JP2003524747A - Automated parallel capillary electrophoresis system - Google Patents

Abstract

(57) Abstract: An automatic electrophoresis system (30) using a capillary cartridge having a plurality of capillaries (32). The cartridge has a first array of capillary ends protruding from one side of the microtiter plate (68) to allow simultaneous electrophoretic analysis of the samples in the wells of the plate. The system includes a stacked dual carousel device, a gel transfer module, a multi-wavelength beam generator (52), and an off-line capillary regenerator.

Description

Detailed Description of the Invention

TECHNICAL FIELD OF THE INVENTION The present invention relates to an apparatus for performing electrophoresis. More specifically, the present invention provides
The present invention relates to an automated electrophoresis system using a capillary cartridge formed so that a commercially available standard-sized microtiter tray can be used, the electrophoresis system including a stacked dual carousel device and a multi-wavelength beam generator. , A gel transfer system and an off-line regenerator designed to avoid sample cross-contamination, improve system performance, and increase throughput.

BACKGROUND OF THE INVENTION Electrophoresis is a well-known technique for separating macromolecules. In electrophoresis applications, the molecules of the sample to be analyzed move in a medium to which a certain voltage is applied. Often, the sample is propagated through a gel that acts as a sieving matrix that helps to retard and separate individual molecules as they migrate.

One application of gel electrophoresis is in DNA sequencing. Prior to electrophoretic analysis, a DNA sample is prepared by a well-known method. The result is a solution of DNA fragments of all possible lengths corresponding to the same total sequence order, each fragment ending with a label corresponding to the identification of a terminal base.

This separation method uses a capillary filled with a conductive gel. To introduce the sample, one end of this capillary is inserted into the DNA reaction bottle. After introducing a small amount of sample into the ends of the capillary, both ends of the capillary are placed in another buffer solution. Then, a voltage is applied across the capillary. The voltage drop at this time causes the DNA sample to move from one end of the capillary to the other end. Due to the difference in the migration speed of this DNA fragment,
It will be separated into bands of fragments of similar length. As these bands traverse the capillary tube, they are typically read at any point along the capillary using one of several sensing techniques.

The most widely used fluorescent dye for labeling DNA samples is 49
It has a maximum absorption wavelength in the range of 0 to 580 nm. The basic sensing technique is a CCD camera with a wide-angle lens and a capillary tube array located below the camera lens, the plane of which is located parallel to the CCD imaging chip, and the capillary array described above. And a laser beam that is irradiated so as to traverse. However, the single laser line used in this basic detection technique cannot conveniently accept all labels simultaneously. Therefore, multiple lasers or optical filters are used to compensate for this drawback.

Usually, multiplex DNA preparation reactions are performed using commercially available microtiter trays, which have a large number of small volume wells each capable of holding a sample on the order of 200-1,000 microliters. . This microtiter tray is standardized in size. In the biotechnology industry, the microtiter trays that are currently the preferred choice have a rectangular array of 8 columns by 12 rows of wells. Center spacing between adjacent wells in a single row is about 0.9c
Although it is m, this value may change from 1/10 to 2/10 mm. This also applies to the spacing between adjacent wells in a single row. This 96
The rectangular array of wells is designed to fit within a predetermined area (footprint) of less than 7.5 x 11 cm.

The reduction in size allows a larger number of wells to be accommodated in a microtiter tray having the same footprint. New trays have been introduced that have wells arranged in the same predetermined footprint at four times the density of conventional ones, and are rapidly becoming the industry standard. That is, this new tray consists of 16 columns by 24 rows of wells with an interwell spacing of approximately 0.45 cm.

Analyzing thousands of DNA samples in a DNA sequencing project is not uncommon. Needless to say, carrying out thousands of experiments using one capillary is time-consuming.

In the conventional device, a means for simultaneously analyzing DNA bands in a large number of capillaries has been proposed. Such a device is described in Yeung et al., U.S. Pat.
5,498,324, the entire contents of which are incorporated herein by reference. This U.S. Patent teaches a means for detecting separated DNA bands in multiple capillary tubes arranged parallel to each other.
However, in such a system, it is necessary to fill each capillary tube with gel and introduce the sample into each capillary tube.

Therefore, it takes a considerable time to fill each capillary tube with gel. Moreover, considerable effort is required to reproducibly and reliably introduce the reaction sample into one end of each tube.

It is also not uncommon to perform several consecutive sample analyzes using the same capillary. However, this obviously carries with it the risk of cross-contamination of the sample, which can also be a disadvantage of conventional methods. SUMMARY OF THE INVENTION One object of the present invention is to provide an apparatus capable of simultaneously introducing a sample from a standard size microtiter tray directly into multiple capillary tubes.

Another object of the invention is to provide a stacked dual carousel device, thereby avoiding cross-contamination of DNA samples without compromising the capabilities of the system.

[0012] Another object of the present invention is to provide a gel transfer module, which allows the gel to be uniformly and rapidly distributed in the capillary tube.

Another object of the present invention is to provide an off-line capillary regenerator, which cleans the capillary cartridge off-line completely and improves the system throughput while minimizing the cost increase.

Another object of the present invention is to provide an apparatus capable of generating a multi-wavelength beam. This multi-wavelength beam device allows the simultaneous detection of multiple DNA samples labeled with different fluorescently labeled dyes.

These objects are achieved by providing a disposable capillary cartridge that can be cleaned during electrophoretic analysis and that has a plurality of capillary tubes. In this case, the first end of each capillary tube is held by a mounting plate, which together form an array in the mounting plate. The spacing between these first ends corresponds to the spacing between the centers of the wells of a standard size microtiter tray. Therefore, the first ends of these capillaries can be simultaneously immersed in the sample in the wells of the microtiter tray. The cartridge is provided with a second mounting plate, which holds the second end of the capillary. In another aspect, instead of using this second mounting plate, the second ends of the capillary tubes are bundled together and received by a liquid transfer chamber, preferably a high pressure T-shaped mounting member. ing.

A plurality of plate holes may be provided in each mounting plate, and a capillary tube may be inserted into these. In such a case, the plate hole is hermetically sealed, allowing the side of the mounting plate having the exposed capillary end to be pressurized. The application of positive pressure in the vicinity of the capillary opening of the mounting plate allows the introduction of air and fluid during the electrophoretic operation, and further, the application of this positive pressure allows the gel and gel from the capillary tube to be regenerated during regeneration. It can also be used to extrude other materials. When inserting these capillary tubes into these plate holes, it is possible to prevent them from being damaged by using a needle made of a cannula and / or a plastic tube. Also, if metal cannulas or the like are used, they can also serve as electrical contacts for current flow during electrophoresis.

In a preferred embodiment, the stacked dual carousel device can avoid the problem of cross-contamination of DNA samples without compromising the capabilities of the system. The system uses a buffer with a gel, which provides a medium for migrating DNA from one end of the capillary tube to the other during electrophoresis. Since this buffer also moves through the capillary tube during electrophoresis, it is necessary to keep one end of the capillary tube immersed in the buffer so that the buffer is continuously replenished with the buffer. is there. Therefore, this buffer may be contaminated with the DNA sample during electrophoresis. This DNA in the buffer can then migrate into the capillary tube during subsequent runs of the electrophoresis if the electrophoresis is performed sequentially with the same buffer. The above stacked dual carousel device provides a buffer tray for each DNA sample tray and avoids reusing the same buffer tray to achieve DN
It avoids the problem of cross contamination of the A sample. Also, since the stacked dual carousel device has an additional carousel for holding the buffer tray, there is no need to replace the sample tray for the purpose of providing space for this additional buffer tray. Therefore, this dual carousel device can avoid the above contamination problem without compromising the system's capability.

In another preferred embodiment of the invention, the detection system uses both a multi-wavelength beam generator and a multi-wavelength detector, which allows different labeling dyes in the same instrument without switching lasers or optical filters. It is possible to simultaneously detect a plurality of DNA base sequence samples labeled with.

The multi-wavelength beam generator has 457 nm, 476 nm, 488 nm, 496 nm,
Provided by an Argon ion laser capable of producing a multi-wavelength beam with wavelengths of 502 nm and 514 nm. This multi-wavelength beam generator compensates for the different absorption spectra in different labeling dyes, improves the uniformity of the peak detection signal in the DNA fragment, and improves the signal / noise ratio of the detection signal.

In another preferred aspect of the invention, the gel transfer module moves the gel rapidly and uniformly through the capillary. The gel transfer module uses a gel syringe to move the gel because the gel is too viscous to be pumped. The gel transfer module comprises a gel carriage for holding a disposable gel cartridge. The stepper motor linear actuator comprises a movable actuator shaft, which is arranged to drive a Teflon plunger located at one end of the gel syringe, which causes the gel substance to be placed at the other end of the gel syringe under high pressure. It is designed to flow rapidly through the member. In addition, the gel transfer module relaxes the gel in the capillary tube using the same members used for electrophoresis to achieve a uniform distribution of the gel.

In another aspect of the gel transfer module, a compressible gel bag is utilized. In this embodiment, the gel bag is arranged inside a high pressure chamber, which comprises a hollow cylinder having an open top and a closed bottom, and a cap removably attached to the top of the cylinder. An outlet assembly having an inner end removably attached to the gel bag and an outer end connected to the T-shaped attachment member is attached to the high pressure chamber. This high pressure chamber is also connected to a pressure regulating assembly that can increase or decrease its internal pressure. When the pressure inside the high pressure chamber increases, the gel is squeezed out through the outlet assembly and delivered to the T-shaped mounting member.

In another preferred embodiment of the present invention, a simplified offline capillary regenerator completely cleans the capillary offline so that an increase in system throughput can be achieved while suppressing an increase in system cost. Has become. An operator can perform electrophoresis while cleaning the previously used capillary cartridge with an offline capillary regenerator. Since it typically takes about 20 minutes to completely clean, it is not necessary to wait for the system to completely clean the capillary cartridge 909 between successive runs of electrophoresis, and thus this Off-line capillary regenerators can improve system throughput.

This off-line capillary regenerator comprises a small number of low cost components, including a solvent container to hold the cleaning fluid, a manifold to select the cleaning fluid, and a simple controller to manage the cleaning. I will do it. This simplification of the offline capillary regenerator has the advantage that an increase in system throughput can be achieved while suppressing an increase in system cost. [Detailed Description of Preferred Embodiments] FIG. 1 schematically illustrates a usage pattern of the apparatus of the present invention. The cartridge 30 of the present invention comprises a plurality of capillary tubes 32 of substantially the same length. These capillary tubes 32 are connected to the sample side connection array (array) 3
4 and the gel-side connection array 36. The capillary tube 32 ends with an array of first capillary ends 38 on the sample side and a second on the gel side.
Ends with an array of capillary ends 40.

That is, both ends of the capillary tube 32 of FIG.
It extends through the individual plate holes in 2. The base member 42 is preferably made of polycarbonate or acrylic resin or the like. Alternatively, each array at the ends of the capillaries may be held by another mounting plate having plate holes, and then each mounting plate may be fixed to the base member. Further, instead of passing each capillary through an individual plate hole, one or more capillary tubes may be brought together to pass through a common hole or no holes at all.

Between these two arrays, the capillary tube 32 is attached to the base member 4
The thermoelectric member 44 mounted on the 2 is penetrated. This thermoelectric member 44 is provided in the window area 4
It is arranged on both sides of 6. This thermoelectric member is used to control the temperature of the capillary tube within a predetermined range. The thermoelectric member 44 may be composed of two or more members as will be apparent to those skilled in the art. Further, the temperature may be controlled by using another temperature control means such as a fluid circulation system or air convection.

The capillary tubes 32 are arranged parallel to each other in the window region 46 adjacent to each other. The length of each capillary tube from the end of the first capillary to the window region 46 is substantially the same in all capillary tubes 32. This length is determined by taking into consideration the optimization of the analysis time of the sample (that is, the minimum allowable time) and the minimum allowable analysis capacity of the separated sample. Nominally, this length is in the range of approximately 50-70 cm. The window region 46 represents a region where incident excitation light can access a parallel capillary tube, and is a region where fluorescence emitted from the capillary tube can be accessed. That is, this window region 46 allows for detection of the band 50 in various capillary tubes.

As shown in FIG. 1, the excitation light source comprises a laser 52 and a prism 54 is used to focus a light beam 56 through the window region 46 and onto the capillary tube 32. Then, the fluorescence beam 58 is detected by the CCD camera 60, and the band 5 is detected.
0 is set to be captured. It should be noted that other lighting and sensing means can be used, as known to those skilled in the art.

