ES2278508B1 - SILICON CARBIDE SENSOR SYSTEM (SIC) SEMI-INSULATING, PROCESSING PROCEDURE AND ITS APPLICATIONS. - Google Patents

Abstract

Semi-insulating silicon carbide (SIC) sensor system, manufacturing process and its applications. The present invention relates to devices made with microelectronic technologies on a semi-insulating Si carbide substrate for monitoring the biological behavior of organic organs, tissues, cells or molecules. It also refers to its manufacturing process.

Description

Sensor system in silicon carbide (SiC) semi-insulating, processing procedure and its applications.

Technical sector

This invention falls within the sector of semiconductor technologies in terms of material and process manufacturing refers to and in the biomedical sector as far as the application.

The objective of the present invention is the use of Semi-insulating SiC as a substrate of any microsystem or microdevice for biomedical applications of monitoring and recording and that at least partially resolves inconveniences and limitations of the systems realized on other semiconductor substrates for biomedical applications.

State of the art

The present invention relates to systems of recording and monitoring of biological signals originating in living entities, whether cells or cell cultures, tissues, organs or whole organisms. In particular, the present invention makes reference to the use of new materials in physical devices for simultaneous and / or multi-frequency uptake of different biological signals

The biological signal register is a extremely important activity in device development doctors and for the exploration of living things. There are many of techniques and methods for recording biological signals. These differ from each other primarily based on (1) the nature of the biological signal to be recorded, (2) the principle of application for signal pickup, (3) the registration period and (4) the device application system on the entity biological

In recent years, and thanks to the advances made in microelectronics and microsystems technologies, it they have developed microsystems capable of monitoring different physicochemical parameters on a single platform and in a way simultaneous. Using multiple microsensors arranged on a same substrate, these types of devices allow measuring various physiological parameters (e.g. temperature, electrical impedance, pH and [K +]) of a cell culture or an organ simultaneously, minimally invasive and spatially located, facilitating the extraction of correlations useful for diagnosis and prognosis between the monitored parameters [1] [2] [3].

Despite its enormous advantages, a problem common in these devices lies in their technological heritage. He If ultrapure crystalline is the material par excellence in microelectronics and, therefore, also in the development of microsystems Despite its numerous advantages, such as possibility of incorporating microelectronic circuitry and Photoelectronics and even nanotechnologies, the Si also presents strong disadvantages Its opacity to ultraviolet radiation and visible, for example, hinders optical inspection and its coupling with fluorescence detection systems in applications such as cell cultures. Moreover, your relative fragility greatly hinders its handling in applications clinical and involves a risk in its introduction and / or implant in living beings. Finally, the resistivity of the Si substrate distorts the electrical register at certain frequencies, since the currents applied for registration partially escape through of the substrate. This phenomenon also decreases the effectiveness of techniques necessary in the creation of recording electrodes, such as electromigration platinization, and prevents its use as device in other analytical techniques of interest that require significant voltages, such as electrophoresis.

There are currently alternatives to Si To solve these problems. Different materials, such as glass or various types of plastic polymers and silicones such as PMMA, PMMS or polymides, and combinations between them have been used as substrates for, for example, the creation of electrophoresis microsystems, manufacturing devices for cell culture or for local monitoring of various parameters in living tissue. These substrates require various techniques to its manufacturing, as the photolithographic process of wet engraving in glass, hot-embossing and molded techniques in polymers, etc. Even so, and despite its proven functionality, These devices do not solve some of the problems of Si e They even introduce some of their own. Neither glass nor polymers allow to create the whole range of three-dimensional structures available in Si technologies. In addition, neither of these two types of substrate allows the integration of microelectronic circuitry, Photoelectronics or nanotechnologies. Many polymers are strongly opaque at visible and ultraviolet wavelengths, and the glass is remarkably opaque to the latter. Most of polymers also do not allow the deposition of metals to electrodes or their platinization using standard techniques, decreasing their reliability. The increase in resistance mechanics is not excessively significant in glass, and it is achieved in exchange for high flexibility in most polymers, making them poorly indicated for tissue penetration alive

SiC is a semiconductor material with a Long history as an abrasive material in the industry. But nevertheless, it has not been until the last decade of the twentieth century when, thanks to development of new processes to obtain ultra pure SiC (microelectronic quality), this material has reached a remarkable relevance in the area of microelectronics as a new substrate for creating high power devices, high frequency and high temperature The SiC has numerous properties that make it indicated for this type of applications: wide gap width electronic, high thermal conductivity, high breaking voltage, high saturation rate of load carriers, high thermal stability, low coefficient of thermal expansion, low density and high inactivity and chemical resistivity [4].

