Patent Grant
9381511
This application claims priority under 35 U.S.C. §119 to patent application no. DE 10 2011 077 101.8, filed on Jun. 7, 2011 in Germany, the disclosure of which is incorporated herein by reference in its entirety.
The conduct of biochemical processes is based particularly on the handling of liquids. Typically, this handling is carried out manually with aids, such as pipettes, reaction vessels, active probe surfaces or laboratory equipment. These processes are sometimes even automated by means of pipetting robots or special appliances.
Microfluidic systems are sometimes also designated as what are known as lab-on-a-chip systems (pocket laboratory or chip laboratory) which accommodate the entire functionality of a macroscopic laboratory on a plastic substrate of only the size of a plastic card. Lab-on-a-chip systems are typically composed of two main components. A test carrier or a disposable cartridge contains structures and mechanisms for implementing the basic fluidic operations (for example, mixers) which may be composed of passive components, such as ducts, a reaction chamber, preceding reagents, or else active components, such as valves or pumps. The second main component comprises actuation, detection and control units. Such systems make it possible to carry out biochemical processes in a fully automated way.
Such a lab-on-a-chip system is described, for example, in publication DE 10 2006 003 532 A1. This system comprises a rotor chip which is provided so as to be rotatable with respect to a stator chip. The rotor chip can be coupled by means of fluidic ducts to the stator chip for the purpose of filling or emptying the rotor chip.
The system and the method have the advantage, as compared with conventional solutions, that the cartridge does not have to be centrifuged in a centrifuge or exposed to another force field in order to transfer the component between the first and the second chamber. As compared with the use of a centrifuge, in a stationary system many parameters, such as, for example, the temperature of the component, can be set more simply. Furthermore, more flexible processing of the component is possible, since processing is independent of the rotational speed of the centrifuge.
Advantageous refinements of the disclosure may be gathered from the subclaims.
In the present context, “component” means a liquid, a gas or a particle.
In the present context, “chamber” preferably means a line portion, which is designed to be open on both sides or only on one side, or an essentially closed space which has an inflow and/or an outflow.
According to one refinement of the system according to the disclosure, the pressure device is designed as a pump and/or pressure accumulator, the pump and/or pressure accumulator preferably being connected by means of a pressure connection to the cartridge or being integrated into the cartridge. The necessary pressure can thereby be provided in a simple way in order to transfer the component between the first and the second chamber. Moreover, a highly compact set-up can be achieved by means of integration. The “pressure” may be an overpressure or an underpressure with respect to the ambient pressure.
According to one refinement of the system according to the disclosure, there is provision whereby the pressure accumulator stores the component itself under pressure and supplies it to the first or the second chamber or stores under pressure a fluidic aid which pressurizes the at least one component. The pressure accumulator is designed, in particular, as a gas cartridge, bubble store or spring accumulator. The aid is preferably a gas, in particular air, or water.
According to one refinement of the system according to the disclosure, the cartridge has a housing which is closed at one of its ends by means of an adapter, the adapter having the pressure connection. A plurality of functions are thereby integrated into the adaptor: to be precise, on the one hand, an especially sterile closure of the housing and, furthermore, incorporation of the pressure connection. Alternatively, the pressure connection may also be arranged at that end of the housing which lies opposite the adapter.
According to one refinement of the system according to the disclosure, the adjustment device comprises an electrically operated, mechanically operated and/or pressure-operated actuator which rotates the first drum and/or moves it along the mid-axis. The axial movement can therefore be provided in addition to the rotational movement and preferably takes place along the longitudinal axis of a housing of the cartridge.
According to one refinement of the system according to the disclosure, the actuator has a shaft which is connected directly or indirectly to the first drum in order to rotate the latter. The first drum can thereby be rotated, without the other drums having to be rotated.
According to one refinement of the system according to the disclosure, the adjustment device comprises a first slope which cooperates with a second slope of the first drum in order to bring the latter out of a first position, in which it is in positive engagement with a housing of the cartridge in a direction of rotation about the mid-axis, into a second position along the mid-axis, in which the positive connection is cancelled and the first drum rotates about the mid-axis by virtue of the action of a restoring means or of a further actuator. A type of “ballpoint pen mechanism” is thereby provided.
According to one refinement of the system according to the disclosure, the actuator actuates the first slope for cooperation with the second slope. That is to say, the actuator actuates the ballpoint pen mechanism.
According to one refinement of the system according to the disclosure, the first drum is preceded or followed by a second and/or a third drum with respect to the mid-axis, the actuator actuating the second and/or the third drum for the purpose of rotating the first drum. That is to say, the actuator acts directly upon the first drum in order to rotate this.
