provided are only for illustration, not for limiting the scope of the present invention. The scope of the invention will be defined by the following claims.

Throughout this application, various references or publications are cited. The entirety and disclosures of these references or publications are incorporated into this application in order to more fully describe the present invention. It should be noted that the transition word "comprises" is synonymous with 'including', 'contains' or 'featured by', and is inclusive or open-ended, which does not exclude other unlisted elements or methods step.

Description of drawings

1A-1C are one of the modular devices of the present invention.

2A and 2B are another modular device of the present invention.

Figures 3A-3C show a modular device with outer walls equipped with complementary snap fits.

Figures 4A-4C show another modular device with complementary snap fits on its outer walls.

Figures 5A-5D show a modular device with markings on the inner wall of the housing. Figure 5E shows a top view of the modular device equipped with markers.

Figures 6A-6C show a modular device with snap fits and markers.

7A and 7B show a modular device including a connection port.

Figure 8 shows an array of 16 modular devices.

Figure 9 shows another array of 16 modular devices.

Figures 10A and 10B show sets of devices including modular racks and modular devices.

Figure 11 shows another device set comprising modular racks and modular devices.

Figure 12 shows a set of devices comprising modular devices and positioners.

13A and 13B are top and perspective views of a positioner.

Detailed ways

Example 1

Method of manufacturing a modular device

This example illustrates the method of manufacturing one of the modular devices of the present invention. Before assembling, prepare the shell (10), the base (20) and the membrane (31) respectively. Plastic, such as polypropylene, is injected by plastic injection molding techniques to manufacture the housing (10) in the desired size and shape. In one embodiment, a housing groove (11) is made in the bottom of the housing (10). The base (20) is made of silicone rubber, wherein the silicone rubber has different hardness levels (Shore hardness) such as 10A to 50A, or 30A to 50A. The membrane (31) is cut to an appropriate size consistent with the bottom of the housing (10). Molecular probes can be immobilized on the membrane (31) either before or after assembly of the modular device.

Then, the membrane (31) is attached to the bottom of the casing (10) by thermal melting or ultrasonic welding, forming a pre-assembly of the casing (10) and the membrane (31). In addition, adhesive glue can be used as needed, directly applied to the outer edge of the housing (10) or the housing groove (11) to connect the membranes. Finally, silicone rubber is wrapped around the bottom of the pre-assembly to form a base, which is fixed with a pressing mold, thereby sealing the gap between the housing (10) and the membrane (31).

Example 2

Leak and pressure testing of modular installations

This example demonstrates that the modular device of the present invention can withstand higher pressures.

Due to the fibrous structure of membranes such as nylon membranes, once the solution touches the surface of the membrane, the molecules in the liquid will quickly penetrate into the membrane. If the various compartments of the device are not completely sealed, fluid leakage between the compartments may occur. Thermolysis technology can be used to apply a certain temperature and pressure to destroy the fiber structure of the membrane, thereby forming individual and independent hybridization chambers to avoid cross-contamination. However, in previous designs, the aspect ratio of the device was usually high, and the ends of the membrane and housing assembly could be twisted or bent after thermal melting. In this case, the membrane and the shell cannot be tightly and completely connected, and the fibrous structure of the membrane is not completely destroyed. Therefore, there is still a possibility of leakage and cross-contamination between hybridization chambers. In one embodiment, the aspect ratio of the modular device of the present invention is 2:1, which is much lower than that of previous designs (eg, 8:1).

Comparing the present invention with previous designs, we found that with the modular design and elastic base, the membranes embedded in the modular devices of the present invention can withstand higher pressures. In one embodiment, the membranes of the present invention can withstand pressures up to 7 psi, or about 380-400 mmHg. Generally, a small peristaltic pump can generate a negative pressure of about 300mmHg, and a small diaphragm pump can generate a negative pressure of 400mmHg.

The present invention provides a more robust design so that the hybridization device can withstand greater mechanical forces from the hybridization device or from manual manipulation. Membranes embedded in modular units have less chance of rupture, thereby minimizing the risk of leakage and cross-contamination.

The strength of membranes embedded in modular devices can be tested using the following methods:

1. Prepare a fixture with a known area that can be completely covered by the internal opening of the modular unit.

2. Place the modular unit on top of the jig with the membrane facing up. Put the whole setup on an electronic balance.

3. Pull the modular unit down until the membrane ruptures.

4. Measure the force required to cause the membrane to rupture, thereby calculating the pressure that the membrane can withstand.

Example 3

Modular device

Figure 1A is one of the modular devices of the present invention, said modular device comprising a housing (10) with a hybridization zone (30), a base (20) and a membrane (31). Figure 1B is a bottom view of the modular device shown in Figure 1A, where the device does not contain a membrane. Figure 1C is another modular device in which the housing (10) has a housing groove (11).

Figure 2A is another modular device of the present invention, wherein the housing (10) has three hybridization regions (30).

