WO2001028682A1

WO2001028682A1 - Electromagnetic system for manipulating fluids

Info

Publication number: WO2001028682A1
Application number: PCT/ES2000/000383
Authority: WO
Inventors: Antonio Ivorra Cano; Ivan Erill Sagales; Abdelhamid Errachid; Jordi Aguilo Lobet
Original assignee: Consejo Superior De Investigaciones Cientificas
Priority date: 1999-10-15
Filing date: 2000-10-06
Publication date: 2001-04-26
Also published as: ES2158808A1; ES2158808B1; AU7790800A

Abstract

The technology disclosed makes it possible to build systems formed by a reading device that will only act as a controlling device in given applications, and a card or cartridge which is inserted into said piece of equipment. The cartridge has a series of conduits and cavities made from a sheet structure. One or several areas are covered with an elastic membrane that in turn has several areas with ferromagnetic material or permanent magnets. The reading device has a set of electromagnets which are activated by an electronic system when the cartridge is inserted. Said electromagnets are disposed in such a way that they selectively act upon each of the magnetic areas causing deformations in specific points of the elastic membrane, said points serving as valves or suction pumps enabling circulation of fluids inside the cartridge, suctioning of external fluids or expulsion of fluids to the outside.

Description

TITLE

Electromagnetic system for fluid handling.

SECTOR OF THE TECHNIQUE Area of the technique: fluidics and electronic control.

Application areas. The present invention allows to create iiistrumentation applicable to chemical analysis and chemical synthesis.

STATE OF THE TECHNIQUE. The use of automated systems in the control of small volumes of fluid (of the order or less than lml) is becoming increasingly important in the chemical and biochemical analysis sector (clinical diagnosis, environmental control, industrial process control ...) . The advantages that characterize this approach are: decrease in labor costs, reduction of the quantities of reagents needed, obtaining data in a shorter time and greater repeatability.

Conventional robotic devices have been adapted to perform typical operations in a chemical laboratory: pipetting, sample handling, mixing solutions ... The systems thus obtained are excessively expensive and bulky, and this has limited them to very specific clinical trials in A large number of samples are handled.

It is especially interesting to apply a fluid handling system in the measurement of chemical parameters using sensors (ion selective electrodes, biosensors, optical sensors ...). These sensors require that the sample be conducted to an active surface and, in most cases, require a prior or subsequent calibration process, that is, the active surface must be contacted with fluids of known composition. It is currently possible to automate these processes using valves, peristaltic pumps and other discrete components. This is how FIA (Flow Injection Analysis) systems are built. But, again, bulky and relatively complex systems are obtained for unskilled personnel. There is a need to obtain portable and simple equipment that allows for cheap and short-term clinical analysis. This has motivated the appearance of equipment in which the sample is inserted into a card or cartridge, usually disposable, that It contains the sensors and which in turn contains some container with calibration liquids. When the cartridge is introduced into the portable equipment, by means of certain techniques such as the rupture of containers, the capillarity or the conduction of fluids by external circuit, different liquids (generally the sample and a single calibration liquid) are automatically conducted to the active surfaces that transmit the corresponding signals to the equipment, through connectors located in the cartridge. The following patents correspond to this type of systems: US5096669, WO9744672, US5293770, US4436610, US5325853.

At the beginning of the 1990s, the possibility of integrating different laboratory components in the same device and in a miniaturized format was raised. This is what has been known as "Miniaturized Total Analysis Systems" or "μ-TAS" (see "Miniturized Total Chemical Analysis Systems: a Novel Concept for Chemical Sensing" A.MANZ et al. Sensors and Actuators, Bl (1990 ) 244-248). Since then, many components have appeared (valves, pumps, filters, capillaries.) That can be integrated into a single device with the aim of achieving what is popularly known as "lab-on-a-chip". These components base their operating principle on different phenomena: piezoelectricity, electrostatic force, thermal deformations, electrokinesis ... Only electrokinesis seems to be providing satisfactory results when a complete system is intended (see US5858195 patent), but, in any case , these systems are usually only valid for volumes of liquids much lower than 1 μl and the presence of any impurity in the sample can make them totally unusable.

DESCRIPTION OF THE INVENTION BRIEF DESCRIPTION OF THE INVENTION The technical problem posed is the development of a technology that allows the construction of integrated fluidic systems for small volumes of the order of hundreds of μl. Different typical processes in a chemical laboratory (conduction, mixing, filtering ...) must be carried out in a card or cartridge of reduced cost. The system must facilitate the analysis tasks using sensors (electrochemical, optical, thermal ...).