The configuration shown in FIG. 1 allows the sample to be introduced into the first capillary ends 38 of all capillary tubes 32 substantially simultaneously. In particular, according to this configuration, various samples can be introduced by simultaneously immersing the array of first capillary end portions 38 in the plurality of wells 62 of the standard size microtiter tray 64 as described above. ..

To enable this, the individual capillary ends are spaced apart from each other and the spacing arrangement is substantially the same as that of an array of multiple wells of standard size microtiter tray 64. . That is, the spacing between adjacent first capillary ends is about 0.9 cm, and the overall array footprint of the first capillary ends is less than 7.5 cm x 11 cm, thus standard size microtiter plates. It corresponds to the tray.

The array of second capillary ends 40 is inserted into the wells 66 of the second microtiter tray 68, where it comes into contact with a buffer 70 as is known to those skilled in the art. Since the wells 66 of the second microtiter tray 68 are separated from each other, there is little risk of cross-contamination between the second capillary ends 40.

A voltage source 72 is used to provide a potential difference between the two capillary end arrays. As shown in FIG. 1, one voltage level is applied to each well 62 of the first microtiter tray 64 via an individual lead 74 and a second voltage level is applied in a substantially similar manner via an individual lead 76. It is applied to each well 66 of the second microtiter tray 68. That is, an electric current is applied to the individual sample via the lead 74 and passes through the first capillary end 38, the capillary tube 32 and the second capillary end 40 into the well 66 of the second microtiter tray 68. The buffer solution 70 is energized and finally passes through the lead 76.

2A and 2B show a plan view and a side view, respectively, of an example of a cartridge 80 of the present invention. The cartridge 80 includes a base member 82 made of, for example, polycarbonate or acrylic. First and second mounting plates 84 and 86 are mounted on the base member 82, respectively. The plates are preferably formed from an electrically insulating material.

The array of first capillary ends 88 includes a first mounting plate 84.
Projecting from the bottom surface 90 of the second mounting plate 86, the array of second capillary ends 92 projects from the bottom surface 94 of the second mounting plate 86. Capillary tube 96
Is fixed through the plate holes formed in the mounting plates 84 and 86, and protrudes from the upper surfaces of the mounting plates 84 and 86. Preferably, each capillary tube 96 is protected by a tube assembly (assembly) 102 fixed to the plate holes of the mounting plates 84, 86 at their penetrations.

As clearly shown in FIG. 2A, the tube assemblies project from the mounting plates 84, 86 in a rectangular array of 8 rows and 12 columns, respectively, with the associated capillary tubes. The distance between the adjacent plate holes to which these tube assemblies 102 are fixed and the distance between the adjacent capillary ends 88, 92 are both the distance between the adjacent wells of the standard size microtiter tray 64. It corresponds to. As a preferred example, the spacing between adjacent capillary ends is about 0.9 cm, and the overall array of capillary ends, and thus the array of plate holes through which the capillaries 96 penetrate, has a footprint of about 7.5 cm x 11 cm or less. .

The upper surfaces 98 and 100 of the respective mounting plates 84 and 86 are respectively provided with 10
First and second enclosures, shown as 4, 106, are provided. In the preferred embodiment, each of these enclosures is provided with an inlet 108 and an outlet 110.
The outlet 110 of the first enclosure is connected to the inlet 108 of the second enclosure via a plastic tube 112. The inlet 108 of the first enclosure is connected to a first plastic shutoff valve 114 and the outlet 110 of the second enclosure is a second plastic shutoff valve 11.
Connected to 6. Conversely, these plastic shutoff valves 114, 116 are connected to first and second quick disconnects 118, 120, respectively.

During operation, the cartridge 80 may be connected to the pump assembly 122. The pump assembly 122 is configured to circulate a temperature controlled liquid refrigerant through the enclosures 104, 106. In this case, the first quick disconnect 118 of the cartridge is the output 124 of the pump assembly 122.
And the second quick disconnect 120 is connected to the input 126 of the pump assembly 122. With this configuration, the temperature of the portion of the capillary tube 96 that protrudes from the upper surfaces 98 and 100 of the mounting plate and is located in the enclosures 104 and 106 can be maintained. In order to do this, it is necessary that the mounting plates 84, 86 be liquid-tightly sealed to the base member 82. This liquid-tight seal needs to be formed between the plate hole and the tube assembly 102 and the capillary tube 96, or on the capillary tube 96 itself.

The capillary tube 96 leads between two arrays of tube assemblies 102 in the area of the cartridge not covered by the enclosures 104, 106. As mentioned above, thermoelectric temperature control means 128 or the like is disposed on either side of the window section 130 of the capillary tube 96 to control the temperature of the capillary tube not within the enclosures 104, 106.

The capillaries 96 are arranged parallel to one another in at least part of the window area 130 and are readable by the sensing means. Preferably the base member 82
There is an opening 132 in which the window area 130 is arranged.
This makes it possible to arrange at least a part of the irradiation means or the detection means under the base member, so that the capillary tube 96 exposed therefrom can be seen in a straight line.

FIG. 3A illustrates a needle 1 used to form a tube assembly 160.
40, which can be inserted directly into the mounting plate 162 as shown in FIG. 3B. The needle 140 includes a metallic cannula 142. In a preferred embodiment, the cannula 142 has an inner diameter of 0.064 inches,
It consists of a stainless steel tube with an outer diameter of 0.072 inches. The cannula 142 is provided with a bevel 144 at the end immersed in the well.

Within the cannula 142, a polyetheretherketone (PEEK) polymer tube 146 is coaxially disposed and acts as a sleeve. The polymer tube 146 has an inner diameter of about 0.006 inch and an outer diameter of 0.0625 inch. Therefore, the polymer tube 146 can be easily inserted into the cannula 142.

A capillary tube 148 attached to the needle 140 passes through the center of the polymer tube 146 along the longitudinal axis of the needle 140. The capillary tube 148 is made of fused silica and has an inner diameter of about 0.003 inches,
The outer diameter is about 0.006 inch. That is, the capillary tube 14
8 is fitted inside the polymer tube 146. This capillary tube 1
48 terminates in an end 150 that is substantially flush with the tip 152 of the cannula 142. That is, the gap between the two ends 150, 152 is approximately 0.035 inches.

A UV curable, medical grade epoxy sealant 154 is used at both ends of the polymer tube 146 to secure the polymer tube 146 and the capillary tube 148 to the cannula 142. Preferably, the epoxy sealant 154 forms a gas-tight and liquid-tight seal through the cannula 142. The epoxy sealant prevents the polymer tube 146 from being exposed to the atmosphere and prevents the capillary tube 148 from making direct contact with the cannula 142.

The needle may be formed in a shape other than that illustrated in FIG. 3A. For example, instead of a tubular cannula, the needle may simply consist of a capillary tube, covered with an injected or coextruded plastic material, and the cover fixed to a metal strip. Also, other configurations are possible.

FIG. 3B shows a hollow high pressure compression mounting member 164 made of nylon into which the needle 140 has been inserted to complete the tube assembly 160. The needle 140 can also be fixed to the cylindrical inner wall of the compression mounting member using an epoxy sealant. Each tube assembly 160 is then inserted into a plate hole 166 drilled in the mounting plate 162, which plate hole 166 can also be sealed with an epoxy sealant. This allows
An air-tight and liquid-tight seal is formed between the bottom surface 168 of the mounting plate 162 and the surface 170, and even if positive pressure is applied to the bottom surface of the area where the plate hole for fixing the tube assembly is provided, the mounting plate is attached thereto. I can bear it.

The compression mounting member 164 may be omitted altogether, and the mounting plate 162 may be provided with a plate hole having a size corresponding to the outer diameter of the needle 140. In that case, the needle is directly inserted into each plate hole of the mounting plate 162 and fixed there by using an epoxy resin. Such a mountingless approach can improve the structural integrity of the mounting plate 162 due to the reduced size of the plate holes. Further, since the interface where the epoxy sealant is used is reduced, the airtightness and the liquid-tightness can be improved. Further, it should be understood that the capillaries 148 encapsulated in the capillary tube 148 or the polymer tube 146 can be directly held in the appropriately sized plate holes formed in the mounting plate 162.

It is understood that in the preferred embodiment, one capillary tube is retained in each plate hole, regardless of whether compression fittings are used, cannulas and / or polymer tubes are used. It should be. The spacing of the array of plate wells preferably corresponds to that of the wells of a standard size microtiter tray. However, it is also possible to form the plate hole off center (center deviation) and incline the end of the capillary.

Further, it should be understood that the array of capillary ends can be fixed in the desired shape without drilling holes in the mounting plate 162. For example, the ends of the individual capillaries can be arranged and fixed in a desired shape on the mounting plate 162 by adhesion or tightening. In addition, a plurality of capillaries may be put together and the ends thereof may be held while being kept in a desired shape with acrylic or the like. What is important is that the array has capillary end spacing that corresponds to the well spacing of a standard size microtiter tray.

The conductive plate 172 is fixed to the mounting plate 162 by screws, an adhesive, or any other known means. The conductive plate 172 has an array of conductive holes 174 corresponding to the plate holes 166 in the mounting plate. Each conductive hole 174 is formed by an H-shaped slit, and a pair of tabs 176, 178 are formed between the H legs. When the needle 140 is inserted into this conductive hole 174, these tabs 176, 178 retract and the needle 14
It comes in contact with both sides of 0.

Since this conductive plate 172 is entirely conductive, all needles 140 in the array will share a common electrical connection. The voltage applied to the conductive plate 172 appears outside each needle 140 in the array. During electrophoresis application, this voltage appears in the buffer in each well in which the capillary end 150 is inserted.

The voltage difference can be applied to the end of the first capillary by other means as well as known to those skilled in the art. For example, instead of contacting the common plate to which the needles are connected, the voltage leads may be connected directly to each needle. Alternatively, each lead may be immersed in the liquid in each well. Another alternative is to apply the voltage through a metallization, eg gold. In this case, the metallization is deposited only on the outer surface of the end of each capillary that contacts the liquid in the well. Further, the voltage may be applied directly to the well via one or more leads, as described above. One of ordinary skill in the art will appreciate that any other approach can be chosen to energize this first capillary end.

FIG. 4 shows a monitor plate 190 for use with the cartridge illustrated in FIGS. 2A and 2B. In the cartridge of the present invention, the conductive plate 172 is provided on at least the needle of the first mounting plate 84 as described above.
Is provided. The monitor plate 1 is attached to the second mounting plate 86.
90 can be provided.

The monitor plate has an array of monitor holes 192. The array of monitor holes 192 is aligned with the second array of plate holes formed in the second mounting plate 86. Each monitor hole 192 has a separate electrical contact 19
4 and the electrical contacts 194 are electrically connected to the monitor plate connector 196 via individual leads 198. Each needle in the second mounting plate 86 contacts a corresponding electrical contact 194 in the monitor plate.

The purpose of this monitor plate is to provide a means for measuring the presence of electrical continuity between any needle in the second mounting plate 86 and the needle in the first mounting plate 84. Is. To this end, the monitor plate 190 is made substantially similar to the conductive plate 172 and the mounting plate 8
It will be understood that it can be fixed at 6. Importantly, each electrical contact 194 connects only to one needle in the second mounting plate.

FIG. 5 shows a cartridge 200 in which a first array 202 and a second array 204 are partially arranged on a first carousel 206 and a second carousel 208, respectively. The CCD camera 210 is arranged above the cartridge portion between the arrays 202 and 204, and is adapted to detect a band (not shown in FIG. 5) in the capillary. Each carousel 206, 208 has eight platforms 212 on which standard size microtiter trays are mounted.

The wells in each titer tray hold one or more liquids such as sample, gel, buffer, acidic solution, basic solution. As shown in FIG. 5, the first carousel holds six sample trays 214, one buffer tray, and one waste tray, one sample tray below the first needle array 202. Is located in. Further, as shown in FIG. 5, the second carousel has a pair of acidic solution trays 220, a pair of basic solution trays 222, and a pair of waste liquid trays 224 (one of them is
One is located below the second needle array 204) and holds one buffer tray 226 and one gel tray 228. That is, the first carousel 206 is a sample side carousel, and the second carousel 208 is a gel side carousel.

The cartridge is detachably attached to the automatic electrophoresis apparatus. During operation, the lifting means raises and lowers the platform beneath either of the two needle arrays 202, 204. The microtiter tray is a needle array 202, 2
When approached to one of 04, the needles and associated capillary ends of these arrays are dipped into the contents of each well of the microtiter tray.
When the platform beneath any of these needle arrays is lowered, the carousel associated with this platform is rotated to allow different platforms 212 carrying different microtiter trays to rise.