According to one refinement of the system according to the disclosure, the cartridge has a housing which is closed at one of its ends by means of an adapter, the actuator being fastened to the adapter. A plurality of functions are thereby integrated into the adapter: to be precise, on the one hand, an especially sterile closure of the housing and, furthermore, the accommodation of the adapter. The actuator is preferably integrated into the adapter.
According to one refinement of the system according to the disclosure, the adapter has a flexible diaphragm which can be actuated on one of its sides by means of the actuator and which acts on its other side upon the first, the second and/or the third drum. A sterile closure can thereby be provided. The actuator preferably lies outside the inner space of the housing.
According to one refinement of the system according to the disclosure, the second chamber precedes or follows the first drum with respect to the mid-axis and is formed in the second and/or the third drum. Since a plurality of drums, particularly with a plurality of chambers which are adjusted with respect to one another, are provided, the most diverse possible processes can be carried out automatically by means of the system.
According to a further refinement of the cartridge according to the disclosure, the second chamber and/or a third chamber precedes or follows the first drum with respect to the mid-axis, the first chamber preferably being conductively connectable selectively to the second chamber or to the third chamber by means of the adjustment device. The mixing chamber may therefore precede and/or follow the first drum or else be provided in the first drum itself. Moreover, the mixing chamber may preferably be connected selectively, as required, to different further chambers.
According to a further refinement of the cartridge according to the disclosure, a second drum, which has the second chamber, and/or a third drum, which has the third chamber, are/is provided. However, for example, the second drum may just as well also have the second chamber and the third chamber. The same applies to the third drum. Since a plurality of drums, particularly with a plurality of chambers which are adjusted with respect to one another, are provided, the most diverse possible processes can be carried out automatically by means of the cartridge.
According to one refinement of the system according to the disclosure, a plurality of second chambers are provided which can be acted upon by means of the pressure device with pressures different from one another, a respective second chamber preferably being connected by means of a respective pressure connection in the adapter to the pressure device, or all the second chambers being connected by means of a single pressure connection in the adapter to the pressure device, a respective second chamber more preferably being connected by means of a respective valve to the single pressure connection.
According to one refinement of the system according to the disclosure, the pressure device drives the actuator. Advantageously, therefore, only one energy source is required for the actuator and the pressure device.
Exemplary embodiments of the disclosure are illustrated in the figures of the drawings and are explained in more detail in the following description.
In the drawing:
In the figures, the same reference symbols designate identical or functionally identical elements, unless specified otherwise.
The cartridge 100 comprises a housing 102 in the form of a small tube. For example, the housing 102 may be designed as a 5 to 100 ml, in particular 50 ml, centrifuge tube, 1.5 ml or 2 ml Eppendorf tube or, alternatively, a microtiter plate (for example, 20 μl per cavity). The longitudinal axis of the housing 102 is designated by 104.
The housing 102 accommodates, for example, a first drum 108, a second drum 106 and a third drum 110. The drums 106, 108, 110 are arranged one behind the other and with their respective mid-axes coaxially to the longitudinal axis 104.
The housing 102 is designed to be closed at one end 112. A restoring means, for example in the form of a spring 114, is arranged between the closed end 112 and the third drum 110 arranged adjacently to the latter. The spring 114 may be designed in the form of a helical spring or a polymer, in particular an elastomer. The other end 116 of the housing 102 is closed by means of a closure 118. The closure 118 can preferably be removed in order to extract the drums 106, 108, 110 from the housing 102. Alternatively, the housing 102 itself may also be disassemblable, in order to extract the drums 106, 108, 110 or to reach the chambers, for example the chamber 136.
According to a further exemplary embodiment, the spring 114 is arranged between the closure 118 and the second drum 106, so that the spring 114 is stretched in order to generate a restoring force. Other arrangements of the spring 114 may also be envisaged.
A respective drum 106, 108, 110 may have one or more chambers:
Thus, for example, the second drum 106 comprises a plurality of chambers 120 for reagents and also a further chamber 122 for accommodating a sample, for example a blood sample, which has been taken from a patient.
The first drum 108 following the second drum 106 comprises a mixing chamber 124 in which the reagents from the chambers 120 are mixed with the sample from the chamber 122. Moreover, the second drum 108 comprises, for example, a further chamber 126 in which the mixture 128 from the mixing chamber 124 flows through a solid phase 130. The solid phase 130 may be a gel column, a silica matrix or a filter.
The third drum 110 which in turn follows the first drum 108 comprises a chamber 132 for accommodating a waste product 134 from the chamber 126. Furthermore, the third drum 110 comprises a further chamber 136 for accommodating the desired final product 138.
The aim, then, is to control various processes within the cartridge 100 by means of an actuator 139. Thus, for example, the mixing chamber 124 is first to be connected fluidically to the chamber 122 in order to accommodate the sample from the chamber 122. The mixing chamber 124 is thereafter to be connected to the chambers 120 in order to accommodate the reagents from these. The reagents and the sample are subsequently to be mixed in the mixing chamber 124. The processes in the chambers 126, 132 and 136 are also to take place in a similar way.