In existing integrated micro-fluidic systems (lab-on-a-chip), the force that allows the conduction of the fluids is created in the same substrate in which the conduction, from external energy in the form of electricity. An alternative is to apply the force from outside the substrate. The solution proposed here, and in which much of the novelty of the present invention resides, is to make certain parts of the conduit channel system deformed by applying a magnetic field from the outside. This allows to create valves and pumps integrated in the substrate.

The proposed technology allows the realization of systems formed by a reading device, which in certain applications will simply act as a controller, and a card or cartridge that will be inserted into said equipment. The cartridge has a series of ducts and cavities constructed from a laminar structure. One or several areas are covered with an elastic membrane that in turn contains various areas with ferromagnetic material or permanent magnets. The reader has a set of electromagnets that are activated from an electronic system when the cartridge is inserted. These electromagnets are arranged so that they act selectively on each of the magnetic areas, causing deformations at specific points of the elastic membrane. These points will act as valves or suction pumps, allowing the circulation of fluids inside the cartridge, the suction of external fluids, or the expulsion of fluids outwards. A typical application of the system will be the realization of portable equipment that allows the analysis of fluids by electronic sensors and requires a process of calibration or previous preparation of the sample. The system is a simple, economical and compact alternative to existing μ-TAS systems. In addition, it allows the manipulation of moderate volumes and unpurified liquids (eg blood).

DETAILED DESCRIPTION Conduction channels, pumps and valves.

Figures 1, 2, 3 and 4 allow to understand the construction and operation of the basic elements of this technology. The development of a cartridge in which it is possible to move a liquid between internal deposits, from (12) to (13), is presented.

The system of deposits and conduction channels is formed from holes and incisions made in the intermediate plate (2). Figure 3 shows a top and bottom view of the plate. The plates (2) and (3) will preferably be constructed with rigid materials

(PVC, ceramics, glass ...) and will be firmly joined. The method of attachment will depend on the plate material; Some of the most common are: adhesives, welding of plastics (ultrasound) and anodic welding. The intermediate plate (2) can be manufactured from a uniform plate by a machining process or by a chemical attack after a photolithographic process. It is also possible to resort to the injection of the material (plastic) into a mold.

The number and size of internal deposits and channels can be increased if intermediate layers are added and, in this way, there will be different channel heights with which these can be crossed. The use of multiple layers can also be used to simplify the manufacturing process. If the upper channels are made on the lower surface of the upper plate it will only be necessary to work one of the surfaces of each layer. It is possible to construct the ducts from longitudinal cuts in the plate when it is limited by an upper and a lower plate. This method can be useful when precision is required in the duct section.

Structures equivalent to the proposal can be made by accumulating different layers of material, avoiding the process of joining between plates. For example, if the material of the different layers is photocurable, the formation of ducts will be carried out by a photolithographic process after curing the lower layers.

Between the different plates, partially or totally obstructing the ducts, it is possible to place layers of material that perform some physical-chemical function (sieving, filtering, osmosis, catalyzing ...).

The existence of one or several membranes of elastic material (eg latex) is one of the key elements in the operation of the structure. In this case, the elastic layer (1) completely covers the upper surface of the cartridge and is fixed to the intermediate plate (2) by means of an adhesive, an adherent sheet on both sides or by welding between both materials. Fixing should not be done on the entire surface. In certain areas (14, 15 and 16) the membrane must be able to separate and, therefore, there must be no connection with the intermediate plate (2). Figure 4 shows a possible pattern of union between the membrane and the plate, in the areas (14, 15 and 16) the membrane is free. In the case that a sheet of adherent material is used, this figure would correspond to its appearance. The membrane will separate from the intermediate plate due to tensile forces in the presence of sufficiently strong magnetic fields. This is achieved by fixing ferromagnetic material (6, 7 and 8) on the membrane. Some solutions are: material introduction ferromagnetic in the composition of the membrane, fixation by means of adhesive plates of ferromagnetic material (Fe-Ni alloys) and deposition of filings of ferromagnetic material and subsequent covering with a material that allows the movement of the membrane. When the cartridge is inserted into the reading equipment, in some applications it may be permanently, the cores of a set of electromagnets, belonging to the reading equipment, are located a short distance from the active elements of the cartridge (valves and pumps). In the case described (figures 1, 2, 3 and 4) the electromagnets (9, 10 and 11) are placed on the valve (14), the suction / compression element (15) and the valve (16) respectively. These three elements form the pump that allows the transfer of fluids if currents are applied to the electromagnets in a suitable sequence.