When the platform 212 is raised, the peripheral surface of the platform contacts the opposing surface, thereby sealing the pressure chamber below the bottom surface of the needle array. A pressurized inert gas, such as helium, is added to the pressure chamber for about 30 times.
When introduced at a pressure of psi, a uniform force is applied to the sample in the wells of the microtiter tray held on the platform. This introduces a portion of each sample into the corresponding array at the end of the first capillary.

Alternatively or instead of applying pressurized helium to introduce the sample into the first capillary end, a high voltage is applied for a short time, on the order of 20-40 seconds, to apply the sample to the first capillary. It can also be moved to the end of the capillary. The use of high voltages for this purpose, however, can be size-selective. That is, larger molecules are more likely to be introduced at the end of the first capillary, potentially causing distortion in later electrophoretic analysis.

Next, the operation of the automatic electrophoresis apparatus shown in FIG. 5 will be described. First, various microtiter trays are filled with designated buffers, gels, samples, etc. The gel tray 228 on the carousel 208 is then raised to the capillary tube (not shown in FIG. 5) via the second capillary end (hidden in FIG. 5) associated with the second needle array 204. Will be introduced in. Then, the gel tray 228 is lowered. The sample tray 214 on the carousel 206 is then raised and the sample is introduced via the first capillary end associated with the first needle array 202 (hidden in FIG. 5). Then, the sample tray 214 is lowered. The carousels 206, 208 then rotate to position the buffer trays 216, 226 below the corresponding needle arrays 202, 204. A potential difference is then applied across the two needle arrays and electrophoretic analysis is performed.

When this electrophoretic analysis is complete, the cartridge is regenerated. This is done by flushing the gel and sample from the previous analysis under pressure and cleaning the capillary tube with acidic liquid 220 and / or basic liquid 222. The cartridge is then ready for reuse and the analysis of samples in the other one sample tray 214 is possible.

Of course, the number of platforms formed on the carousels 204, 206 can be arbitrarily selected. Further, it is possible to configure this platform in a linear or square arrangement. All that is needed is to attach any first microtiter tray to the first
Storage and positioning system that can be moved to the second needle array 206 and also to any second microtiter tray below the second needle array 208.

6A and 6B show a cartridge 2 having a first mounting plate 282.
Shown respectively at 80 side and plane, where the array of plate holes in the first mounting plate 282 has been rotated 90 degrees. Otherwise, the arrangement for connecting the capillary tube to the first mounting plate is substantially the same as in the previous example. The ends of the first capillaries formed in the array with the desired gap project from the bottom surface of the first mounting plate 282 and are retained in plate holes formed in the first mounting plate.

The second mounting plate 284, however, is not the same as the cartridge example described above. In the cartridge 280, the second mounting plate 282 acts as a pressure holding member for the pressure cell 286 having a substantially cylindrical outer wall surface. For clarity, FIG. 6A shows the capillary tube on the first mounting plate with a portion omitted. Further, the capillary tube on the second mounting plate 284 is omitted altogether. However, in reality, all of these capillary tubes are present.

The second mounting plate has a beveled surface (slope) 288 which is symmetrical in the radial direction, and a plurality of plate holes 290 are formed in it. These plate holes 2
Each of the 90 is fitted with the PEEK polymer tube 292, and the capillary is fitted and fixed in the PEEK polymer tube 292 by using the UV curing epoxy resin as described above, and is hermetically and liquid-tight in the plate hole 290. Forming a seal. The capillary tube is inserted through the PEEK polymer tube,
The second end of each capillary tube communicates with the internal cavity of the pressure cell. In the preferable example of this cartridge, the second mounting plate provided with the PEEK polymer tube and the capillary tube has been described, but the same needle as that described above may be used. Further, a capillary tube alone fixed with epoxy can be similarly used. Importantly, each capillary tube 294 is held in the plate hole 290 in a gas-tight and liquid-tight manner, with the second end of the capillary tube being at the pressure cell 286.
Is in communication with the internal cavity of the.

Similar to the cartridge 80 of FIGS. 2A and 2B, this cartridge 280 is provided with thermoelectric control means 298 and enclosures 300, 302, the capillary tubes of which are arranged parallel along at least part of the window area 304. Has been done. 6A, 6
Although not shown in B, these enclosures 300 and 302 may be provided with an inlet and an outlet for circulating the refrigerant, like the other cartridges 80.

As shown in FIG. 6A, the second mounting plate 284 has a frusto-conical upper portion with a flat top 310. The curved conical surface 288 provided with a number of plate holes 290 is advantageous in terms of structural integrity when positive pressure is applied from below the second mounting plate. Furthermore, by providing plate holes 290 on such a surface, the plate holes 290 can be spaced farther apart, which also improves the structural integrity of the pressure cell 286.

The pressure cell 286 is fixed to the base member of the cartridge 280 and protrudes through the bottom of this base member. With such a configuration, the pressure cell 286
May have an inlet 312 and an outlet 314 on opposite sides of its tubular outer wall, respectively. It is also possible to easily provide this inlet at the flat top portion 310 of the second mounting plate 284 and the outlet at the bottom surface of the lower portion 316 of the pressure cell 286. In such a case, the pressure cell can be mounted on the base member, rather than protruding through the bottom of the base member, and the pipe attachment member is connected to the outlet through a hole formed in the base member. , Then the hole is sealed.

FIG. 7 shows a valve arrangement for a pressure cell 320 having an inlet 322 on the top surface 324. In other respects, it is substantially the same as the pressure cell 286. In addition to the inlet 322, the pressure cell 320 is provided with an outlet 326, which is connected to a waste liquid valve 328. This drain valve 328 is opened to drain the contents of the internal cavity of the pressure cell 320.

Access to this inlet 322 is controlled by a stop valve 330. Liquid is introduced into pressure cell 320 via inlet 322 using pump 332. Preferably, the pump is a high pressure liquid chromatography (HPLC) pump and the pumping capacity is 4-40 milliliters per minute at a pressure of about 2000 psi. The pump 332 is connected to the multi-valve manifold 334.
4 allows one of the four liquids to be selectively delivered to the pressure cell. The four liquids, namely gel, buffer, acidic liquid and basic liquid, are held in separate containers 336, 338, 340 and 342, respectively. An additional container holding a similar liquid may be retained for reserve or may be connected in series to the container to increase the total supply.

The waste liquid valve 328, the shutoff valve 330, the pump 332 and the multiple valve manifold 334 are all under the command of a controller, preferably a microcomputer. That is, the contents of the internal cavity of the pressure cell are regulated by this controller. Such a controller is adapted to accept inputs from various pressure and temperature monitors and other sensors to prevent damage to the pressure cell 320.

During operation, the internal cavity of pressure cell 320 is filled by pump 332. This forces the pumped liquid to the end of the second capillary that communicates with the internal cavity of the pressure cell 320. Filling the array of first capillaries and the pressure cell 320 with the appropriate fluid in the appropriate sequence allows the electrophoresis operation described above with respect to the apparatus of FIG. 5 to be performed.

After the analysis, the pressure cell and capillary tube are regenerated and ready for the next analysis. This is accomplished by flushing the gel and sample from all capillary tubes simultaneously. However, using the pressure cell 320, thousands of psi
Pressure of the order of is applied. These increased pressures allow the viscous gel to drain more quickly from the capillary tube. This allows the cycle time between analyzes to be reduced to about 1 to 2 hours, including the regeneration operation.

FIG. 8 shows an exploded cross-sectional view of a pressure cell 350 similar to pressure cell 286 of cartridge 280. Like other pressure cells, this pressure cell 350 is preferably made from aluminum or stainless steel. The pressure cell 350 is provided with a threaded inlet 352 which is mounted on the top surface 3 of the upper portion 356.
54 is formed. This upper part includes a second mounting plate. The pressure cell 350 is further provided with a threaded outlet 358 on the bottom surface 360 of its lower portion 362. High pressure pipe fittings can be screwed into these threaded inlets 352 and threaded outlets 358.

The upper portion 356 and the lower portion 362 are held together by a plurality of bolts (not shown). These bolts are inserted through bolt holes 368 formed around the bottom surface 360 of the lower portion 362. These bolts are then screwed into corresponding threaded holes 370 formed in the bottom surface 372 of the top 356. O-ring 3
64 is partially fitted into a square groove 366 formed in the second mounting plate 356. O-ring 364 acts as a seal between top 356 and bottom 362. Instead of the O-ring, a gasket or the like can be used to act as a seal.

An internal cavity 374 is formed in the central portion of the pressure cell 350, which is formed between the upper portion 356 and the lower portion 362. In addition, a plurality of plate holes 376 are formed in the upper portion (second mounting plate). For clarity, a plurality of plate holes 376 are shown only on one side of the upper portion 356 in FIG. However, it should be understood, of course, that it also exists on the other side of top 356. The plate hole 376 extends from an inclined surface 378 formed on the upper portion 356 to the internal cavity 374.

Capillary tube 380 is retained in these plate holes 376 and its second end 382 communicates with internal cavity 374. Each capillary is P
Fitted within an EEK polymer tube, the PEEK polymer tube extends well outside of bevel 378 from a point in each plate hole near inner cavity 374. However, for clarity, this PEEK polymer tube is not shown in FIG. It should be noted that only the capillary tube or a needle composed of a capillary tube, a PEEK tube, and a cannula may be inserted into each plate hole 376 with its dimensions adjusted.

As described above, both ends of the plate hole 376 are sealed (sealed) with the UV-curable epoxy sealant to maintain the airtightness and liquid-tightness of the plate hole 376. For the pressure cell, the end 384 of each plate hole near the internal cavity 374 is tapped or roughened. This provides a surface to which the epoxy encapsulant will readily adhere during assembly.

The liquid contained within the internal cavity 374 is in contact with the material forming the internal cavity. When this liquid further contacts the second capillary end 382, the electrical connection between the internal cavity 374 of the pressure cell 350 and the first capillary end fixed to the first mounting plate is completed. That is, by grounding the pressure cell 350 via a contact provided therein, the internal cavity 374 is grounded, and the circuit necessary for performing electrophoresis is completed. Alternatively, the potential of the pressure cell 350 may be floated because the pressure cell 350 is electrically isolated from the base member on which it is placed. This allows a high voltage to be applied to the pressure cell 350 rather than the needle associated with the first capillary end.

FIG. 9 shows another arrangement for the plate holes 390 in the second mounting plate 392 having a top surface 394 and an inlet 396. Each set of three plate holes 398 is offset at an angle with respect to the center of the top surface 394. This gives the maximum spacing between the plate holes. From the point of view of structural integrity, such an arrangement is preferable to the radial spoke-like arrangement of the plate holes as shown in FIG. 6B.

FIG. 10 shows an electrophoretic device 400 designed for use with a capillary cartridge formed as shown in FIGS. 6-9. The device comprises a user interface 402 (shown as a video display terminal and keyboard), which is in communication with a controller 404 (preferably a microprocessor-based computer or the like). The user interface 402 allows the user to enter commands, accept status information, and observe the collected data.

The apparatus 400 further comprises a data calculation computer 406, which receives and stores the video signal from the CCD camera 408.
To process. The data arithmetic computer 406 is provided with optical read / write data storage means 410 and / or magnetic read / write data storage means 412. Signal and image processing software is provided inside the data calculation computer 406 so that the signal data from the CCD camera 408 can be analyzed. Further, the data calculation computer 406 is a controller 404.
And responds to requests from the controller 404 and exchanges data and control information as needed.

The device 400 further comprises a high voltage electricity supply 414 adapted to apply the required voltage across the ends of the capillary tube. The operation of the high voltage electricity supply unit is instructed by the controller 404.

The controller 404 directs the operation of the pump interface 416 including a large number of electronic switches. The pump interface 416 regulates the operation of the solenoid valve 418. This solenoid valve 418 connects the gas inlet 420 to the chamber 422 which is connected to an inert gas source such as a pressurized helium tank. The pump interface 416 further regulates the operation of the high pressure liquid chromatography (HPLC) pump 426. The HPLC pump 426 directs the liquids in the containers 428, 430, 432, 434, ie gels, buffers, acids and bases, through the multi-valve manifold 440 to the pressure cell 436 of the cartridge 438 under the direction of the controller. It is designed to be supplied selectively.

A carousel 442 having multiple platforms is rotated by a rotor 444. A platform 448 located below the first mounting plate is configured to move up and down by an elevating means 446 such as a hydraulic pump. This causes the microtiter tray 450 on platform 448 to be moved toward or away from the array of capillary ends, as described above. The rotor 444 and the elevating means 446 are the controller 40.
4 and is driven by the controller 404.

The apparatus 400 further includes a light source 452 (preferably a laser), and irradiates the capillary tube 454 according to an instruction from the controller 404. That is, the light source 452 illuminates the capillary tube 454 from below through the opening of the base member of the cartridge 438 as described above.
Since the detection of the capillary band is performed in a dark place, the light enclosure plate 456 is attached to the camera 4
08, the light source 452, and at least the window region of the capillary tube 454 is covered.

