Device having a specific support structure for receiving, analysing and treating samples.

The invention relates to a micromechanical structure for purposes of biotechnology, so particular disease and hunger, for purposes of biotechnology, genetic engineering, cell research, for the pharmaceutical industry, for healing and exploring particular hitherto incurable diseases, also for agricultural research to new sources of food and to develop energy sources and restore the environment. For the purposes of medicine, for example, blood tests but also of tissues or cells, such as antibody, Antigenimmobilisierung for the production of monoclonal antibodies for the production of antibiotics, insulin, but also for remedy, sera, bacteria and other substance investigations and comparative experiments. Always there is the task of a safe kontollierten dealing with the particular substance, during and after an investigation, reaction or the like, particularly when the substances may constitute a danger to the environment.

In order to fulfill the purposes mentioned, in particular to combat disease and hunger in the world, it is necessary to be able to handle in investigations, reactions, tests, comparative studies and test series with particularly hazardous substances safe even if the amounts of substance yet are so low.

Object of the invention is to provide a clean, safe storage and handling of substances that are dangerous or can be - whether before, during or after an investigation, reaction, test or the like - to facilitate or ensure.

This object is achieved by a microstructure according to claim 1. This microstructure has many advantages. They can be manufactured in large quantities at low cost. It is suitable for the secure storage of a variety of substances as a sample for testing, for treatment, for studies, for comparison, for reactions etc.. The arrangement of suitable cavities each other in the structure in the manner of a matrix or array allows simple process control, simple examination and implementation of desired reactions of desired small amounts of substances and their targeted treatment and investigation. The structure of the cavities consists of inert material, ie it changes in the investigations, treatments not, the cavities are reliably closed and are not attacked by most pollutants.

Training and further developments of the invention are given in further claims and in the description and drawing of an embodiment. Combinations of these features must be the invention. In the drawings:<dl id="dl0001"><dt>Fig. 1</dt><dd>a structure with a single cavity and a particular surface orientation of the crystalline material;</dd><dt>FIG. 2</dt><dd>a modification of Figure 1;</dd><dt>Fig. 3</dt><dd>a structure of crystalline material;</dd><dt>Fig. 4</dt><dd>a structure in a modification of Figure 3;</dd><dt>Fig. 5</dt><dd>a structure in a constructive modification of FIG 1;</dd><dt>Fig. 6</dt><dd>a modification to Figure 2 or 4, wherein a structured part in the middle thereof between two different parts is arranged (sandwich structure).</dd><dt>Fig. 7</dt><dd>a modification of FIG 6 with additionally arranged in the base plate and cover plate means.</dd><dt>Fig. 8</dt><dd>a further modification of FIG 6 or 7 with additional layers or plates.</dd><dt>Fig. 9</dt><dd>a version with measuring or detecting device; </dd><dt>Fig. 10</dt><dd>a structure with measuring and detecting device, and optionally storage;</dd><dt>Fig. 11</dt><dd>a device with a biosensor in particular field effect transistor;</dd><dt>Fig. 12</dt><dd>a modification of the embodiment of Fig. 11;</dd><dt>Fig. 13</dt><dd>means for detecting certain substances in fluids;</dd><dt>Fig. 14</dt><dd>a device for automatic examination with documentation of the test results;</dd></dl> Referring to FIG. 1, a structure 1 of walls with one, preferably a plurality of cavities therein for receiving small amounts of substance, and the block is completed by a cover 3. Block 1 and cover 3 are made of crystalline material, such as semiconductor material. Similarly to the closure of the container according to the invention with a second mask is generated a counterpart = lid 3 which corresponding elevations 4 to the wells having 2, since the masks are geometrically identical. The masking technique allows a high precision in the manufacture; it is known from the semiconductor technology.

The abovementioned technique is advantageous to employ a crystal directional anisotropic etching process, as this can be realized with high geometric precision and very tight tolerances, taking advantage of the self-limiting effect of (111) crystal planes, depressions. The container in Fig. 1 can be produced in (100) silicon, wherein the laterally defining (111) planes forms an angle of 54.7 ° to the wafer surface.

The cover 3 can be provided with an elevation 4, which has the same 54.7 ° inclination to the crystal surface as the container block 1 in the region 2, thereby properly tight manner. This is true even if the lid has a plurality of protrusions, and the block 1 has a plurality of recesses second If there is insufficient accuracy of fit, the surveys produced by etching and depressions on the cover 3 and Block 1 for individual applications of particularly dangerous substances, a circumferential seal can also be used. Fig. 5 shows an embodiment, which in turn corresponds to the 54.7 ° bevel collecting 4 of the lid and form with another one closure. In addition, adhesives or other bonding techniques to increase the tightness can be applied. In particular, a laser beam in the seam welding method can be applied on the peripheral rim of the lid. A plurality of cavities 2 is not limited in the block of the container size, training and distribution.