As shown in
The actuator 139, projections 200, slots 204, slopes 206, projections 212, slopes 218, 220, projections 240 and slopes 242 form, in the integration with the restoring spring 114, the abovementioned adjustment device 300 for the defined rotation of the first drum 108 with respect to the other drums 106, 110 about the longitudinal axis 104.
If the actuator 139 then releases the second drum 106, the spring 114 displaces the first drum 108 in the second direction 243 again by means of the third drum 110. As a result, the second drum 106, together with its slopes 220, is likewise moved in the second direction 243 again, with the result that the slopes 242 of the first drum 108 come to lie against the slopes 206 of the housing 102 and slide along these, while at the same time a further rotational movement of the first drum 108 into a third position takes place, as illustrated in
The process described above may be repeated as often as desired in order to rotate the first drum 108 in a defined manner with respect to the other drums 106 and 110.
Instead of the actuator 139, a centrifuge could be used, as before. For this purpose, the cartridge 100 may have an external geometry such that it can be inserted into a receptacle of a rotor of the centrifuge, in particular into a receptacle of an oscillating rotor or fixed-angle rotor of a centrifuge. During centrifuging, the cartridge 100 is rotated at a high rotational speed about a center of rotation 140 indicated diagrammatically in
As a further alternative, a further actuator, not illustrated, could also be used instead of the restoring means 114.
Basically, the actuator 139 may be electrically operated, mechanically operated and/or pressure operated. In particular, a piezoelectrically, electrostatically, semi-mechanically/manually or electromagnetically operated actuator 139 is appropriate. Here, “operating” means the active principle which the actuator 139 utilizes in order to generate the actuation force for actuating the second drum 106 (or, depending on the embodiment, also one of the other drums 108, 110). For example, the actuator 139 may have an electromagnet which cooperates with a metal part which is arranged in one of the drums 106, 108, 110 and which the electromagnet protracts or repels by means of suitable activation of the latter, in order thereby to achieve the above-explained adjustment of the drums 106, 108, 110 with respect to one another. The pressure force applied to the second drum 106 by means of the actuator 139 amounts typically to 0.5-100 N.
A suitable control device, not illustrated, is preferably provided, which activates the actuator 139 so that the drums 106, 108, 110 assume at the desired time the position with respect to one another which is desired in each case. For this purpose, the control device may have a timer and/or an integrated circuit.
According to one refinement, the system 103 may be provided without the projections 200, slots 204, slopes 206, projections 212, slopes 218, 220 and restoring spring 114. Instead, the actuator 139 has a shaft which is connected directly to the first drum 108. The actuator 139 then, as a result of suitable activation by means of the control device, rotates the first drum 108 with respect to the then fixed other drums 106, 110, in order to connect the various chambers, for example the chambers 120, 124, conductively to one another. In order to achieve a suitable movement (a rotational movement about the longitudinal axis 104 and/or a movement along the longitudinal axis 104 in the first and/or the second direction 207, 243) of the drums 106, 108, 110 with respect to one another, two or more actuators 139 may also be used.
In this exemplary embodiment, the cover 118 is designed in the form of an adapter for holding the actuator 139. The actuator 139 extends through the adapter 118 and thus engages directly on the second drum 106 in order to move the latter in the first direction 207, that is to say downward in
Alternatively, the actuator 139, for example the actuating member, is connected fixedly to the second drum 106. The drum 106 can thereby be moved quickly back and forth along the longitudinal direction 104 by means of the actuator 139, with the result that a mixing chamber for mixing components could be provided in one of the chambers 120, 122. If the selected amplitude of the back-and-forth movement is sufficiently low, this movement can take place without the drums 106, 108, 110 being rotated with respect to one another, that is to say the “ballpoint pen mechanism” is not triggered.
The pressure device 101 has the function of acting upon at least one component 500, in particular a liquid, for example a reagent, with a pressure difference, in order to transfer it, for example, out of the chamber 120 into the chamber 124. For this purpose, the chambers 120, 124 are first arranged opposite one another (by the rotation of the first drum 108, as described above) and are thereafter connected, pressure-tight, to one another. Moreover, the second drum 106 seals off with respect to the adapter 118, so that a corresponding pressure-carrying duct in the adapter 118 is connected, pressure-tight, to the chamber 120. The pressure device 101 then, for example, applies a pressure which is above the ambient pressure to the adapter-side end 502 of the chamber 120. The chamber 124 is, for example, bled toward the surroundings, so that the pressure drives the component into the chamber 124. Alternatively, the chamber 124 may in turn be connected conductively to further chambers 126, 132, 136 (see
Alternatively, the pressure device 101 may also be provided for supplying the pressure difference by means of generation of a vacuum.