During operation, the capillary tube 454 is first cleaned and then the pump 4
The gel is filled via the pressure cell 436 by driving 52. This pump 452 is switched off. Next, the platform 448 supporting the microtiter tray 450 holding the sample is raised by the elevating means 446. This forms a seal between the platform 448 and the lower surface of the chamber 422. In addition, this allows for the first in the well of the microtiter tray 450.
The capillary end of is dipped. Chamber 422 is sealed and solenoid valve 418 is opened to allow pressurized helium gas to be introduced via inlet 420. This applies a uniform positive pressure on the order of 30 psi into each well of the microtiter tray 450, forcing at least a portion of the sample into the first capillary end. As mentioned above, the high voltage may be applied for a short time for this purpose.
Platform 448 is lowered, carousel 442 is rotated, and buffer-filled microtiter tray 450 is moved below the end of the first capillary. The buffer tray is then raised, the first capillary end is dipped into the buffer solution, the pressure cell 436 is filled with buffer solution, and the second capillary end is also contacted with buffer solution. After that, the high voltage source 414 is switched on and an electrophoresis test is performed. Light source 452 and camera 408 are used to simultaneously inspect bands in all capillary tubes 454. Video signal data from camera 408 is processed and stored in computer 406. This processed data is then displayed on the user interface 402. After this inspection, the cartridge 438 is regenerated (ie, cleaned) and prepared for the next inspection.

The configuration of the carousel device shown in FIG. 5 has the problem of buffer solution contamination. As shown in FIG. 5, there are six sample trays 214 and one buffer solution tray 216 on the first carousel 206. After the sample is introduced from the sample tray 214 on the first carousel 206 via the first capillary end (hidden in FIG. 5), the sample tray 214 is lowered and both carousels 206, 207.
Are rotated so that both buffer trays 216 and 226 are placed under the corresponding needle arrays 202 and 204, respectively, and the needle arrays 202 and 2 having a potential difference of two are arranged.
Applied over 04 and electrophoresis is performed. While contacting the first capillary end (hidden in FIG. 5) with the buffer tray 216, some of the DNA sample from the first capillary end diffuses into the buffer tray 216, Contaminate 216. This contamination is due to D from another sample tray 214.
It adversely affects the accuracy of the electrophoresis test after using the NA sample. This is because the same buffer tray 216 as that used in the previous test is used in the subsequent electrophoresis test.

The problem of this contamination is that the sample tray 214 is buffered with the buffer tray 216 until a one-to-one match is obtained between the set of sample trays 214 on the first carousel 206 and the set of buffer solution trays 216. It can be avoided by replacing. With this arrangement, each sample tray 214 will have a single corresponding buffer tray 216. This arrangement avoids contamination problems, but adversely affects the ability of the first carousel. Assuming that the first carousel 206 has eight platforms, there is a one-to-one match between the set of sample trays 214 and the set of buffer trays 216 to avoid the above contamination problem. In an attempt to obtain, this first carousel 206 can only have a maximum of three sample trays 214.

FIG. 11 shows a stacked dual carousel device in the sequencer module 600, which does not interfere with the system's capabilities, and has a 1: 1 ratio between the set of sample trays 214 and the set of buffer trays 216. It achieves concordance and avoids pollution problems. The stacked dual carousel device comprises an upper carousel 601 and a lower carousel 602, which are aligned and spaced along a common axis.

As a preferred example, both of the carousels 601, 602 have seven sections 618 for receiving the microtiter trays 214, 216 and one large notch for passing the microtiter trays 214, 216. 620 and. The large notch 620 in the upper carousel 601 is adapted to allow the tray originally located at the site 618 of the lower carousel 602 to pass through the upper carousel 601 to the needle array 603.

As an example, the upper carousel 601 holds a sample tray 214,
The lower carousel 602 holds a buffer solution tray 216 corresponding to the sample tray 214. FIG. 12A shows the arrangement of this tray on the lower carousel 602. In this tray arrangement, the lower carousel 602 can hold six buffer trays 216 and one waste tray 224. Further, the upper carousel 601 can hold six sample trays 214. As a preferred example, each carousel contains 6 sample trays, 6 buffer trays and 1
One drainage tray and one water tray can be provided. The water tray is provided to rinse the capillaries and the first ends of the electrodes. However, the number of each tray type provided on the carousel varies depending on the size difference of commercially available microtiter trays.

Each of the carousels 601 and 602 in the stacked dual carousel apparatus is provided with a rotor 604 and a motor 608 for selectively rotating the carousels 601 and 602 at a selected angular position. More specifically, the motor 608 selectively rotates the carousels 601 and 602 to move the sample tray 21.
4. Arbitrary part 618 accommodating the buffer solution tray 216 or the waste solution tray 224 is arranged under the needle array 603. This motor 608 is the controller 40
4, the carousels 601 and 602 are selectively rotated toward a predetermined angular position.

As a preferred example, each of the carousels 601 is included in this laminated dual carousel device.
, 602 for motors 602 are provided. The motor 608 is a stepper motor and is available from Pacific Scientific (Wilmington, MA). As another example, the laminated dual carousel device is provided with a DC motor 608 and a clutch mechanism for selectively engaging and rotating the carousels 601 and 602.

The angular positions of the two carousels are automatically detected. For this reason, each carousel 601 and 602 is further provided with an encoder 612 that is operatively engaged with the rotor 604. The encoder 612 senses angular position data of the rotor 604 and transmits it to the controller 404. As a preferred example, this encoder 612 (for example, model number A
G612XKRR; Stegman Corporation; Bandaria, Ohio)
Is equipped with an optical sensor and has a 2048 pulse resolution value.

This angular position can be detected by arranging the holes (holes) 613 linearly along the periphery of the carousel so as to be adjacent to each part. For a carousel with eight sites, one lead hole, three coded holes and a tail hole are provided. The leading and trailing holes merely indicate that coded holes may exist between them. Each of these three coded holes may be present or absent. This allows coding for 8 = 2x2x2 sites. These holes are the upper carousel 601
Illuminated by an LED arranged above. That is, LED light passes through these holes and is detected by the carousel position detector located below the lower carousel 602. The carousel position detector generates angular position data from a series of holes through which LED visible light is transmitted and transmits this data to controller 404.

The controller 404 uses the angular position data from any of the above examples to determine the rotational position of each carousel 601 and 602, and selectively rotate each carousel 601 and 602 by the motor 608 to determine the predetermined position. Place it in an angular position. More specifically, the controller 404 uses the position data and uses the carousels 601, 6
First, the rotational momentum of the carousels 601 and 602 that causes 02 to exceed the predetermined angular position is compensated.

The stacked dual carousel array further includes a DC motor 605.
The motor 605 has a movable member and moves the selected trays 214, 216, 224,
If necessary, the needle array 603 is moved back and forth along the common axis. The controller 404 also moves the selected tray 214, 216, 224 via the DC motor 605 along the common axis.

The DC motor 605 has an ammeter and measures the current drawn by the DC motor 605. When a DC motor encounters a load, the current drawn by this motor increases, causing its moving members to move continuously. Therefore, the tray 21
When 4, 216, 224 rise to reach needle array 603, or when trays 214, 216, 224 fall to reach carousel 601, 602, the current increases rapidly. When this rapid increase in current is detected, it is determined that the trays 214, 216, and 224 have reached the correct positions, and the controller 404 operates to stop the DC motor.

In the preferred example shown in Figures 12a and 12b, the diameter and thickness of each carousel 601, 602 is 23.5 inches and 3/8 inches, respectively. Further, each carousel 601 and 602 has a circular hole 610 with a diameter of 1.375 inches in the center,
It is adapted to receive the rotor 604. In addition, each carousel 601, 6
In No. 02, four holes 611 having a diameter of 5/16 inch are provided at equal intervals along the circumference of a circle concentric with the center of the carousels 601 and 602 having a diameter of 4 inches.
The carousels 601 and 602 are bolted to the bearing assembly fixed to the drive shaft through the four holes 611, so that the carousels 601 and 602 are balanced on the bearing assembly so as to achieve controlled rotation. Has been converted.

In the preferred example, two rectangular openings 613, 614 are provided in each carousel 601.
, 602 are formed with a plurality of portions 618. This carousel 601, 602
The size of the opening of the upper surface 613 is slightly larger than the sizes of the trays 214, 216, and 224. The length and width of the top opening 613 are, for example, 5.95 inches and 4.187 inches, respectively. This carousel 601, 602
The size of the opening of the bottom surface 614 is slightly smaller than the sizes of the trays 214, 216, and 224. In this way, the size of the bottom opening 614 is slightly smaller, so that the peripheral portions of the trays 214, 216, and 224 are placed on the portion 618. The length and width of this bottom opening 614 are, for example, 5.45 inches and 3.687 inches, respectively. A recess 615 is formed in each portion 618 on each carousel 601, 602 to match the tabs (ears) of the trays 214, 216, 224 to ensure proper orientation.

In a preferred example, the notch 620 is an opening that is entirely divided by the carousels 601 and 602. In this example, the movable member of the motor 605 moves within the periphery of the carousels 601 and 602 to avoid hitting the carousels 601 and 602. Because this opening is carousel 601,6
This is because it is entirely separated by 02.

In another example, the cutouts 620 are partially delimited by the carousels 601, 602 and are not delimited along the peripheries of the carousels 601, 602.
In this example, the movable member of the motor 605 need not move within the perimeter of the carousels 601, 602 to avoid hitting the carousels 601, 602. This is because this opening is not divided along the peripheral edges of the carousels 601 and 602. Therefore, the movable member of the motor 605 may be movable outside the peripheral edges of the carousels 601 and 602 in this example.

The sequencer module 600 (FIG. 11) also includes various components described above that are operated in conjunction with a stacked dual carousel device to perform electrophoresis. These members include a CCD camera 408, a laser 452, a high pressure chamber 422, an array of capillary tubes 454, an optical window region 130, and an enclosure forming the coolant region 300. The solvent / gel transfer module 800 described below with reference to FIGS. 14A to 14C sends the solvent or gel to the sequence module 600 via the solvent / gel inlet 606.

FIG. 13 illustrates the operation of the stacked dual carousel device described in FIGS. 11, 12A and 12B. After the solvent / gel transfer module 800 fills the capillary array 454 with gel in step 705, the motor 608 and rotor 604 are driven by the controller 404, as described in more detail below in FIGS. 14A-C. The carousel 602 rotates to place the notches 620 underneath the needle array 603 in step 700.1 to prevent the trays 216, 224 on the lower carousel 602 from moving vertically in a later step 700.2. ing. The controller 404 also sends commands to the motor 608 and rotor 604,
The upper carousel 601 is rotated to position the sample tray 214 below the needle array 603 in step 700.1.

In Step 700.2, the controller 404 drives the motor 605,
The sample tray 214 of the upper carousel 601 is moved along the common axis towards the needle array 603. At step 700.3, the controller 404 increases the gas pressure in the high pressure region 422 or applies a voltage to transfer the sample from the sample tray 214 to the capillary array 454. In step 700.4, the controller 404 drives the motor 605 to move the sample tray 214 along the common axis away from the needle array 603.

As shown in FIG. 13, feedback is provided from the stacked dual carousel device to the controller 404, ensuring that the controller 404 issues its command at the correct time. For example, an encoder 61 that operatively engages the rotor 604.
2 sends feedback to the controller 404 indicating position 1 of the carousels 601, 602. However, until the carousel position feedback 1 indicates that the sample tray 214 on the upper carousel 601 is below the needle array 603, the controller 404 will continue in step 700.2 to the sample tray 214.
The command for moving the motor to the capillary inlet 603 is not transmitted to the motor 605.

Similarly, the ammeter of motor 605 sends feedback to controller 404 indicating the vertical position of sample tray 2. However, the tray position feedback 2
Controller 404 does not communicate a command to move the sample to capillary array 454 at step 700.3 until sample tray 214 indicates that it has been moved below needle array 603.

The pressure transducer in the high pressure region 422 transmits the pressure value in this region (valve state 3) to the controller 404. However, the valve state feedback 3 is
The controller 404 proceeds to step 70 until it indicates that the 22 valves are in the correct position.
At 0.4, the command for moving the sample tray 214 away from the capillary tube inlet 603 is not transmitted via the motor 605. Finally,
Until the tray position feedback 2, as determined by the ammeter of the motor 605, indicates that the sample tray 214 has returned to the upper carousel 601, the controller 404 directs step 701 to introduce buffer into the capillary array 454. Do not convey.