Initially, the tanks (12 and 13) are insulated by the valves (14 and 15), note that the flexible membrane obstructs the ducts (Figure 2). In addition, it is possible to seal the tanks to avoid losses of evaporation fluid by adding adhesives on the holes (4 and 5) that will be removed by the user before inserting the cartridge.

The pumping process begins by opening the valve (14), for this it is necessary that the reading equipment apply a sufficient current to the electromagnet (9), so that the lower ferromagnetic material (6) forces the lifting of the elastic membrane and the duct is no longer clogged After this step, the membrane will be lifted in the area (15) by applying current in the electromagnet (10). This fact will cause the suction of the fluid, initially air, through the channel (17). Then, the valve (14) will be closed, stop applying current on (9): the elasticity of the membrane will perform this work. Moments later, the valve (16) will open and no more current will be applied to (10), whereby the fluid will be pushed to the reservoir (13) through the conduit (18). Finally, the valve (16) will be closed and a new cycle will be started if necessary.

An interesting feature of this type of pumps is the fact that the flow is discrete, in each cycle a fixed amount of fluid is transferred. The amount transferred depends on the volume that forms when the membrane rises in the area (15), if it is possible to narrow the survey, it is possible to limit this volume. The height stop may be the core of the electromagnet, but, also, an intermediate plate can be placed attached to the cartridge at its ends.

It is possible to modify the geometry of the constituent elements of the pump, but It is also possible to modify its structure. By adding one or more suction / compression elements (activated sequentially), the use of the valves can be avoided, since their function is only to prevent reflux and improve efficiency. In fact, the valve (16) is not absolutely necessary in the scheme proposed In the described components, ferromagnetic material without permanent magnetization is used as a magnetic field sensitive material. The use of permanent magnets is a more expensive and complex alternative but requires lower excitation currents and allows the 'active' closing of the valves: with the proper polarity of current, the electromagnet will push the elastic membrane towards the plate. The shape of the cartridge in this case is flat, similar to a card, but there is the possibility of adopting other geometries using the processes and elements that have been described.

The following section shows the use of valves as selector devices. In this case, the valves remain fully open or closed for a relatively long period of time. If these same valves are activated by short pulses, it is possible to partially restrict fluid circulation.

Integration of electronic components.

It has been mentioned that one of the most important applications of the proposed technology is fluid analysis using electronic sensors. In a large number of cases, the sensors may be external, that is, they will be part of the structure of the reader but not of the cartridge. Especially interesting is the case of optical sensors. These are capable of providing many important parameters: absorption spectrum, reflection spectrum, attenuation ... It will be interesting to obtain optical parameters of the fluid in certain cavities of the cartridge, for example: the fluid to be analyzed will be mixed with a reagent and the resulting color will determine the degree of presence of a specific chemical species To obtain this information with external sensors, some areas will be created in the cartridge that allow the passage of light, without significant losses, in the spectral region of interest. This will be achieved by properly choosing the materials of the different layers or by drilling (certain layers in these areas of interest. The result can be defined as an optical window. Figure 8 corresponds to a sectional cut of a possible optical window, in which the fluid is It is limited by two transparent plates, (43 and 44). schematize the related devices in the light source reader equipment (39), converging lenses (40) and sensor (41)

In other cases, it will be interesting that sensors and electronic components are integrated in the cartridge Figures 5, 6 and 7 show a cartridge in which electronic components have been integrated (38), consider that it is a reference electrode (Ag-AgCl ) and pH sensitive ISFETs The cartridge is partially inserted into the reader, leaving the calibration liquid reservoir (36) and the ducts (34) and (35) outside. The liquid to be analyzed is absorbed by the duct (34 ) thanks to the suction created by the pump formed with the elements (23, 24 and 25) The expulsion of fluids occurs through the duct (35) after leaving the valve (25) By means of the valves (20, 21 and 22) it is it is possible to select the fluid that will circulate through the chamber in which the sensors are located (38) This fluid can be air that will empty chamber and ducts, calibration liquid to calibrate ISFETs periodically, or liquid to be analyzed

The components are mounted on a printed circuit board (31) that will adapt as an intermediate layer, as described in the previous section. Part of this board will be used as a connector (28)