The pressure device 101 is designed, for example, as a pump. For example, it may be a hand-operated or electrically operated pump.
Alternatively, the pressure device 101 may be designed as a pressure accumulator. The pressure accumulator 101 may be designed, for example, as a spring accumulator which initially contains the component 500 itself and, particularly as a result of the actuation of a valve, conveys the component 500 through the chamber 120 into the chamber 124. Furthermore, there is the possibility that the pressure device 101 stores a fluidic aid under pressure. In particular, compressed air may be considered as an aid. When the air expands, it drives the component 500, in particular a liquid, out of the chamber 120 into the chamber 124 or through a multiplicity of chambers, as described above.
The pressure device 101 is provided, in particular, outside the cartridge 100 and is connected, for example, by means of a pressure connection 504 to the cartridge 100, in particular the adapter 118. Alternatively, the pressure device 101, particularly in the form of a compressed gas accumulator, could also be integrated into the cartridge 100, in particular into one of the chambers 120, 122, 124, 126, 132, 136.
The exemplary embodiment according to
The exemplary embodiment according to
In one embodiment, the adapter 118 possesses a plug device (not illustrated), with the result that, for example, the housing 102, the second drum 106 and/or the chambers 120, 122 are contacted and sealed off. The plug device may have pins (not illustrated) which engage from above into the chambers 120, 122 or other orifices of the drum 106 and close the latter in a pressure-tight manner. During plugging together, the pins may also open the, for example, previously closed chambers 120, 122 or other orifices, in particular may pierce a covering film. A duct which is connected to a pressure connection 504 and issues into an assigned chamber 120, 122 may run in turn in a respective pin itself.
The exemplary embodiment according to
Moreover,
Alternatively, the spikes 802 may also be provided so as to be extendable. Piercing of a respective covering film is then consequently possible independently of actuation by the actuator 139.
Furthermore, there is the possibility of providing the actuator 139 so as to be pressure-operated, for which purpose the actuator 139 is connected (not illustrated) in a pressure-conducting manner to the pressure device 101 and is thus driven by the latter. In the simplest case, the adapter 118 and the second drum 106 form with one another a chamber (not illustrated) which is acted upon with pressure by the pressure device 101, the actuator 139 thus being formed. Furthermore, the actuator 139 could be provided in the form of a concertina which is provided between the adapter 118 and the second drum 106.
The actuator 139 may also be provided elsewhere, for example between the first drum 108 and the second or the third drum 106, 110.
In the simplest case, the actuator 139 may even be omitted, in which case the rotation of the drums 106, 108, 110 in relation to one another takes place manually, in particular by triggering the ballpoint pen mechanism.
A control unit, not illustrated, regulates the interaction of the actuator 139, which predetermines the spatial position of the drums 106, 108, 110, and of the pressure device 101, which controls the pressure for controlling the component 500 (or a plurality of components).
Furthermore, the drums 106, 108, 110 or the chambers 120, 122, 124, 132, 136 may be designed such that further process steps and structures can be integrated, for example sedimentation structures, mixed structures and duct or siphon structures for conducting and switching the liquids.
The housing 102 and the drums 106, 108, 110 may be produced from the same or different polymers. The one or the plurality of polymers may be, in particular, thermoplastics, elastomers or thermoplastic elastomers. Examples are cycloolefin polymer (COP), cycloolefin copolymer (COC), polycarbonates (PC), polyamides (PA), polyurethanes (PU), polypropylene (PP), polyethylene terephthalate (PET) or poly(methyl methacrylate) (PMMA).
One or both of the drums 106, 110 may be formed in one piece with the housing 102.
Although the disclosure was described in the present context by means of preferred exemplary embodiments, it is in no way restricted to these, but can be modified in many different ways. In particular, it should be pointed out that refinements and exemplary embodiments described in the present context for the system according to the disclosure can be applied correspondingly to the method according to the disclosure, and vice versa. Furthermore, it is pointed out that, in the present context, “one” does not rule out a multiplicity.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2011 077 101 | Jun 2011 | DE | national |
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|---|---|---|---|
| 4889692 | Holtzman | Dec 1989 | A |
| 5573951 | Gombrich et al. | Nov 1996 | A |
| 6096276 | Laursen | Aug 2000 | A |
| 20070099189 | Gomez-Elvira Rodriguez et al. | May 2007 | A1 |
| 20120107185 | Lebedev | May 2012 | A1 |
| 20120312380 | Daub et al. | Dec 2012 | A1 |
| Number | Date | Country |
|---|---|---|
| 10 2006 003 532 | Jul 2007 | DE |
| 0220160 | Mar 2002 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20120312380 A1 | Dec 2012 | US |