Following completion of step 700, as indicated by tray position feedback 2, the sequence module 600 introduces buffer solution into the capillary array 454 in step 701. In step 701.5, controller 404 drives motor 608.
Also, the rotor 604 is driven to rotate the upper carousel 601 so that the notch 620 is located below the needle array 603. Also, step 70
At 1.5, the controller 404 drives the motor 608 and rotor 604 to rotate the lower carousel 602 so that the buffer tray 216 is located under the needle array 603.

In step 701.6, the motor 605 is driven by the controller 404 to move the buffer solution tray 216 from the lower carousel 602 to the needle array 603 through the notch 620 of the upper carousel 601. In step 701.7, the controller 404 activates the ultrasonic transducer to rinse the capillary tube inlet 603.

At step 701, feedback is provided from the stacked dual carousel device to the controller 404 to ensure that the controller 404 issues its command at the correct time. That is, the encoder 612 provides feedback indicating the position 5 of the lower carousel 602 and the position 5 of the upper carousel 601 to the controller 40.
Send to 4. However, the carousel position feedback 5 causes the upper carousel 601 to
Until the notch 620 and the buffer tray 216 of the lower carousel 602 are below the needle array 603.
6, the command for moving the buffer solution tray 216 to the capillary tube inlet 603 is not transmitted to the motor 605.

Similarly, the ammeter of the motor 605 sends feedback to the controller 404 indicating the vertical position of the buffer tray 216. However, until the tray position feedback 6 indicates that the buffer tray 216 has been moved below the needle array 603, the controller 404 does not communicate the command to activate the ultrasonic transducer in step 701.7. Finally, the ultrasonic transducer
Feedback indicating the state is sent to the controller 404. Controller 404 does not initiate electrophoresis in step 702 until transducer state 7 indicates that capillary inlet 603 has been rinsed.

The stacked dual carousel device was loaded with the capillary array 4 in step 704 as described below in the description of the solvent / gel transfer module of FIGS.
54 is reproduced. In Step 704.15, the controller 404 drives the motor 608 and the rotor 604 to rotate the upper carousel 601.
The cutout portion 620 is arranged below the needle array 603. Further, in step 704.15, the controller 404 drives the motor 608 and the rotor 604 to rotate the lower carousel 602, and the waste liquid tray 224.
Are placed underneath the needle array 603. In step 704.16, the motor 605 is driven by the controller 404 to move the waste liquid tray 224 from the lower carousel 602 to the needle array 603 via the cutout portion 620 of the upper carousel 601.

In a preferred example, as previously described in the description of the stacked dual carousel device, the controller 404 issues commands to the members of the electrophoretic device for electrophoresis and DNA.
Manipulate the analysis. Therefore, the controller 404 operates the work listed in the left column of FIG. The data processing computer 406 is used exclusively to process the data obtained from performing the DNA analysis (step 703). This is because DNA data processing is typically computationally intensive. Therefore, the data processing computer 406 operates the operations listed in the right column of FIG. Controller 4
04 and data processing computer 406 are connected to a local area network and are connected via a data processing user equipment interface 706.

14A-C illustrate a solvent / gel transfer module 800, which is D
After NA analysis, it is used to regenerate the capillary array 454 and to refill the capillary array 454 with gel. That is, FIG.
14B shows a front view of the gel transfer module 800, FIG. 14B also shows its side view, and FIG. 14C shows its rear view. During DNA analysis, the sample is moved from the capillary inlet 603 of FIG. 11 through the capillary array 454 from right to left.

During the regeneration of the capillaries, the solvent is transferred from the solvent containers 801 to 803 shown in FIG. 14A through the solvent / gel inlet 606 of FIG. 11 and further to the sequence module 6 of FIG.
00 through the capillary array 454 from left to right. Similarly, during refilling of the capillary array 454 with gel, the gel is passed from the gel syringe 804 shown in FIG. 14B through the solvent / gel inlet 606 of FIG. 11 and further through the capillary array 454 of the sequence module 600 of FIG. Moved from left to right.

The solvent containers 801, 802 and 803 store methanol, water and soapy water, respectively. Feeder tube 806 in each solvent container 801 to 803
Transfers the solvent towards the HPLC pump and wash solvent system 807. Similar to the previous example, this wash solvent system 807 comprises a high pressure cell (HP cell) that produces a pressure increase to effect more rapid regeneration of the capillary array 454.

The support rails 808 provide the structure necessary to hold the components of the solvent / gel transfer module 800. This member includes solvent containers 801-803 and a gel syringe 80.
4. Includes HPLC pump, wash solvent system 807 and controller 404. The controller 404 regenerates the capillary array 454 and refills the capillary array 454 with gel material via the other components of the solvent / gel transfer module 800.

15A-C illustrate the gel syringe 804 shown in FIG. 14B in more detail. In contrast to the solvent in solvent containers 801-803, the gel is too viscous to pump. Therefore, in the electrophoresis apparatus, the gel syringe 804 is used for transferring the gel. The gel syringe 804 has a gel tube carriage 891, in which a gel cartridge containing a gel substance 892 is held. Since this gel cartridge is of the disposable type, it can be removed from the gel tube carriage 891 after refilling the capillary array 454 with gel material and used in subsequent electrophoresis and DNA analysis runs. It is replaced with a new gel cartridge.

The stepper motor linear actuator 893 has a movable actuator shaft 897 having a pressing member 898. The front surface of the pressing member 898 is in contact with the Teflon plunger 894 arranged at one end of the gel syringe 804, and the gel substance is transferred through the syringe cap 899 and the high pressure attaching member 895 provided at the other end of the gel syringe 804. It is supposed to be distributed. The controller 404 shown in FIG. 14C selectively drives the stepper motor linear actuator 893 to control gel transfer. The cylindrical tube 896 is a gel syringe 80.
4 outer structure is formed. The O-ring has a gel material 892 and a high pressure mounting member 895.
It prevents leakage from around the Teflon plunger 894 when moving toward.

In a preferred example, a stepper motor linear actuator (AMSI
(Available from Corporation, Smithtown, NY) can output a linear force of 140 pounds and can expel 10 mL of gel with 6,000 pulses. The cylindrical tube 896 is made of standard acrylic resin, and the syringe cap 899 is made of stainless steel. This high pressure mounting member 895 is Swagel
available from ock.

FIG. 16 illustrates solvent / solvent gel syringe 804 and HPLC wash solvent system 807.
It is shown integrated into a gel transfer module 800. Solvent manifold 8
Reference numeral 50 connects the three inlets from the feeder tube 806 of the solvent containers 801 to 803 to the outlets. The feeder tube 806 from the solvent containers 801-803 is connected to the inlet of the solvent manifold 850 by a tube 860. 14
The controller 404 shown at C controls the solvent manifold 850 to select one solvent from the three solvent containers 801-803. The inlet of the HPLC pump 807 is connected to the outlet of the solvent manifold 850 via the tube 861, and the outlet of the HPLC pump 807 is connected to the inlet of the valve manifold 851 via the tube 862.

The valve manifold 851 connects the two inlets and outlets. One inlet of the valve manifold 851 is connected to the gel syringe 804 via a tube 863,
The other inlet of the valve manifold 851 is connected to the outlet of the HPLC pump 807. The outlet of the valve manifold 851 is connected to the solvent / gel inlet 606 via a tube 864. The controller 404 shown in FIG. 14C includes an inlet or HPLC pump 8 connected to a gel syringe 804 via a valve manifold 851.
One of the entrances connected to 07 is selected.

In a preferred example, the tube 860 connecting the feeder tube 806 of the solvent containers 801 to 803 to the inlet of the solvent manifold 850 comprises a standard Teflon tube with a diameter of 1/8 inch. The tube 861 connecting the outlet of the solvent manifold 850 to the inlet of the HPLC pump 807 is a PEEK tube having a diameter of 1/16 inch. In addition, the outlet of the solvent manifold 850 is HP
Tube 861 connected to the inlet of LC pump 807, HPLC pump 80
A tube 862 connecting the outlet of 7 to the inlet of the valve manifold 851, and a tube 863 connecting the gel syringe 804 to the inlet of the valve manifold 851.
, And the tube 864 connecting the outlet of the valve manifold 851 to the solvent / gel inlet consists of PEEK tubing with a diameter of 1/16 inch.

In a preferred example, this HPLC pump 807, available from Alltech Corporation (Model No. 301300), has a non-metallic pump head. Also available from All-Tech Corporation (Model N
o. 97500) This valve manifold 851 is a non-metal valve.

FIG. 13 illustrates the operation of the solvent / gel transfer module 800 shown in FIGS. 14A and 16. Following the DNA analysis in step 703, the correct rotational position of the carousels 601 and 602 in step 704.15, and the accurate movement of the waste liquid tray in step 704.16, the controller 40 in step 704.17.
4, the solvent / gel transfer module 800 is driven, and the used gel is discharged from the capillary array 454 via the HP cell.

As shown in FIG. 16, the controller 404 is used to discharge the used gel.
Selects the inlet from the water container 802 via the solvent manifold 850,
Also, the inlet is selected from the HPLC pump 807 via the valve manifold 851. This HPLC pump 807 transfers water from the solvent manifold 850 to the HP cell via the valve manifold 851 and, as described above, the capillary array 45.
4, resulting in a pressure increase for a more rapid regeneration. The waste tray 852, which was moved correctly in step 704.16, collects the used gel from the capillary array 454.

After the gel is removed from the capillary array 454, the solvent / gel transfer module 800 is driven by the controller 404 at step 704.18, and the HP
The rinse solution is passed through the cell into the capillary array 454. In order to perform this rinsing, as shown in FIG. 16, the controller 404 controls the solvent manifold 85.
The inlet is selected from the methanol container 801 via 0 and the inlet from the HPLC pump 807 via the valve manifold 851. The HPLC pump 807 transfers methanol from the solvent manifold 850 through the valve manifold 851 to the HP cell, causing a pressure increase for a more rapid rinse of the capillary array 454 as previously described. The waste tray 852, which was moved correctly in step 704.16, collects the spent solvent from the capillary array 454.

After rinsing the capillary array 454 with methanol, the controller / 404 drives the solvent / gel transfer module 800 to rinse the capillary array 454 with soap solution from the container 803. In order to perform this rinsing, as shown in FIG. 16, the controller 404 controls the solvent manifold 85.
0, the inlet is selected from the soap container 803, and the valve manifold 851
The inlet is selected from the HPLC pump 807 via. This HPLC pump 8
07 is HP for the soap liquid from the solvent manifold 850 through the valve manifold 851.
Transfer to the cell, causing an increase in pressure for a more rapid rinse of the capillary array 454 as described above. The waste tray 852, which was moved correctly in step 704.16, collects the spent solvent from the capillary array 454. Further, the solvent / gel transfer module 800 is driven by the controller 404, and the regeneration treatment with the solvent from the three solvent containers 801 to 803 is continued until the cleaning of the capillary array 454 is completed.

Feedback is provided from the solvent / gel transfer module to the controller 404, as shown in FIG. 13, to ensure that the controller 404 issues its command at the correct time. For example, controller 404 may wait until HP pump status feedback 17 indicates that gel has been ejected from capillary array 454.
The solvent / gel transfer module 800 is driven to remove the rinsing liquid from the capillary array 45.
Do not pass to 4. Similarly, the controller 404 issues a command to refill the capillary array 454 with gel material at step 705 until the HP pump status feedback 18 indicates that the capillary array 454 has been rinsed with methanol and soapy water. There is no.

In a preferred aspect, controller 404 determines HP pump status feedback 17. The controller 404 calculates the HP pump status feedback by calculating the amount of solution passing through the capillary array 454 from the HP pump flow rate specified by the manufacturer and by calculating the time elapsed since the pump was started. Judge 17

Following the capillary regeneration in step 704, the solvent / gel transfer module 800 is driven by controller 404 in step 705.19 to refill the capillary array 454 with new gel via the HP cell. To refill the capillary array 454 with new gel, the controller 404 selects an inlet from the gel syringe 804 via the valve manifold 851, as shown in FIG. The gel syringe 804 transfers the gel through the valve manifold 851 to the HP cell, producing a pressure increase for a more rapid refill of the capillary array 454 as previously described. The waste tray 852, which was correctly moved in step 704.16, collects all the solvent or gel that is ejected from the capillary array 454 in step 705.19.

After filling the HP cell and capillary array 454 with gel in step 704.18, the process can be continued in one or two ways. As an example, the gel in the HP cell can be used as a buffer in electrophoresis after step 702. In this case, the process continues with step 705.20. As another example, before step 705.20, solvent /
The gel transfer module 800 is driven to transfer the gel from the HP cell, and the process 70
The HP cell is filled with buffer using a process similar to 4.