Figure 2B is a bottom view of the modular device shown in Figure 2A, where the device does not contain a membrane

Figure 3A-C shows a modular device with different types of complementary snap-fits (40, 40') on the outer walls. Complementary snap fits (40, 40') in Figure 3A are distributed along the outer walls of the modular device. Complementary snap fits (40, 40') in Figure 3B are located at both ends of the outer wall of the modular device. The outer walls of the modular device shown in Figure 3C have different types of complementary snap fits (40, 40').

Figures 4A-C are another modular device with complementary snap fits (40, 40') on its outer walls, wherein the device contains three hybridization regions. Complementary snap fits (40, 40') in Figure 4A are distributed along the outer walls of the modular device. Complementary snap fits (40, 40') in Figure 4B are located at both ends of the outer wall of the modular device. The outer walls of the modular device shown in Figure 4C have different types of complementary snap fits (40, 40').

Figures 5A-E show a modular device with multiple markings (50) on the inner wall of the housing (10). Figures 5A and 5B show two differently shaped markers (50). The marker (50) shown in Figure 5C spans the entire vertical wall of the housing (10). Figure 5D shows another modular device with markers (50), the upper edge of the housing (10) also contains a number of colored markers or aligners (51). Fig. 5E is a top view of one of the modular devices of the present invention, wherein the inner wall of the housing (10) is equipped with marks (50).

Figures 6A-C are modular devices with snap fits (40, 40') and markers (50). The modular device of Figure 6A is provided with snap fits (40, 40') and markers (50). Figure 6B shows an array of four modular devices, each with snap fits (40, 40') and markers (50). Fig. 6C is an exploded view of the modular device in Fig. 6B.

Figure 7A shows a modular device comprising a port (12) and a hybridization zone. Figure 7B shows another modular device with a port (12) comprising three hybridization regions.

Figure 8 shows an array of 16 modular devices arranged in a 4x4 pattern, where each modular device has a hybridization zone. The array consists of a base plate (21) for the placement of individual modular units

Figure 9 shows another array of 16 modular devices arranged in a 4x4 formation. The array comprises a base plate (21) for housing individual modular devices with one or three hybridization zones.

Figure 10A is a set of devices comprising a modular rack (60) and modular devices arranged in a 4x1 format, where each modular device has a hybridization zone. Figure 10B is a set of devices comprising a modular rack (60) and modular devices arranged in a 4x3 format, where each modular device has three hybridization zones. Figure 11 shows another set of devices comprising a modular rack (60) and modular devices arranged in a 4x1 format, where each modular device has one or three hybridization zones.

Figure 12 shows a set of devices comprising modular devices and positioners (63). Figure 12 shows that on the hybridization device, four modular devices are sandwiched between a pair of positioners (63). Fig. 13A is a top view of the locator (63), and the locator (63) is equipped with a slot (64). Figure 13B is a perspective view of the retainer (63) with slots (64).

Claims (12)

1., for carrying out a modular device of hybridizing, comprise with lower part:

I) have the shell of one or more hollow open, each opening corresponds to a hybridising region, and described hybridising region is used for containing for carrying out the material of hybridizing or liquid; And

Ii) film be connected with outer casing bottom, described film is between shell and the base being attached to outer casing bottom.

2. modular device according to claim 1, described outer casing bottom also has a groove to put into base.

3. modular device according to claim 1, described shell comprises one or two feature following further:

I) at least the outer shell outer wall on one side is furnished with one or more buckling body; And

Ii) at least the outer casing inner wall on one side is furnished with one or more mark.

4. modular device according to claim 3, the buckling body on described outer shell outer wall is identical type or dissimilar.

5. one comprises the device group of modular device according to claim 3, wherein two or more modular device is arranged in an array to hybridize, wherein modular device has the hybridising region of equal amts or different quantities, and the film in each hybridising region described is fixed upper same type or dissimilar probe to hybridize.

6. device group according to claim 5, also comprises one or more steady arm, is used for locating module formula device.

7. modular device according to claim 1, described shell comprises one or two feature following further:

I) modular device is navigated to the Port on hybridization device; And

Ii) at least the outer casing inner wall on one side is furnished with one or more mark.

8. one comprises the device group of base plate and modular device according to claim 7, and wherein two or more modular device is arranged in an array, and be placed on there is multiple hollow open base plate on.

9. device group according to claim 8, wherein modular device has the hybridising region of equal amts or different quantities, and the film in each hybridising region described is fixed upper same type or dissimilar probe to hybridize.

10. one comprises the hybrid device of module rack and modular device according to claim 7, and described module rack can support two or more modular device.

11. devices according to claim 10, wherein modular device has the hybridising region of equal amts or different quantities, and the film in each hybridising region described is fixed upper same type or dissimilar probe to hybridize.

12. devices according to claim 1, described modular device and hybrid device or other any can carry out hybridizing device or She Bei Knot close and use.