The cavities 2 (and the elevations 4) may, in particular square, rectangular, be circular, oval or diamond-shaped. You can down taper or expand towards - see Figure 1 and Figure 2 -.. Or keep the same cross-section, if they are bored, for example using a laser beam (Fig. 4). You can also have other cross sections or shapes (openings, channels form).

An additional layer or plate 5 serves as a support or intermediate support (removably) advantageously of the same material, such as silicon or the like, as the bottom of the container, also hermetically sealed manner.

The worked out from a block of material structure 1 forms advantageously (for mass production), a flat plate with through cavities 2 such openings, channels or the like desired shape wet chemically etched with advantage of silicon while the cover 3 and the bottom 5 of this material of the structure 1 preferably well connected, in particular hermetically sealed lockable material such as glass, quartz glass, ceramic or silicon plastic or silicon metal composite material.

In FIG. 6, as shown, the bottom 5 or to the structure 1 side coated with a layer 7, for example, a filter layer, a sedimentation layer, an inert, or catalytic or otherwise reacting layer of a material, or even absorbent material can be. A nonwoven fabric or other large pore or provided with large open area non-woven fabric, fiber laminate, foam or similar permeable structure may be used depending on the application (collecting, storing, reacting). It may be an inert support or an active carrier material which is used for the layer 7 and below could against if valves or other devices (see Fig. 8) are arranged. Block 1 with the cavities 2 includes these distributed advantageous to a grid in XY on the surface of the preferred silicon crystal as an array or in matrix form (see. FIG. 3), so that they filled eg by means of automatic devices with substances fumigated seeded, diluted, destitute, sucked or the like., mixed or can be made to react. The feed or sampling elements are then programmatically line by line, until the entire surface is scanned, as is known in automatic analyzers or handling machines or robots for medical or other research purposes.

The material of the block 1 must be inert in each case relative to the substance being examined, treated, diluted, to be mixed or to be brought to a reaction or is tested for its absence (composition or anti-tests).

Depending on the purpose for which the invention is applied, the cavities for the investigation or storage (storage containers) can be designed more in particular, in which the cavities 2 are only part of trial or examination or reaction chambers in block 1 - see Figure . 7. the matrix or array arrangement in the XY direction is as previously maintained and also the substantially sandwich-like structure of FIG. 6. in addition is 8 or 9 associated in the cover plate 3 and the base plate 5 respectively of the cavity a more fitting recess, the overall volume of the chamber or volume of the cavity 2 substantially increased. Can now take place feed or discharge of a medium in the plane, for example if the same to-medium all chambers or to be discharged.

As a rule, for the purposes of the aforementioned substances as solids are examined in a fluid; it can also gases into a liquid or gas or liquid to be examined in a solid. This applies in particular for immune reactions, for assaying enzymes or microorganisms. It can be found in one or more properties such as flow, density, surface or boundary effects, special characteristics of particles, permeability, friction, adhesion at or analyzes of substances / mixtures chemical or physical properties or its amendment. It can be a storage under certain conditions such as pressure or vacuum are investigated over a certain time in the simplest case, or by external influence, a response, or the lack of response to be investigated. External influences may include: radiation, heat treatment, application of reagents, measuring the change of material properties in heat, cold, steam, humidity or supplied materials / particles, by applying electrical / electrochemical, or magnetic means, by application of sound, infrasound, ultrasound , Furthermore, colorimetric, spectrophotometric or fluororometrische studies, for example using as reagent Reagenzpapieren can be carried out as a layer 7th Heating and / or cooling elements can be guided through the plates 3 and 5 of the chambers, 2 10 and 11, for example in the form of each tempered media in channels or it can thermocouples, in particular Peltier elements may be disposed at least partially in the area of ​​these cavities. Substances can be used with fluorescent labels, radioactive labels or enzyme labels with carriers or without carriers, bonded or separable, organic or inorganic, with cells or cell fragments, gel or other for the detection of microorganisms, bacteria, viruses and other things, but also to detection of cancer, for the determination of individual substances in the blood or to determine the pH value, blood sugar, blood cholesterol or for the detection of narcotics or other blood. The appropriate test methods, in particular biological / medical, Chemical composition / physical are known, especially in blood test, to test sera etc. Even research methods for other body fluids such as lymph, urine, etc. are known, depending on whether small particles labeled or unlabeled, organic / be inorganic, used with or without a carrier of a known type, fluoroscopy are recommended using X-rays, but also investigations with the aid of gamma rays, visible light infrared or ultraviolet light (optical process). Evaluation by means of optical fibers are shown for example in Fig. 9 and 10. In tests of the flow properties of substances or substance mixtures is advantageous, as shown in FIG. 8 to control the inflow, outflow or both (flow rate) with the help of micro-valves 12 and 13 in the cover or base 5 of the block 1 with the microcavities second The micro valves themselves are known per se (see for example EP-A-0250948). They are preferably in the same array or in the same matrix arranged in XY direction as the cavities 2 in block 1 and thereby give a simple evaluation possibility for respective investigations. In the bottom 5 7 may be arranged as shown in Fig. 6 is a layer. Below the bottom 5 is still a further support part or end plate 14 be arranged, which includes a detecting means such as photo-elements in the same array arrangement for analysis to a microprocessor (not shown here). can forward. The lines for supply and removal of substances, reagents, etc. are not shown, nor is the radioactive sources which advantageously from above, ie above the lid 3, radiate in Fig. 8. The parts 3 and 5 can also be 8 in Fig. Advantageously glass, quartz or silicon ceramic or a silicon composite material and at least partially transparent, at least partially reflective. Top or bottom may be possibly replaced by foil strips of opaque material, at least partially, for example, may also be on the cover 3, if it contains the microvalves, another plastic film can be adhered, which causes a hermetically sealed closure, but are pierced by a hollow needle can. Films or layers may be optically opaque or out, they can be designed as heating layers 10 or heat sink 11 or formed specular / nichtspiegelnd, permeable to certain wavelengths filternd, partially transparent or similar for optical purposes. Also, carbon or diamond layers and / or mask layers that are time- or partially kavitätenabdeckend usable.