Participate the stacked dual carousel in the remaining tasks of step 705. Step 705
． At 20, the controller 404 rotates the upper carousel 602 via the rotor 604 to move the notch 620 below the needle array 603. Further, in step 705.20, the controller 404 rotates the lower carousel 604 via the rotor 604 to move the buffer tray 216 below the needle array 603. Also, in step 705.21, the controller 404 causes the buffer tray 216 to pass from the lower carousel 602 through the motor 605 through the large opening of the upper carousel 601 to the needle array 60.
Move to 3.

Step 705 equilibrates the capillary array 454,
The step of circulating the buffer through step 4 (step 705.22) is completed. Due to the differential pull through the capillary array 454, the bubble and pressure differential will be step 705.1.
It occurs within the gel in capillary array 454 during gel transfer at 9. Step 705.22 removes this pressure differential and bubbles, by equilibrating the capillary array 454 and circulating a buffer solution through the capillary array 454. This technique is similar to electrophoresis in step 702, but
However, in the electrophoresis of step 702, DNA is clearly present, whereas in step 70
The difference in 5.22 is that no DNA is present in the capillary array 454.
Specifically, a voltage is applied across the capillary array 454 to induce relaxation of the gel and movement of buffer through the capillary array 454. Step 705.2
After circulating the buffer through the capillary array 454 at 2, the process for the next DNA analysis is begun, beginning with introducing the sample at step 700.

As in step 704, as shown in FIG.
Feedback from the gel transfer module to the controller 404 continues. The controller 404 processes this feedback to ensure that it issues commands at the correct time. For example, controller 404 does not issue any commands beyond step 705.19 until gel syringe feedback 19 indicates that capillary array 454 has been filled with new gel. Similarly, controller 404 does not issue a command to rotate upper carousel 601 and lower carousel 602 at step 705.20 until HP pump status feedback 19 indicates that the gel has been pumped into capillary array 454. .

In a preferred embodiment, the controller 404 uses gel syringe feedback 1
9 is judged. That is, the gel syringe feedback 19 is determined by calculating the amount of the solution passing through the capillary tube array 454 from the replacement speed of the gel syringe and calculating the elapsed time after the gel syringe is started.

Similarly, in step 705, the encoder operatively engaged with rotor 604 sends feedback to controller 404 indicating the position of carousel 20. However, the carousel position feedback 20 indicates that the large opening in the upper carousel 601 and the buffer tray 216 in the lower carousel 602 causes the needle array 60
Controller 404, until it is shown below.
At 21, the command for moving the buffer tray 216 is not issued.

The ammeter of the motor 605 also sends feedback to the controller 404 indicating the vertical position of the buffer tray 216. However, until the tray position feedback 21 indicates that the buffer tray 216 has been moved to the needle array 603, the controller 404 does not communicate the command to circulate the buffer solution to the capillary array 454 in step 705.22. . Finally, the controller 404 receives feedback about the high voltage state of the capillary tube current 22. It should be noted that the controller 404 does not proceed to step 700 for introducing the next DNA sample until the high voltage state 22 indicates that the buffer is circulating through the capillary array 454.

FIG. 17 shows an off-line capillary regenerator 900, which is used to regularly clean the capillary cartridge 909. To completely clean the capillary cartridge 909, the operator removes it from the automated electrophoresis system and attaches it to the offline capillary regenerator 900. Thus, the operator can mount another clean capillary cartridge 909 in the automated electrophoresis system and perform DNA analysis with this capillary cartridge while the previously used capillary cartridge 9 is used.
09 is completely cleaned with the offline capillary regenerator 900. Although it takes 20 to 30 minutes to completely clean the capillary cartridge, it is not necessary to wait until the capillary cartridge 909 is completely cleaned during the continuous execution of DNA analysis. It will improve the throughput of the system.

This offline capillary regenerator 900 is a low cost and simplified version of the solvent / gel transfer module 600 described above with reference to FIG. This is because it does not include all items included in the solvent / gel transfer module 600. For example, the offline capillary regenerator 900 does not have a camera, laser or gel syringe. Further, the offline capillary regenerator 900 does not include a gel syringe for transferring gel. This is because if the gel is delivered off-line prior to moving the capillary cartridge, undesired curing of the gel during transfer of the capillary cartridge from the off-line capillary regenerator 900 to the automated electrophoresis system will result in capillary array 454.
Because it can occur at the end of the. The simplicity of this offline capillary regenerator 900 provides the advantage of increasing system throughput at low cost.

The solvent containers 901, 902 and 903 store methanol, water and soapy water, respectively. Feeder tube 906 in each solvent container 901-903
Transports the solvent towards the solvent manifold 905. This solvent manifold 9
05 connects three inlets to one outlet. The three inlets of this solvent manifold are connected to the feeder tubes 906 of the solvent containers 901-903 to establish a one-to-one correspondence between the set of inlets and the set of feeder tubes 906.

The HPLC pump 906 has one inlet, which is connected to the outlet of the solvent manifold, and the HPLC pump 906 also has one outlet, which outlet is at one end of the capillary cartridge 909, the solvent inlet 907. It is connected to the. The off-line capillary regenerator 900 also has an HP cell, similar to the solvent / gel transfer module 600 described in FIG. 14A, which creates a pressure increase for a more rapid regeneration of the capillary cartridge 909. The controller also controls the operation of the solvent manifold 905 and the HPLC pump 906. The waste liquid container 904 collects the waste liquid during the capillary regeneration at the other end of the capillary cartridge 909.

In a preferred example, the controller is a simple low cost digital signal processing system that accepts status feedback and commands the HPLC pump 906 and solvent manifold 905 in a predetermined order as described below. Emit. Alternatively, a general-purpose computer such as a personal computer may be used to execute a simple control program to manage the offline capillary regenerator.

After the operator mounts the capillary cartridge 909 on the off-line capillary regenerator 900, the internal controller selects the inlet from the water container 901 via the solvent manifold, and the HPLC pump 906 is operated. H
The PLC pump 807 transfers water from the solvent manifold 850 to the HP cell, creating a pressure increase for a more rapid regeneration of the capillary cartridge 909 as before. The waste liquid container 904 that has been correctly moved beforehand is the capillary cartridge 9
Collect used gel from 09.

After this gel is removed from the capillary cartridge 909, the offline capillary regenerator 900 allows the capillary cartridge 90 to pass through the HP cell.
A rinse of 9 is performed with methanol. First, the controller selects the inlet from the methanol container 902 via the solvent manifold 905.
The HPLC pump 906 transfers the methanol from the solvent manifold 905 to the HP cell, creating a pressure increase for a more rapid regeneration of the capillary cartridge 909. The waste liquid container 904 that has been correctly moved in advance is the capillary cartridge 9
Spent solvent from 09 is collected.

Next, the offline capillary regenerator 900 rinses the capillary cartridge 909 through the HP cell using the soap water from the container 903. First, the controller selects the inlet from the soap container 903 via the solvent manifold 905. The HPLC pump 906 transfers soapy water from the solvent manifold 905 to the HP cell, creating a pressure increase for a faster rinse of the capillary cartridge 909. The waste liquid container 904, which has been correctly moved in advance, collects the used solvent from the capillary cartridge 909. Controller 40
4, the off-line capillary regenerator 900 is driven to drive the three solvent containers 8
The solvent regeneration process from 01-803 is repeated until the washing of the capillary array 454 is complete.

FIG. 18 illustrates another preferred example of the capillary cartridge 1180. In this example, the capillary tube is the electrode / capillary array 1
Extends from a first end 1188 located within 181. These capillary tubes then pass inside the multi-lumen tube 1183. This multi-lumen tube is detailed in US patent application Ser. No. 08 / 866,308, which is hereby incorporated by reference. The multiple lumen tube 1183 is held in place by a tube holder 1185.
Also, these capillary tubes pass through the optical sensing area 1187 without protection by multiple lumen tubes. Beyond this optical sensing area 1187, the capillary tubes have a common end, are bundled together and secured in a high pressure T-shaped mounting member 1182 of conductive material. The mounting member 1182 is grounded during electrophoresis.

The tube holder 1185 and the T-shaped attachment member 1182 are fixed to the cartridge base 1186. Cartridge base 1186 is made of polycarbonate for electrical insulation. The base 1186 is detachably attached to the shuttle 1179. The shuttle 1179 comprises a set of rail couplings 1184 protruding from its bottom. These rail couplings 1184 are arranged to fit into the rail system (not shown in FIG. 18) of the sequencer module 400 in FIG. 10 or the sequencer module 600 in FIG. This rail system allows shuttle 1179 to move in and out of position. Also, this base 1186 is the shuttle 117
9 to allow the cartridge 1180 to be discarded (or washed) and a new (or cleaned) capillary cartridge to be installed when the shuttle 1179 is removed from its position. This rail system and shuttle 11
In combination with 79, the newly installed capillary cartridge is placed in the same position as the discarded capillary cartridge in relation to the camera and laser (not shown in FIG. 18) when shuttle 1179 is in place. It is possible to repeat the arrangement.

In the preferred example, the shuttle 1179 includes an electrode / capillary array 118.
Extend the length of the base 1186 with an opening that accommodates 1. In other words, the shuttle 1179 has a plurality of detachable fasteners 1178 and is used as a base 118.
It is attached to 6.

The electrode / capillary array 1181 is held in place by the current supply / monitor board 1190 shown in FIG. The board 1190 is preferably a printed circuit board for high voltage supply.

The board 1190 preferably includes a plurality of large holes 1193 so that a set of fasteners can be used to attach the board 1190 to the base 1186. However, the board 1190 may be attached to the base 1186 using any other means, such as gluing.

The board 1190 further comprises a plurality of tube holes 1194 arranged to align with holes provided in the base 1186. This allows the board 1190
The first end of the capillary tube may project through the tube hole 1194 when attached to the base 1186. Multiple pins 1195
(Preferably gold plated) is further disposed on the board 1190. Position at least one pin in close proximity to each tube hole to provide a pin and hole pair 119.
2 is formed. Each pin and hole pair 1192 is dipped into the sample well of the sample microtiter tray.

The board 1190 is further provided with a high voltage lead wire 1198. The lead wire 1198 connects each pin 1195 to a corresponding connector terminal 1196 formed around the board 1190. Each connector terminal 1196 is preferably configured to receive a high voltage connector with about 50 electrical connections. This high voltage connector has a lead wire 1198 connected to a high voltage power supply (
It is preferably connected to a power supply line from Bertan (not shown in FIG. 19). This ensures that when the capillary tube is filled with gel, pin 1
A closed electrical circuit is formed from 195 to the second electrode connected to the high voltage T-shaped mounting member 1182. This second electrode is preferably connected to the ground of the system.

In addition, the high voltage connector is also connected to a current monitor that monitors the current. In current monitoring, the current flowing through each power supply line is preferably monitored in multiple power supply lines simultaneously or sequentially. This makes it possible to perform integrated current measurement by this current monitor.

FIG. 20 shows a multi-wavelength beam generator. This wavelength beam generator is a laser head 1200, preferably 457 nm, 476 nm, 488 nm, 496.
An argon ion laser capable of generating a multi-wavelength laser beam with wavelengths of nm, 502 nm and 514 nm is provided. The beam generator further comprises a laser emitter tube 1207. The laser emitter tube 1207 is connected to the argon ion laser 1200 by an optical coupling assembly 1202.

The optical coupling assembly 1202 includes a fiber coupler 1201 connected to the laser head 1200, and an optical fiber cable 120 connecting the fiber coupler 1201 to the laser emitter tube 1207.
3 and 3. This fiber coupler 1201 has a laser head 12
00 is aligned with the colorless optical fiber cable 1203. The optical coupling assembly 1202 allows the laser emitter tube 1207 to be located far away from the laser head 1200 and produces a laser beam, or coherent light, at the laser emitter tube 1207. Furthermore, this allows the heat-generating laser head 1200 to be positioned in the less sensitive area of the sequencer.

The laser emitter tube 1207 comprises a one-dimensional concentrator 1208. The one-dimensional concentrator 1208 is preferably a positive cylindrical optical lens with a focal length of 10 cm and is placed at the output end 1204 of the laser emitter tube 1207. This laser emitter tube 1207 is further provided with an optical fiber cable 1
A fiber emitter tube 1205 for receiving 203 and a beam expander 1209, preferably a negative tubular optical lens with a focal length of 1.9 cm, disposed between the fiber emitter tube 1205 and the one-dimensional concentrator 1208. It is equipped with. The laser emitter tube 1207 is preferably contained within a 1 inch inner diameter and 6 inch long tube.