These characteristics of SiC as a substrate in microtechnologies has made it widely used in the area of aerospace and automotive industry applications by example [5].

Apart from these characteristics, as material semiconductor, the SiC also has other characteristics that They are suitable for use in the biomedical field.

Both the Si substrate and the SiC are considered as biocompatible materials as titanium and for both ideal for implantable systems, for example. But also the SiC has advantages over the Si as soon as it has a lower protein adhesion and lower platelet aggregation, when puts in contact with blood) [6].

Because it is also very chemically inert and very resistant in extreme mechanical and environmental conditions, much has begun to be used for surface coatings for implantable joint prostheses and lately as a coating for stents and other intravascular prostheses due to its good hemocompatibility (lower adhesion of proteins and lower platelet aggregation).

A recent study concludes that SiC has superior mechanical and tribological properties (hardness, resistance to friction and prolonged use) that make it a material suitable for orthopedic use with respect to other materials most commonly used for these applications such as chrome-cobalt and molybdenum alloys (CoCrMo) or the titanium-6 aluminum-4 vanadium Ti-6A1-4V and even steel 316L stainless (SS 316L) [7].

In the biomedical field and with microelectronic technologies, SiC nanoporous structures have been created that allow its use as a semi-permeable material for the creation of membranes that can act as an interface in vivo in biomedical applications. Therefore, it can be used, for example, for use in an artificial implant of the pancreas, kidney or for an oral implantable drug dispenser [8].

The semi-insulating SiC has other features, in addition to those mentioned above (biocompatibility and resistance), which can be very useful in the biomedical field. Features like presenting a remarkably high intrinsic resistivity, although it may be doped to reach semiconduction levels typical of Si and although it presents a multitude of polytypes with different surface characteristics (e.g., polar, non-polar), is manipulable at nanometric scales, and allows the integration of active components of greater resistance and range of application that Si itself. Another feature is that the semi-insulating SiC is transparent in the visible range and infrared.

All these features can be very useful in what biomedical microdevices. Has not been found no reference of its use as a substrate for devices for biomedical applications and specifically for biological signal monitoring. Its use can improve the features currently presented by the devices made in Si substrate for biomedical applications of monitoring and recording

References

[1] Minimally invasive silicon probe for electrical impedance measurements in small animals. Ivorra A, Gomez R, Noguera N, Villa R, Sola A, Palacios L, Hotter G, Aguilo J, Biosensors and Bioelectronics, Volume 19, Issue 4, 15 December 2003 , Pages 391-399 .

[2] New technology for multi-sensor silicon needle for biomedical application. A. Errachid , A. Ivorra , J. Aguió , R. Villa , J. Millán , J. Bausells , N. Zine . Sensors and Actuators B: Chemical, 78 (1-3) ( 2001 ) pp. 279-284 .

[3] Patent ES 2 154 241 A1. Multisensor microsystem based on Si. Applicant: CSIC .

[4] Silicon carbide electronic devices. Encyclopedia of Materials: Science and Technology. ISBN: 0-08-0431526. pp 8508-8519 .

[5] Silicon carbide: Recent major advances. Choyke WJ, Matsunami H, Pensl G. Berlin: Springer Verlag, 2003 .

[6] Evaluation of MEMS materials of construction for implantable medical devices. Kotzar , G., Freas , M., Abel , P., Fleischman , A., Roy , A., Zorman , C., Moran , JM, and J. Melzak ( 2002 ) Biomaterials 23: 2737-2750.

[7] Micro / nanoscale mechanical and tribological characterization of SiC for orthopedic applications. Xiaodong Li , Xinnan Wang , Robert Bondokov , Julie Morris , Yuehuei H. An , Tangali S. Sudarshan . Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2004 , Volume 72B, Issue 2, Pages 353-361 .