The micro-valves can be controlled and driven in a conventional manner or as described in the manner as described in German patent application DE-A-38 11 052.0-31. The reaction in the cavities can then be effected by moving for example on piezoelectric routes, magnetic, electrostatic or similar. In this case, a nutrient solution, a mutant, a Reganz or the like diluted, enriched, are dosed and the residence time are controlled by respective closing and opening of the microvalves. The heat treatment or cooling treatment can be by means of Peltier elements, heat pipes, Thomson-Joule coolers or the like performed.

As sensors, arranged in the same array in the lowest layer, in turn, silicon sensors are preferred, especially for the study of physical or chemical properties such as black and white or gray scale, contrast, turbidity, transmittance, transparency, reflection, conductivity, resistance, capacitance, pressure, strain , temperature volume, quantity, time, etc. in order to evaluate the measured values ​​are passed on to a microprocessor or microcomputer, not shown. The readout can follow in a conventional manner, if the evaluation is carried out visually, eg the type of DE-A-38 17 153.8-33.

The storage and documentation of the data of the measurement or test program and the storage of, for example patient data disease or data or data from sera or pharmaceuticals can be carried out on the same chip (lowermost layer in Fig. 8 to 10). The storage can take place either with the help of an optical memory, for example, according to DE-A-3804751 with amorphous silicon as a storage medium (bubble memory) or as an integrated semiconductor memory device (DE-A-38 17 153) or a RAM device (DE -A-37 01 295.9-52). Referring to FIG. 9, it is possible in a simple manner in an optical or optoelectronic evaluation using an optical waveguide 15, which passes through the micro-chamber or cavity 2 in block 1 or comes close to it and is etched in interesting area of ​​his coat and eg is coated to achieve a response in particular substrate.

Modifications of the embodiment of FIG. 9 are manifold possible, especially for photoelectric or other photoelectric evaluation not only by means of optical fibers. The light guides are preferably V-grooves, at the bottom thereof disposed adjacent fixed and not only continuously available but also cut obliquely corresponding to the inclination of the pit, and at least partial surfaces 15a, 15b of the light guide 15 (sectional area) or the V-pit are reflective , The arrangement parallel to the pit across the pit from above or below 90 degrees, 180 degrees or the like occur. The optical fibers are taken out and are for evaluation to photocells, such as line sensors or arrays, connected for the purpose of analog or preferably digital readout. The readout can be done in rows and ranks, described for example by scanning using a photo-electric line sensor as described in DE-OS 3,804,200. Here, an optical bus can be used. A suitable optical data system is described in DE-PS 3 619 778. transmitters and receivers, in particular diodes may be integrated into the structural unit. The mines are in their V-angle (slope adjustable or changeable, see DE-A-3613181). An integrated optical waveguide and their structure and applications are described in the journal Laser and Optoelectronics, no. 4, 1986, pages 323 to 336. On page 338 of the same journal are also described applications of optical fiber sensors in medicine.