FIG. 22 schematically shows the optical processing performed by the laser emitter tube 1207. The laser light generated by the fiber emitter tube 1230 is expanded by the beam expander 1231. This laser light is then focused by the one-dimensional focusing device 1233 in only one direction. The resulting beam is directed towards the capillary array 1235. The resulting laser beam is narrowed in one direction and elongated in the other direction. 22A
~ C show the footprint of the laser beam in each process step.

FIG. 21 shows another example of the multi-wavelength beam generator, which shows two laser heads 1.
211 and 1215 are provided. The first laser head 1211 is similar to the laser head 1200, and the second laser head 1217 is for generating laser beams of different wavelengths. This second laser head 1217 is preferably a solid-state laser that produces a laser beam with a wavelength above 532 nm. As another example, the second laser head 1217 generates a multi-wavelength laser beam having a different wavelength from the beam generated by the first laser head 1211.

In this example, two optical coupling assemblies with fiber couplers 1213, 1217 and optical fiber cables 1225, 1221 are provided. The two optical coupling assemblies function similarly to the optical coupling assembly 1202 of FIG. The laser beams generated by the two laser heads 1211, 1215 and delivered by this optical coupling assembly are combined in a laser emitter tube 1224 designed to receive the laser beams from the two laser sources.

This laser emitter tube 1224 has two input terminals 1210 and 121.
2 and one output terminal. That is, the first fiber emitter tube 1227 that receives the laser beam from the first laser head 1211 is located at the portion of the first input terminal 1210; the second fiber that receives the laser beam from the second laser head 1215. The emitter tube 1223 is located at the location of the second input terminal 1212; the one-dimensional concentrator 1226 (preferably having a focal length of 10c).
m positive cylindrical optical lens that outputs a combined laser beam)
Is located at the position of the output terminal 1214.

The laser beams received by the first and second fiber emitter tubes 1227, 1223 are combined by a dichroic filter 1229. The dichroic filter 1229 transmits the laser beam from the first fiber emitter tube 1227 and reflects the laser beam from the second fiber emitter tube 1223, whereby the first and second fiber emitter tubes 1227, The laser beam from 1223 is combined.

The beam expander 1222, which is preferably a negative cylindrical optical lens having a focal length of 1.5 cm, includes the dichroic filter 1229 and the one-dimensional concentrator 12.
And 26. This beam expander 1222 and concentrator 1226
22 and 22A-C optically function substantially similar to the optical processes described in FIGS.

In a preferred example, the polarization in the laser heads 1200, 1211, 1215 is removed to maximize laser power. In the example described in FIG. 21, the combination of multi-line and unpolarized emission increases the laser power by more than 4 times compared to a polarized single line laser.

FIG. 22 shows a laser beam applied to the capillary array 1235 without an angle. However, as shown in FIG.
The citation configuration) improves the coupling efficiency of pump laser light in the detection window.
This further reduces the laser power required to excite the 96 (or more) capillary array, allowing the use of a portable air-cooled argon ion laser in the DNA sequencer instrument. In other words, the multi-wavelength laser emitter tube described in FIG. 20 or 21 retains the focusability of the laser beam over a wide range of capillary arrays while maintaining a large number of capillary arrays (eg,
Aligned to illuminate 1000 capillary tubes).

24 and 25 show a CCD camera 1257 and a laser emitter tube 1243.
It shows the one combined with. As a preferred example, the laser emitter tube 1243 is placed perpendicular to the surface of FIG. 25 with a small tilt angle, so that the laser beam from the laser emitter tube 1243 will hit the capillary array 1200 as shown in FIG. .

The laser emitter tube 1207 is arranged at the same level as the capillary detection window, and the beam emitting end of the laser emitter tube 1207 faces in the direction opposite to the operator. As a preferred example, the laser emitter tube 12
07 is fixed to the lower end of a tube control arm 1267 rotatably connected to the arm mount 1265. The arm mount 1265 is attached to the lower end of the flexible rotor 1261. The upper end of the rotor 1261 is connected to a dial accessible from outside the sequencer. The arm mount 1265 is further mounted on the laser emitter positioning rail 1255 so that it can be moved by the arm mounting position controller 1253. By using such a dial and controller 1253, the laser emitter tube 1207 can be optimally arranged for irradiating the capillary array with the output laser beam.

The CCD camera 1257 is mounted on a camera mount (not shown in FIG. 25), which is mounted on the laser emitter positioning rail 1255. A camera rotation cable (not shown in FIG. 25) causes the CCD camera plate to move horizontally on rails 1255. Camera focus gear 127
1 is connected to the gear control cable 1254, and the CCD camera lens assembly 1
The movement of 269 is controlled. C by the preceding camera controller
The focus of the CD camera 1257 is focused on the portion of the capillary array illuminated by the laser beam from the laser emitter tube 1243.

Another preferred example of a high viscosity liquid transfer system is shown in FIG. This transfer system comprises a high pressure chamber 1401 holding a low viscosity liquid 1413 such as water,
A disposable disposable bag 1411 containing a high viscosity liquid such as gel.

The high pressure chamber 1401 is preferably a cylinder (cylindrical body) made of metal such as aluminum or stainless steel so as to withstand an internal pressure of up to 2000 psi.
1402 is provided. That is, it comprises a substantially hollow body having a closed bottom and an open top. A cap 1404 is detachably attached to the top of the cylinder 1402. The cylinder 1402 and the cap 1404 form a high-pressure chamber 1401, and the liquid 1413 and the disposable bag 1411 are formed.
Is housed.

This gel container 1411 is removably attached to the outlet assembly 1410 (preferably by Swagelock 1409). As the pressure in the chamber increases, viscous liquid is forced through the outlet assembly 1410. The outlet assembly 1410 is fitted to the cap 1404 using a liquid tight fitting (available from Swagelock). The outlet assembly 1410 further comprises a gel discharge tube 1403. Since the pressure around the compressible gel bag 1411 is uniformly applied by the liquid 1413, the pressure resistance requirement of the gel container can be minimized. Therefore, the gel bag 1411 is
It can be economically made from disposable bags that have sufficient capacity for multiple runs of gel.

The pressure inside the high pressure chamber 1401 is controlled by the pressure control assembly 1406.
Can be increased or decreased by. When more liquid is supplied to the chamber 1401 by the pressure control assembly 1406, the pressure inside the chamber 1401 increases. When this internal pressure increases due to excess liquid, or when the cap 1404 is opened and the bag 1411 is replaced, the liquid in the chamber 1401 is released by the pressure control assembly 1406, reducing its internal pressure.

The pressure control assembly 1406 includes a high pressure pump 1423 controlled by the controller 1404. As a preferred example, the high pressure pump 1423 is composed of another HPLC pump. The pressure control assembly 1406 further includes an inlet tube 142 connected to a pump 1423.
1 which is fitted to the bottom of the cylinder by a liquid tight mounting member 1419.

An outlet tube 1427 is also provided on the pressure control assembly 1406. This outlet tube 1427 is preferably the second liquid-tight mounting member 14
It is fitted to the bottom of the cylinder 1402 by 17. The outlet tube 1427 is provided with a release valve 1425 and a pressure transducer 1429 for generating a feedback signal (preferably less than 6 volts) which is in communication with the controller 1404. Release valve 14
25 is controlled by the controller 1404.

The controller 1404 may preferably be configured as a part of the central computer controller 404 shown in FIG. 10 to save space. However, as another example, the central computer controller 404 may be replaced by another type of controller, such as another computer, microprocessor or other electronic device capable of controlling water pumps and valves.

By monitoring a feedback signal indicative of the pressure within chamber 1401, controller 1404 functions as follows: (1) Chamber 140
When the pressure in 1 needs to be increased to some extent, controller 1404
The PLC pump 1423 is driven to introduce liquid into the chamber 1401 via the inlet tube 1421; or (2) when the pressure in the chamber 1401 needs to be reduced to some extent, the controller 1404 opens the release valve 1425. ,
The liquid is released from the chamber 1401. Once a sufficient amount of gel has been extruded, the pump is stopped and the pressure in the chamber is reduced, returning it to its original equilibrium state. The preferred gel filling pressure is 500 psi.

FIG. 27 shows the solvent / gel transfer module 1 used to regenerate the capillary tube array and refill the gel into the gel array after DNA analysis.
A preferred example of 800 is shown. FIG. 28 shows the solvent / gel transfer module 18
It is a rear view of 00. This solvent / gel transfer module 1800 is preferably located adjacent to the sequencer. This solvent / gel transfer module 1800
The purpose is to provide continuous and automatic gel transfer and capillary tube regeneration.

FIG. 29 illustrates a high pressure gel transfer system 1805 (gel transfer syringe 804 of FIG. 16 or high pressure chamber 1401 of FIG. 26) and solvent / gel transfer module 18 of FIG.
It is shown that it is combined with 00. In this preferred example, solvent manifold 1850 connects the four inlets from feeder tubes 1806 of solvent containers 1801-1804 to one outlet. Feeder tubes 1806 from solvent containers 1801-1804, two bottles filled with methanol, one bottle filled with polyvinylpyrrolidone (PVP) (preferably 2% PVP), and one filled with buffer. The bin is connected to the inlet of the solvent manifold 1850. H
The inlet of the PLC pump 1807 is connected to the outlet of the solvent manifold 1850 by a pump connecting tube 1861. The outlet of the HPLC pump 1807 is connected to the inlet of the solvent manifold 1850 by a pump outlet tube 1862. The outlet from the HPLC pump 1807 (not shown in Figure 29) is connected to the high pressure chamber 1805 as previously described.

The valve manifold 1851 connects two inlets to one outlet. One inlet of this valve manifold 1851 is connected to the gel transfer system 1805 by a gel outlet tube 1863. The other inlet of the valve manifold is the HPLC pump 1
It is connected to the outlet of 807. The outlet of the valve manifold 1851 is connected to the liquid transfer chamber 1810 (preferably the high pressure T-shaped mounting member 1182 of FIG. 18) via a manifold outlet tube 1864. The liquid transfer chamber 1810 has a purge valve 186 for discharging the waste liquid therein into a waste liquid container 1865.
7 is provided.

The controller 404 shown in FIG. 10 includes a solvent manifold 1850, an HPLC pump 1807, a pressure control assembly for the gel transfer system 1805, a valve manifold 1851, and a drain valve 1867 to control connected components. Each has a connection.

For example, controller 404 controls solvent manifold 1850 to select a solvent from four solvent containers 1801-1804, or valve manifold 185.
Drive 1 to select the inlet connected to chamber 1804 for receiving gel or the inlet connected to HPLC pump 1807 for receiving solvent.

As a preferable example, the pump connection tube 1861 and the pump outlet tube 186 are provided.
2 and the length of the manifold outlet tube 1864 is minimized to reduce gel and solvent waste. In particular, the pump connection tube 1861 and pump outlet tube 1862 retain old solvent when new solvent needs to be fed to the valve manifold 1851, which wastes this old solvent. Similar waste occurs between the solvent and gel in the manifold outlet tube 1864. Therefore,
The length of this manifold outlet tube 1864 is less than 50 cm, preferably 25
It is less than 10 cm, more preferably less than 10 cm.

As shown in FIG. 28, the solvent / gel transfer module 1800 has a blower 1801 for the laser head located in the sequencer. This laser head is housed on the bottom of the sequencer module. The cooling blower is designed to suck air from the sequencer module and blow it to the exhaust of the washer module 1800. As a result, cold air travels across the laser and is unlikely to cause significant disruption to the sequencer module. A 5 inch diameter flexible hose is connected from the rear of the laser towards the blower intake.
The hot exhaust gas is carried out via another 5 inch diameter hose (connected to the ceiling duct) and released to the outside (not shown in Figure 28).

Similar to steps 700 to 703 of FIG. 13, steps 1901, 1903, 1 of FIG.
905 describes the operation of the stacked dual carousel device described in FIGS. 11 and 12A. Since these steps are substantially the same as each other and the differences between them are obvious, detailed description of the steps 1901, 1903, and 1905 will be omitted.

Further, steps 1907, 1909, 1911 and 1912 of FIG. 31 are shown in FIGS.
10 illustrates the operation of the solvent / gel transfer module 1800 described in. This solvent /
The operation of the gel transfer module 1800 is also substantially the same as that of the solvent / gel transfer module 800, and thus redundant description will be omitted. However, the differences shown below will be described.

In step 1907.17, the rinsing step is performed by rinsing the capillary tube with methanol for 24 minutes and then with PVP for 8 minutes. Process 191
At 1.23, the current monitor mounted between the current / monitor board and the power supply is activated. In steps 1912.25 and 1912.26, a rinse tray is utilized for rinsing the first end of the capillary tube and the pins protruding from the current supply / monitor board.