Reading team

The reader or controller equipment, presents the common characteristics in any measuring equipment Only, the presence of electromagnets and the associated control circuitry is remarkable. Its realization will be evident for those who have knowledge and skills in circuit design

Figure 9 presents a general scheme of the circuitry and components of the reader equipment The electromagnets (49) are excited from a control circuit (48) that responds to the orders of the microcontroller (microprocessor) The sequence of orders will follow a program stored in memory and, in certain cases, it may be modified depending on some events, keyboard press, end of the measurement, command from external equipment The data represented in the viewer will correspond to the information obtained through the internal detectors of the card or through external systems ( 50) (optical system) The signals are extracted from the cartridge through the connector (54) It is also possible to introduce signals or power currents into the card with the same connector The number of electromagnets (49) and optical windows (50) shown in the figure is not significant, it depends on the structure of the cartridge.

The power supply can be provided by any of the usual methods in electronics: batteries, rechargeable batteries, mains adapter ... (The option of rechargeable batteries is especially interesting in portable equipment.)

Figure 10 shows the possible external appearance of the reading equipment.

Technology Capabilities

The methodology to integrate different components in rigid substrate has been described: conduits, cavities, tanks, pumps, valves, optical windows and electronic components. From these elements, it is possible to build a wide range of analysis and synthesis systems without this involving inventive activity. In fact, it would be enough to imitate the FIA (flow injection analysis) systems that are currently carried out from discrete components.

DETAILED EXPLANATION OF THE DRAWINGS

Figure 1: External appearance of a cartridge that allows the transfer of liquids between two internal tanks. It is constructed with two plates of rigid material (2 and 3) and a membrane of elastic material (1). The ferromagnetic elements (6, 7 and 8) are fixed to the membrane. The holes (4 and 5) allow the entry and exit of air.

Figure 2: Longitudinal section of the cartridge in the axis formed by the pump elements (14, 15 and 16). The valves (14 and 16) allow the circulation of the fluid through the channels (17 and 18) when sufficient current flows through the corresponding electromagnets (9 and 11). The suction / compression element is activated by the central electromagnet (10). Figure 3: Appearance of the intermediate plate (2, in the previous figures) in a top view (left) and a lower view (right).

Figure 4: Joint pattern between the flexible membrane and the intermediate plate. Figure 5: External appearance of a cartridge that includes electronic components (38) in the circulation duct. Fluid (26) enters the cartridge through the conduit (34) due to the suction caused by the pump (23, 24 and 25) when the corresponding valve (22) is open. The fluid is expelled (27) through the conduit (35). The valves (22, 21 and 20) select the fluid that circulates through the card: external fluid, internal fluid (reservoir 36) or air (19) The printed circuit board (31), on which the components are located, has a connector (28)

Figure 6 Longitudinal section of the cartridge of Figure 5 by the axis formed by the elements (22, 23, 24 and 25) The adapter (37) allows the connection of the external ducts (34 and 35) Figure 7 Fluidic diagram of the structure of the cartridge of figure 5

Figure 8 Cut of the longitudinal section of an optical window The radiation from the light source (39) passes through the chamber in which the fluid is located (45) and is led to the sensor element (41) Optical elements, converging lenses (40), guide the radiation for greater efficiency Transparent sheets (43 and 44) do not prevent the circulation of radiation in the spectral regions of interest

Figure 9 Electrical block diagram of the reader equipment The microcontroller follows a program stored in memory to activate the electromagnets (49) by means of a control circuit (48) The cartridge detectors (55) provide information to the microcontroller through the connector (54) , after conditioning the signals (47) Also, information can be obtained through optical systems (50) The equipment can be connected to external elements through communications interfaces (52 and 53) Figure 10 External appearance of a portable reader equipment The cartridge is inserted into the groove (56)

EXAMPLES OF EMBODIMENT OF THE INVENTION

An illustrative example is that of Figures 1, 2, 3 and 4 The cartridge has been made with two transparent methacrylate plates of 70 mm by 40 mm and thicknesses of 5 mm and 10 mm The union between them is done by means of an adhesive. intermediate plate (2) has been machined from the original plate The width and depth of all the channels is 1 mm and the height of the protuberances (valves 14 and 16) is 1 mm The tanks (12 and 13) are cylindrical and its diameter is 10 mm The air inlet (4) and air outlet (5) have a diameter of 2 mm