[8] Nanoporous SiC: A Semi-Permeable Candidate Material for Biomedical Applications. AJ Rosenbloom ; DM Sipe ; Y. Shishkin ; Y. Ke ; RP Devaty ; WJ Choyke . Biomedical Microdevices, December 2004 , vol. 6, no. 4, pp. 261-267 (7) .

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Description of the invention

The present invention relates to the manufacture and use of devices made with microelectronic technologies on a semi-insulating SiC substrate for monitoring the biological behavior of organic organs, tissues, cells or molecules. The novelty of this invention is that by means of microelectronic technologies and the use of semi-insulating SiC as a substrate, sensor microsystems have been obtained for medical devices that offer better performance compared to other substrates currently used as Si, SiC not semi-isolated.
lante etc.

In particular, the advantages offered by SiC semi-insulating, as a new biocompatible material for use in devices for monitoring the biological behavior of organs, tissues, cells or organic molecules, are the following:

Transparency at wavelengths visible and infrared.

High mechanical resistance with respect to Yes.

High resistivity that improves significantly the multifrequency electrical register and also allowing an improved deposition of metals to electrodes, that is, the platinization process is optimized. In addition the largest critical electric field allows an application of higher voltages.

Greater biocompatibility than what provide the Yes.

It allows processing using technologies of adapted microsystems and manufacturing environments of the Yes.

It allows the integration of technology microelectronics with photoelectronics at the same time.

It allows the integration of nanotechnologies such as carbon nanotubes.

Thus, an object of the invention constitutes a microsystem useful as a biological signal sensor, hereinafter micro device of the invention, comprising semi-insulating SiC as a substrate for biomedical applications for monitoring organic organs, tissues, cells or molecules.

In addition, the microsystem of the invention can include other necessary elements, defined and known by a technical technician from the technical sector, for the final application of the microdevice as a sensor such as one or more electrodes or other type of sensors, made with technologies microelectronics, for monitoring physical parameters, chemical, optical, electrical and biological in different ranges and frequencies

Similarly, the microsystem may include a device and / or nanotechnological processes for monitoring physical, chemical, electrical and biological parameters; or an integrated or external battery power system, network connection or radio frequency carrier wave; or integrated circuitry in the same substrate for acquisition, treatment, amplification, process, multiplexing or telemetry sending of the captured signals.

On the other hand, depending on the application concrete and technical needs the microdevice of the invention can present different shapes, dimensions and process and encapsulated mechanisms depending on the applications late. A specific embodiment is a microdevice in form microneedle (see example 1).

Another object of the present invention is a manufacturing process of the microsystem of the invention characterized by the following stages:

1. Semi-insulating SiC substrate cleaning with suitable solvents and acids,

2. Deposit of a dielectric layer: this layer it can be composed of one or several dielectric materials stacked; such as silicon oxide, silicon nitride, nitride aluminum, alumina, high K dielectrics, etc.,

3. Deposit of a metallic layer for electrode formation: this layer can be composed of one or various stacked metals such as Titanium, Platinum, Gold or Cobalt,

4. Engraving of the metal layer,

5. Deposit of the passivation layer: this layer it can be composed of one or several dielectric materials stacked, such as silicon oxide, silicon nitride, nitride aluminum, alumina, high K dielectrics, etc.,

6. Opening contacts in the layer passivation, and

7. Separation of the components by sawn of the processed substrate.

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Given the intrinsic nature of the SiC substrate semi-insulating, the layer deposition stage can be ignored dielectric in the manufacturing process, unlike others semiconductor substrates such as Silicon. The thickness of this layer it can vary between 0 (in the case of absence of dielectric layer) and 3 micrometers

The definition of the electrode motifs and its interconnection tracks is done through a process photolithographic with photosensitive resin or using a mask metallic In the case of a lithographic process, it can be perform before or after the deposit of metals.

The engraving of the metallic layer 4) can be done by the "lift-off" technique, through a wet etching with acids or dry plasma etching (RIE / ICP / DECR).

The definition of the contact areas of the Contact Opening stage in the passivation layer (5)) is performed using a photolithographic process with resin photosensitive. The engraving can be of the wet type with acids, or Well dry plasma type (RIE / ICP / DECR).

This manufacturing process also applies to the manufacture of devices for cell cultures.

Let us also indicate that the process of manufacturing described above can also be performed on diamond substrates This semiconductor material presents characteristics similar to those of the semi-alloy SiC.