Although the present invention has been described above with reference to some preferred examples, it should be understood that the scope of the present invention is not limited by these examples. That is,
It will be easy for those skilled in the art to make various changes, but these are also included in the scope of the present invention, and the scope is controlled by the claims below.

[Brief description of drawings]

[Figure 1]   FIG. 3 is a side view showing the arrangement of the device of the present invention.

[FIG. 2A]   The top view which shows one example of the cartridge of this invention, respectively.

FIG. 2B   The side view which each shows one example of the cartridge of this invention.

FIG. 3A   FIG. 4 is a side view showing a tube assembly for the cartridge of the present invention.

FIG. 3B   The side view which shows the mounting arrangement of a tube assembly.

[Figure 4]   FIG. 3 is a plan view showing a monitor plate used with a needle row.

FIG. 5 is a plan view showing an arrangement of devices for use with the cartridge shown in FIGS. 2A and 2B.

FIG. 6A   The side view which shows the 2nd example of the cartridge of this invention.

FIG. 6B   The top view which shows the 2nd example of the cartridge of this invention.

FIG. 7 is a side view showing a valve arrangement for a pressure cell similar to that shown in FIGS. 6A and 6B.

[Figure 8]   FIG. 3 is an exploded vertical sectional view of the pressure cell.

FIG. 9 is a plan view of a second mounting plate of a pressure cell having an alternating array of plate holes.

[Figure 10]   The side view which shows the electrophoresis apparatus of this invention.

FIG. 11   FIG. 3 is a side view showing a sequencer module including a stacked dual carousel device.

[Fig. 12]   The figure which shows the carousel contained in a laminated double arrangement in detail.

[Fig. 13]   The flowchart explaining operation | movement of this invention.

FIG. 14A   Front view of the solvent / gel transfer module in the system.

FIG. 14B   FIG. 3 is a side view of a solvent / gel transfer module within the system.

FIG. 14C   Back view of the solvent / gel transfer module in the system.

FIG. 15A   FIG. 3 is a detailed view of a gel syringe included in the gel transfer module.

FIG. 15B   FIG. 3 is a detailed view of a gel syringe included in the gel transfer module.

FIG. 15C   FIG. 3 is a detailed view of a gel syringe included in the gel transfer module.

Figure 16 shows the flow of gel and solvent through the solvent / gel transfer module to the sequencer module.

FIG. 17   The figure which shows an offline capillary regenerator.

FIG. 18   The side view of the capillary cartridge of this invention.

FIG. 19   The top view which shows an electric current supply / monitor board.

FIG. 20   The figure which shows the multi-wavelength beam generator which used one laser head.

FIG. 21   The figure which shows the multi-wavelength beam generator which used two laser heads.

FIG. 22   The side view which shows the optical processing function of a laser emitter tube.

FIG. 22A   FIG. 5 shows the footprint of a light beam at the output of a laser emitter.

FIG. 22B   The figure which shows the footprint of the light beam after passing through a beam expander.

FIG. 22C   The figure which shows the footprint of the light beam after passing through a one-dimensional focusing lens.

FIG. 23 is a diagram showing a direction in which a light beam from a laser emitter strikes a capillary array.

FIG. 24

FIG. 25   The side view which shows the structure around a detection area.

FIG. 26   The side view which shows the high-pressure chamber which supplies a highly viscous gel.

FIG. 27   FIG. 5 shows a solvent / gel transfer module in a preferred embodiment.

FIG. 28   FIG. 5 is a view showing the back surface of the solvent / gel transfer module.

FIG. 29 shows the flow of gel and solvent through a solvent / gel transfer module in a preferred embodiment.

FIG. 30   The flow figure explaining operation in a desirable mode.

─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Li, Quimbo             United States 16801 Pennsylvania             State College, Stanford               Drive 804, Apartment 14 (72) Inventor Liu, Chang Shen             United States 16801 Pennsylvania             State College, Wauperanid             Live 425, Apartment 106 (72) Inventor Sonnenchain, Bernardo             11219 New York,             Brooklyn, 49T Street             To 1519 (72) Inventor Scheler, Michael, and V.             United States 16686 Pennsylvania             State, Tyrone, W. 16 T               Street 701 (72) Inventor Karnan, John, Earl.             United States 17747 Pennsylvania             Box 360, Earl, County Loganton.             R. Number 1

Claims (19)

[Claims] 1. A system for performing capillary electrophoresis on a plurality of samples, the system comprising: a plurality of capillary tubes, each capillary tube having a first end and a second end. And the first end is arranged in a two-dimensional array, the spacing of which corresponds to the spacing of the array of wells of the microtiter tray, and the second end has a common termination. A positioning device comprising upper and lower carousels carrying titer trays, said positioning device such that the two-dimensional array of capillary ends is inserted into corresponding wells of said microtiter tray. One of which is arranged to position; a capillary and a selected one of a plurality of liquids, said capillary. A device arranged to selectively transfer to the second end of the tube; a light source arranged to illuminate the sample; a camera means arranged to detect the light emitted by the sample; A system comprising: 2. The system according to claim 1, wherein the light source is: a laser head arranged to generate a light beam; a laser emitter tube arranged away from the laser head; A first optical coupling assembly connected to the emitter tube, thereby directing a light beam from the laser head to the laser emitter tube. 3. A system for performing capillary electrophoresis on a plurality of samples, the system comprising: a plurality of capillary tubes, each capillary tube having a first end and a second end. And the first end is arranged in a two-dimensional array, the spacing of which corresponds to the spacing of the array of wells of the microtiter tray, and the second end has a common termination. And a device arranged to selectively transfer a selected one of a plurality of liquids to a second end of the capillary tube; a light source arranged to illuminate the sample, the light source comprising: A laser head arranged to generate a light beam; a laser emitter tube arranged away from the laser head; A first optical coupling assembly connected to the emitter tube, thereby directing a light beam from the laser head to the laser emitter tube; A camera means arranged to detect; 4. The system of claim 3, further comprising means for adjusting the position of the emitter tube. 5. A system for performing capillary electrophoresis on a plurality of samples, the system comprising: a plurality of capillary tubes, each capillary tube having a first end and a second end. And the first end is arranged in a two-dimensional array, the spacing of which corresponds to the spacing of the array of wells of the microtiter tray, and the second end has a common termination. And a device arranged to selectively transfer a selected one of the plurality of liquids to the second end of the capillary tube, the device comprising: selectively selecting one of the plurality of liquid holding containers. A first manifold arranged to connect to the first supply line; and one of the gel supply lines and arranged to selectively connect the first supply line to the second supply line. A second manifold; a first end connected to the second supply line, a second end connected to the second end of the capillary tube, and a first end connected to the waste liquid container A three-way connector having three ends, said third end comprising valve means and said second supply line having a length of less than 50 cm; for irradiating said sample A light source arranged; and a camera means arranged to detect the light emitted by the sample. 6. A positioning device for positioning a microtiter tray such that an array of capillary ends located above is inserted into corresponding wells of the microtiter tray, the device comprising: A carousel and a lower carousel, the carousels are aligned and spaced along a common axis, the upper carousel has a notch, the shape and size of the notch, the microtiter tray is the A first motor coupled to act on the carousel, the first motor being configured to pass through the microtiter tray when mounted on the lower carousel; With each of the carousels arranged to selectively rotate the carousel into a predetermined angular position; operatively coupled to the lifting member A second motor, wherein the elevating member positions the microtiter tray at a first position where the microtiter tray is placed on the lower carousel, and the microtiter tray faces the upper carousel. Between the second position where the array of capillary ends is inserted into corresponding wells of the microtiter tray when the array of capillary ends is positioned above the microtiter tray. A positioning device arranged to move along the common axis; and a controller arranged to control the first and second motors. 7. The apparatus of claim 6, further comprising a sensor arranged to determine the angular position of each of the carousels. 8. A light source for illuminating a sample moving through a plurality of capillaries, said light source comprising: a first laser head for generating a first light beam at a first wavelength; A laser emitter tube having an input terminal and an output terminal of
The laser emitter tube is arranged to receive the first light beam at the first input terminal and to output the focused first light beam at the output terminal, and further from the first laser head Spaced apart; a first optical coupling connected at a first end to the first laser head and at a second end to a first input terminal of the laser emitter tube. An assembly for guiding a light beam from the first laser head to a first input terminal of the laser emitter tube; and a first input of the laser emitter tube. A light source in which an illumination beam from a terminal is directed at the sample. 9. The light source of claim 8, wherein said laser emitter tube is; a fiber emitter arranged to receive the second end of said first optical coupling assembly at said first input terminal. A light source, comprising: a tube; a one-dimensional concentrator arranged near the output terminal; a beam expander arranged between the fiber emitter tube and the one-dimensional concentrator. 10. The light source according to claim 8, further comprising: a second laser head for generating a second light beam having a second wavelength; a second input terminal formed on the laser emitter tube. , The laser emitter tube receiving the second light beam at the second input terminal and being spaced apart from the second laser head; and the second laser head at a first end. And a second optical coupling assembly connected to the second input terminal of the laser emitter tube at a second end thereof; A light source in which a beam is guided to the laser emitter tube through the first and second optical coupling assemblies. 11. The light source of claim 10, wherein the laser emitter tube further comprises: a first disposed at the first input terminal for receiving a second end of the first optical coupling assembly. A second fiber emitter tube disposed at the second input terminal for receiving a second end of the second optical coupling assembly; a second fiber emitter tube disposed in the laser emitter tube; A dichroic filter that optically interfaces with the light beams from the first and second fiber emitter tubes; a one-dimensional concentrator located near the output terminal; and a fiber emitter tube. A beam expander disposed between the one-dimensional concentrator and; A light source provided. 12. A device for adjusting the position of an emitter tube arranged to output a beam of light towards a plurality of samples moving through a corresponding plurality of capillaries, said device comprising: An arm for holding the emitter tube so that the output of the tube is directed to the sample; an arm mount for holding the arm; rail means for moving the arm mount along a first direction; connected to the arm mount A first flexible rotator for moving the arm mount along the rail means; a second flexible rotator connected to the arm mount for moving the arm mount in a direction intersecting the first direction. A device comprising a sex rotator; 13. An apparatus for selectively transferring a selected one of a gel and a plurality of liquids to a plurality of capillaries, the apparatus comprising: selectively delivering one of the plurality of liquid holding vessels. A first manifold arranged to connect to one supply line; one of the gel supply lines and a second manifold arranged to selectively connect the first supply line to a second supply line A first end connected to the second supply line, a second end connected to the second end of the capillary, and a third end connected to the waste container. Having 3
A directional connector, said third end comprising valve means; and wherein the length of said second supply line is less than 50 cm. 14. The apparatus according to claim 13, wherein the length of the second supply line is less than 25 cm. 15. The apparatus according to claim 14, wherein the length of the second supply line is less than 10 cm. 16. A gel transfer system for delivering gel to a plurality of capillary tubes; the system comprising: a longitudinal axis, a first end with an outlet having a high pressure fitting, and the longitudinal axis. A tubular gel-filled container having a second end with a surface movable toward a first end along; a plunger provided in contact with the movable surface; A stepper motor operatively engaged with the jar to apply a force to the plunger to supply gel from the first end of the container; selectively moving the plunger through the motor; A predetermined amount of gel is discharged from the outlet and sent to the passage connected to the capillary tube,
The system is provided with a controller adapted to simultaneously fill the capillary tube with gel. 17. A gel transfer system for delivering gel to a plurality of capillary tubes, the system being substantially; having a first end having an outlet and a second end having an inlet. A rigid chamber substantially filled with a medium; a friable gel-filled container disposed within the chamber and substantially surrounded by the medium, the opening communicating with the outlet A pump means connected to the chamber inlet; a pump medium connected to the pump means for feeding additional medium through the pump means into the chamber, thereby causing the gel-filled container to at least partially Then, a predetermined amount of gel is extruded from the outlet and fed into the passage connected to the capillary tube, thereby filling the capillary tube with gel at the same time. System consisting comprises a; controller and which is adapted. 18. The gel transfer system according to claim 17, wherein the pressure transducer is arranged to sense the pressure of the medium and supplies a read pressure value to the controller; a release valve connected to the chamber. A gel transfer system further comprising: wherein the controller is arranged to operate a release valve in response to the pressure value. 19. An apparatus for cleaning a plurality of capillary tubes having first and second ends, the apparatus comprising: a plurality of containers each holding a solvent; and one of the solvents. A manifold for selectively supplying the second end of the capillary; pump means for pumping the selected solvent to the second end of the capillary; and a pump connecting the pump and the manifold to the capillary tube of the solvent. A controller adapted to control the transfer of the liquid in a predetermined order and at a predetermined time; and a waste liquid container for receiving the waste liquid discharged from the end of the first capillary.