The elastic membrane is a sheet of latex with 0.2 mm thickness The fixation to the intermediate plate (2) has been made by a thin sheet of adhesive material on both sides. This sheet has been previously cut according to the pattern in figure 4

The material of the ferromagnetic elements is the same as that found in the mobile element of the commercial relays (Fe-Ni alloy). Squares of 4 have been obtained. mm side and 0.8 mm thick by machining a uniform Fe-Ni plate (circumferences are shown in the figure) These squares have been fixed to the membrane by means of an adhesive

The reader equipment, controller in this case, has a structure made of methacrylate that is placed on the cartridge and places the cores of the electromagnets at 1.5 mm from the ferromagnetic elements The electromagnets have been extracted from 52Ω commercial relays

The excitation of the electromagnets is carried out with currents of 150 μA following the sequence previously described (the time between operations of a cycle is 0.2 seconds, so the total cycle duration is 1.2 sec) The currents are injected by an electronic circuit controlled by a computer through its parallel port

A second example is shown in Figures 5, 6 and 7 In this case the cartridge measurements are 120 mm by 70 mm. The rigid top plate (30) has a thickness of 10 mm, the printed circuit (32) 1 mm; the bottom plate (32) 5mm; and the closure (33) 5mm. The calibration solution tank (36) is a 20mm diameter and 20mm high cylinder made of PVC and connected in its lower part to the valve (21). The inlet (34) and outlet ducts (35) are Teflon tubes with external diameter of lmm, the connection to the cartridge has been made using silicone. The control equipment is equivalent to the previous one, it only differs in the dimensions due to the inclusion of three more electromagnets. The electronic components that are placed in the internal chamber (38) are a reference electrode and an ISFET (pH sensitive semiconductor device) The external connectors (28) are connected to an ISFETometer that passes the data obtained to the computer through a port of communications This same computer presents the data on the screen, after processing, and is responsible for controlling the electromagnets. Normally the sample (26) circulates through the chamber with sensors (38), but periodically a small amount of calibration liquid is circulated to fix a point on the line that relates pH to the measurement obtained by the ISFETometer, that is, it helps to the computer to provide a correct value.

The rest of dimensions, times and characteristics are equivalent to those of the previous case.

These examples correspond to demonstration equipment. The specified measures and construction methods are not necessarily optimal.

Claims

1. Technology for the manufacture of integrated fluidic systems characterized by the use of one or more elastic membranes with ferromagnetic material attached to them, so that, when applying external magnetic fields, deformations occur in the membrane that lead to opening or closing of ducts or the creation or disappearance of cavities.

2. Technology according to claim 1 characterized by using permanent magnets as ferromagnetic material.

Technology according to claim 1 characterized in that the elastic membrane is partially fixed to a structure composed of layers, in which at least one of them has holes and / or incisions to form ducts and cavities.

4. Valve made according to the technology of claim 3 characterized by the obstruction of a conduit by the membrane in the absence of a magnetic field, but that by applying a sufficiently intense magnetic field on the associated ferromagnetic element, the membrane is separated allowing the circulation of the fluid to one or more ducts.

5. Pump made according to the technology of claim 3 characterized by the presence of one or more cavities, connected by conduits, which increase or decrease its volume depending on the applied magnetic field and its legalization.

6. Pump according to claim 5 characterized by the presence of one or more valves according to claim 4.

7 Cartridge made according to the technology of claim 3 characterized by the presence of at least one of the following elements: valve according to claim 4, pump according to claim 5, or pump according to claim 6.

8. Cartridge according to claim 7 characterized by the presence of one or more sheets that include conductive tracks that allow to add electrical components inside the cartridge, in contact or not with the fluids, and allow to create connectors outside

9. Cartridge according to claim 7 characterized in that, in one or more areas, a light radiation can access internal fluids and the resulting radiation by absorption, reflection or fluorescence can be captured from the outside.

10. System controller manufactured according to claim 1 characterized by the presence of one or more electromagnets, located near the magnetically sensitive areas of the membrane, which are electrically excited by responding to orders and following a certain sequence of execution.

11. Chemical parameter reader characterized by the presence of a controller according to claim 10 and one or more of the following elements: connection to the detectors or other electrical components integrated in the layer structure or optical measurement system.

12. Chemical parameter reader according to claim 11 characterized in that it includes a slot in which a cartridge according to claims 8 or 9 must be inserted, totally or partially.