Finally, another object of the invention is the use of the microsystem of the invention in measurement procedures of biological signals with biomedical monitoring applications of organs, tissues, cells or organic molecules. This microdevice allow the growth and / or adhesion of cells or biological tissues.

The application of this microdevice can be performed invasively or non-invasively on the biological sample; being able to be implanted in living beings and / or tissues temporarily or permanently, as for example in a being
human.

Description of the Figures

Figure 1.- Diagram of the needle designed to be manufactured with microelectronic technologies with semiconductor substrates (Si and SiC) .

Figure 2.- Manufacturing process and cutting section of the needle made with SiC substrate . The diagram indicates the architecture of the technological process.

Figure 3.- In vitro study of needles with Si substrate . The results of the behavior of needles with semi-insulating SiC substrate immersed in physiological serum simulating a biological medium are shown.

Figure 4.- " In vitro " study with semi-insulating SiC substrate . The results of the behavior of needles with Si substrate immersed in physiological serum simulating a biological medium are shown.

Figure 5.- (A) Mask for the manufacture of semi-insulating SiC microdevices for biomedical applications as cell culture monitoring platforms (B) Detail of one of these platforms that in this example contains 16 Platinum electrodes (C) Cutting scheme of the process of manufacturing. (D) Experimental results of the monitoring of a cell culture at different frequencies.

Figure 6.- Scheme of the proposed generic device . Electrophoresis device with T-injection, four cuvettes and two channels.

Figure 7.- Detail of an area of the cross in the electrophoresis channels made in semi-insulating SiC by dry attack by RIE.

Examples of embodiment of the invention

As a description of embodiments of the The present invention details three examples of devices, not Limitations of the scope of the invention, made in substrate of Semi-insulating SiC for monitoring biological behavior of organs, tissues, cells or organic molecules:

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Example 1 Microneedle sensor in semi-insulating SiC substrate

The novelty presented in this first example is the semi-insulating realization in SiC of a needle-shaped microdevice in which one can be integrated or more electrical, chemical or optical sensors through processes micro or nano technological.

An example of Figure 1 shows a needle-type microdevice made with processes semi-insulating SiC microelectronics with the following dimensions: 15 mm in length, 525 µm in width and 350 µm thick, with 4 platinum electrodes of 300 x 300 µm each  and 1,800 Å thick.

Starting materials

- SiC 4 '' Wafer and Semi-insulating Wafer Si 4''

- 1st stage: field oxide deposit (FOX, Field Oxide): 1.5 µm SiO2.

- 2nd stage: Ti / Pt tank: metal for electrode.

- 3rd stage: Lift-off layer Ti / Pt

- 4th stage: deposit of the passivation (SiO2-Si3N4).

The scheme of the process is shown in Figure 2 Technological for the realization of this device. He microdevice has been developed with the procedure that described in the detailed description.

In this specific example, its application is for Intra-tissue bioimpedance monitoring of organs or tissues. Examples of biomedical applications can be, ischemia monitoring and ischemia-reperfusion of organs or tissues in animal experimentation, cardiac surgery, organ transplantation etc.

The results of the Needle behavior with semi-insulating SiC substrate immersed in physiological serum simulating a biological medium. In the Figure 4 shows the results of the behavior of the immersed semi-insulated SiC substrate needles in physiological serum simulating a biological medium. Both results show that the semi-insulating SiC offers the following advantages regarding the Si in the needle-shaped microdevices for monitor the bioimpedance of organs, tissues or cells live:

?

 High resistivity that improve significantly:

-

He multifrequency electrical register.

-

He performance of the platinization process of electrodes

-

The application of higher voltages

?

 Greater resistance mechanics.

Example 2 Microdevice for cell cultures

The novelty presented in this second example is the realization of a SiC substrate microdevice semi-insulator for cell culture monitoring. They are microdevices consisting of a SiC platform semi-insulating dimensions adapted to crop media, with one or more electrical, chemical or optical sensors incorporated by micro or nano technological processes on which the cell culture. The crops can be of different types cell phones and toxic chemicals can be added to them, drugs or other substances of interest to analyze your influence on the culture medium. This influence will be monitored through the micro device.