In Fig. 10 is a block 1 with the bottom 5 and the lid 3 is shown with microcavities 2, in particular extends through recesses in the cover 3 and bottom 5 - similar to that of Fig. 7 - but above the in-array arrangement microcavities 2 each treatment openings, valves, supply and discharge organs, window, dopant ranges are merited, etc. according to the chamber volume in the lid 3, while, for example, an array of photoelectric cells or a CCD array or a MOS field-effect transistor is arranged in the bottom 5 of the reading and evaluating, for example, is connected via the aforementioned optical or an electrical bus to an evaluation unit, in particular with microprocessors of the microcomputer. A light pen 16 scans rows and row by row, the array from, for example, in binary code 8x8 microcavities or cells or 10x10 for direct digital interrogation. Instead of the light pen 16 may also be a piezoelectric, a capacitive, magnetic or electrical sensors are used. The pin 16 is then ready for application of a voltage, power or light irradiation or the like suitable to the window 17 in the lid 3 into the chambers 2 of the block 1 to the direct read-out, for example via a CCD array in the same arrangement as the microcavities or cells, indicated here by the CCD cells 17 '. In the same manner may also be arranged a MOSFET or a RAM device. The readout can be carried out with components of the integrated optics, in particular non-contact and two-dimensionally (see, DE-A-3605018 or US-A-4778989). Instead of the light pen 16 also an ion-selective measuring electrode could be used as a replaceable sensor element, in particular for measuring the ion activity in liquids and on tissue surfaces. Such ion-selective measuring systems are known and commercially available. They are based on a pure electric evaluation principle in contrast to the embodiment of FIG. 9, for example, is used for the optical determination of the catalytic enzyme activity of a substance sample, wherein the conditioned by the emzymatische reaction change of spectral properties of an enzyme substrate or its reaction products are detected per unit time. The enzyme substrate is associated with the exposed portion of a light guide with which the sample substance to be measured is brought into contact.

In the embodiment of Fig. 10 an analysis with the aid of a CCD array, for example, according to DE-A-3817153, or by means of semiconductors according to DE-A-3715674, or by means of liquid crystal elements is recommended, such as in the DE-C-3602796 describes. With such elements, a direct storage of test or analysis result is possible at any time specifically interrogated, even after individual microcavities.

In Figs. 11 and 12, the properties to be examined adapted optronic / electronic sensors are shown, which are generally known under the term "biosensors". Such biosensors generally operate with field-effect transistor 18 in silicon technology. Together, the biosensor produced thereby has a biological component on the surface, di e is connected to the gate of the transistor. This biological component or reagent or enzyme substrate 19 must be capable of respectively desired reaction. Then you can after the workspace is optimally set, by means of one or more voltage sources U1, U2, impose voltage eg when R to drain and source and measure corresponding changes in ion activity. The measurement 12 may also be photoelectrically with the aid of light conductors between the transmitter and receiver, such as diodes, lasers, integrated in FIG.. A biosensor of the kind here at issue is described in DE-C-3634573.

In FIG. 13, a sensor is shown purely schematically on a silicon wafer 20, wherein a sensor chip 21 is reacted with the substance sample, such as a soil sample, a liquid sample, a food sample or a tissue sample with contaminants therein whose proportion is to be determined, for example. It can also be an oxygen demand or oxygen content or the like can be determined. The sensor is a conventional Termistor- or conductivity sensor. Also, sound or ultrasound or infra-sound sensors are suitable if the sample is to be hereby applied. Miniature microphones are known.

In Fig. 14, the embodiment of an automatic test machine is shown. A microcomputer or microprocessor assumes control of the test sequence according to a predetermined test program. The program can be contained in replaceable an external memory, eg in a PROM or EPROM, or an erasable read-write memory. Patient data, data of the test materials, the reagents, etc. are also interchangeable and after a test, the test results in the microcomputer or microprocessor are also stored, in particular in a memory for random access and the recording itself documenting, for example, as a CCD image, thermal imaging piezoresistive or on magnetic tape, electrostatic or ferroelectric etc.

In the embodiment of Fig. 14, a film carrier 23 is shown adhered to the macro chip from a Vielzehl individual chips in FIGS. 1 to 5 or releasably attached, wherein said film carrier has a transport perforation 24, the film with the usual film transports, such as controlled Maltese cross from roll to roll over a treatment period of the program, and from station to station 25, that is here to lead IX. Initially, one or more substances to the test program will be introduced into the microcavities of the chips in Station I. In station II then there is a reaction, either with or without treatment, and after a reaction time is measured automatically and transported to the test station III, as necessary, carry out further tests, the test results are automatically assigned to the individual cavities, optionally individual Probesubstanzherkünften, and patients. The self-documentation and storage takes place in the microcomputer or microprocessor 22 for automatic test control and test applications.