These platforms made on substrates of Semi-insulating SiC have the advantages listed above for cell culture monitoring and also another that results from very useful for this application and its transparency is what allows the use of microscopy techniques at the same time (See figure 5).

Example 3 Microchannel with microchannels for electrophoresis

The novelty presented in this third example is the realization of a semi-insulating SiC microdevice with microchannels and cuvettes made with micro or nanotechnological processes to be applied as biomolecule analysis systems. In addition to the advantages mentioned above, the possibility of applying large voltages and its ease of assembly with the glass by anodic bonding is added .

Specifically, the system presented in this example corresponds to a microsystem for electrophoresis by cross injection. For use, the system is filled with solution buffer and / or electrophoresis gel (e.g. acrylamide, agarose, etc.) by injection through the different receptacles. The substance to be analyzed is deposited in well 1 and injected typically by applying a voltage between electrodes 1 and 2. Once the solute of interest has been inserted into the cross, then a high voltage (0.2 to 5 kV) is applied between electrodes 3 and 4 for the electrophoretic separation of the solute in the separation channel. The usual dimensions of channels are 1-2 cm for the injection and 3-6 cm for the separation, and the cuvettes they usually have an approximate diameter of 1 cm, although none of these dimensions is limiting.

The system is made of semi-insulating SiC. The semi-insulating SiC has been recorded to define the channels to a depth of ~ 20 µm by dry etching by RIE (Reactive Ion Etching), although the channels can also be obtained by wet etching techniques. The depth of the channels has been established in this case for a proposed application (protein electrophoresis) but may vary depending on the application between 0.5 and 200 µm and in no case is it limited by the technological process used here. The system is covered by an insulating substrate (glass) that has been glued tightly (to avoid leaks) to the semi-insulating SiC by means of the anodic welding technique. Other techniques and materials can also be used to seal, such as glass glued with different types of resins and glues, thermal weld of the glass to the semi-insulating SiC, use semi-insulating SiC as a cover by thermal welding or glued with intermediate layers, or use any other electrical insulating material capable of being welded / glued to the semi-insulating SiC so that it covers the separation channels. The glass has been drilled in the areas that remain immediately above the cuvettes to allow access to the wells, although there is the alternative of using a piece of cut glass to not cover the cuvettes if the design (as in this case) allows . The technique used to pierce the glass in this case has been an attack in HF solution, although alternative techniques (such as sandblasting , ultrasonic drill or laser) can be used. It is also possible, although not recommended, to perform this type of systems in open (without coverage).

Detection of the separated sample is performed typically at the end of the separation channel. In this case it has used a laser induced fluorescence system, marking the molecules to separate and then detect them with a microscope confocal and photomultiplier. However, the sample can be mark in many other ways (e.g. radioactivity) and detect with optical systems, radioactive measurement, electromechanical or electric

The design shown in the figure corresponds to a simple microsystem for protein electrophoresis, which could also be used for the separation of DNA by inserting a separation gel, or of any other molecule capable of being electrophoretically separated. This basic design can be expanded and improved in many ways. For example, injection / separation channels can be added to perform multiple parallel electrophoresis or two-dimensional electrophoresis, the separation channel can also be modified to convert it into a wide slab-gel type separation zone.

In addition, the system can be modified extensively to adapt to the different needs presented by the sample. For example, injection wells can be modified to become wells where a polymerase chain reaction (PCR), a ligation, a restriction, a phosphorylation or a cell lysis (among other reactions) takes place, by including electrodes and / or resistors to carry out thermal cycles or apply voltages locally, and by adding the required reagents to the well. Likewise, the channels can also be adapted to become immuno-magnetic capture channels of cells or molecules, solute distribution channels such as fluorescent markers, etc. Detectors can also be integrated to perform on-site detection, such as photodiodes, electrodes or radioactivity counters.

So, starting from the example proposed here as a demonstrator and using conventional microtechnologies, the microsystem described here can be expanded and improved to give place to a total analysis microsystem (m-TAS), in which other reactions take place (apart from the electrophoresis) of importance for the analysis or preparation of the sample, such as PCR or other amplification techniques, hybridization, ligation, restriction, magneto-capture, phosphorylation, radioactive, fluorescent or other labeling, And a long etcetera.

The embodiment of this invention in carbide of semi-insulating silicon (semi-insulating SiC) is innovative and It has numerous advantages over alternative technologies. With respect to silicon, the semi-insulating SiC is clearly superior in its electrical resistance, which allows the application of high voltages (e.g. 1 kV), a fact that results in high electrophoresis Resolution and very fast. In addition, the semi-insulating SiC is transparent to wavelengths typically used in detection and this greatly improves the quality of this comparing it with opaque substrates such as silicon. Its down thermal resistivity allows more effective heat dissipation than in silicon and much more effective than in glass and polymers, minimizing the Joule effects of local heating due to applied electric field that distort the bands of electrophoresis This again allows the application of high electrical potentials without loss of resolution due to distortion of Joule effects. Regarding glass and other polymers, the Semi-insulating SiC has the advantage of being completely integrable in a microtechnological process environment, which allows the integration of active devices and control over the same substrate, as well as all kinds of sensors, such as photodiodes or chemical sensors for the detection of molecules a pull apart.

These are three examples of microsystem or microdevices that manufactured with semi-insulating SiC substrates they present some new advantages over the current ones what allows to improve and expand its biomedical applicability as monitoring of living beings.

Claims (17)

1. Microsystem useful as a biological signal sensor characterized in that it comprises semi-insulating SiC as a substrate for biomedical applications for monitoring organic organs, tissues, cells or molecules. 2. Microsystem according to claim 1 characterized in that one or more electrodes made with microelectronic technologies are included, for the monitoring of physical, chemical, optical, electrical and biological parameters in different ranges and frequencies. 3. Microsystem according to claims 1 and 2 characterized in that a device and / or nanotechnological processes for the monitoring of physical, chemical, electrical and biological parameters are included. 4. Microsystem according to claim 4 characterized in that it has a needle shape. 5. Microsystem according to claims 1 to 5 characterized in that it includes an integrated or external battery power supply system, network connection or radio frequency carrier wave. 6. Microsystem according to claims 1 to 6, characterized in that it includes integrated circuitry in the same substrate for acquisition, treatment, amplification, process, multiplexing or telemetry sending of the captured signals. 7. Method of manufacturing a microsystem according to claims 1 to 7 characterized by the following steps: a) Cleaning the semi-insulating SiC substrate with suitable solvents and acids, b) Deposit of a dielectric layer: this layer it can be composed of one or several dielectric materials stacked, c) Deposit of a metallic layer for the electrode formation: this layer can be composed of one or various stacked metals such as Titanium, Platinum, Gold or Cobalt, d) Engraving of the metal layer, e) Deposit of the passivation layer: this layer it can be composed of one or several dielectric materials stacked, t) Opening contacts in the layer passivation, and g) Separation of the components by sawn of the processed substrate. 8. Method according to claim 8 characterized in that step b) has been omitted. 9. Method according to claim 8 characterized in that the definition of the electrode motifs and their interconnection tracks for the deposition of the metallic layer of c) is carried out by a photographic process with photosensitive resin or by using a metal mask or by a process Lithographic that can be performed before or after the deposit of metals. Method according to claim 8, characterized in that the engraving of the metallic layer d) can be done by the "lift-off" technique, by means of a wet etching with acids or by dry plasma etching (RIE / ICP / DECR) . Method according to claim 8, characterized in that the stacking dielectric material of e) belongs to the following group: silicon oxide, silicon nitride, aluminum nitride, alumina and high K dielectrics. 12. Method according to claim 8 characterized in that the definition of the contact areas of the contact opening stage in the passivation layer (f)) is carried out by a photolithographic process with photosensitive resin and where the engraving can be of the wet type with acids, or dry plasma type (RIE / ICP / DECR). 13. The method according to claim 8, characterized in that the stacking dielectric material of b) belongs to the following group: silicon oxide), silicon nitride, aluminum nitride, alumina and high K dielectrics. 14. Use of the microsystem according to claims 1 to 7 in signal measurement procedures biological with biomedical organ monitoring applications, organic tissues, cells or molecules.

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15. Use according to claim 14 characterized in that it is applied invasively or non-invasively on the biological sample. 16. Use according to claim 14 characterized in that the microdevice is implanted in living beings and / or living tissues temporarily or permanently. 17. Use according to claim 16 characterized in that the living being is a human being.