WO2007010076A1 - Semi-insulating silicon carbide (sic) sensor system, production method thereof and use of same - Google Patents

Semi-insulating silicon carbide (sic) sensor system, production method thereof and use of same Download PDF

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Publication number
WO2007010076A1
WO2007010076A1 PCT/ES2006/070104 ES2006070104W WO2007010076A1 WO 2007010076 A1 WO2007010076 A1 WO 2007010076A1 ES 2006070104 W ES2006070104 W ES 2006070104W WO 2007010076 A1 WO2007010076 A1 WO 2007010076A1
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Prior art keywords
microsystem
semi
layer
sic
substrate
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PCT/ES2006/070104
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Spanish (es)
French (fr)
Inventor
José MILLÁN GÓMEZ
Philippe Godignon
Iván ERILL SAGALÉS
Rodrigo GÓMEZ MARTÍNEZ
Jordi AGUILÓ LLOBET
Rosa Villa Sanz
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Consejo Superior De Investigaciones Científicas
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/685—Microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14542—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring blood gases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means

Definitions

  • This invention is part of the semiconductor technology sector in terms of material and manufacturing process and in the biomedical sector in terms of application.
  • the objective of the present invention is the use of Semi-Insulating SiC as a substrate of any microsystem or microdevice for biomedical monitoring and recording applications and that at least partially resolves the inconveniences and limitations of the systems made on other semiconductor substrates for biomedical applications.
  • the present invention relates to systems for recording and monitoring biological signals originating in living entities, whether cells or cell cultures, tissues, organs or entire organisms.
  • the present invention refers to the use of new materials in physical devices for simultaneous and / or multi-frequency uptake of different biological signals.
  • the registration of biological signals is a very important activity in the development of medical devices and for the exploration of living beings.
  • microsystems have been developed capable of monitoring different physicochemical parameters on a single platform and simultaneously.
  • these types of devices allow measuring various physiological parameters (eg 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].
  • physiological parameters eg temperature, electrical impedance, pH and [K +]
  • the ultrapure crystalline Si is the material par excellence in microelectronics and, therefore, also in the development of microsystems.
  • Si also has strong disadvantages. Its opacity to ultraviolet and visible radiation, for example, makes optical inspection difficult and its coupling with fluorescence detection systems in applications such as cell cultures.
  • its relative fragility greatly hinders its management in clinical applications and poses a risk in its introduction and / or implantation in living beings.
  • the resistivity of the Si substrate distorts the electrical register at certain frequencies, since the currents applied to the register partially leak through the substrate. This phenomenon also reduces the effectiveness of necessary techniques in the creation of recording electrodes, such as electromigration platinization, and prevents their use as a device in other analytical techniques of interest that require significant voltages, such as electrophoresis.
  • Si there are 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 among them have been used as substrates for, for example, the creation of electrophoresis microsystems, the manufacture of devices for cell culture or for local monitoring of various parameters in living tissue
  • substrates require various manufacturing techniques, such as the photolithographic process of wet glass etching, hot-embossing and polymer molding techniques, etc. Even so, and despite their proven functionality, these devices do not solve some of the Si problems and even introduce some of their own.
  • Neither glass nor polymers allow to create the whole range of three-dimensional structures available in Si technologies.
  • neither of these two types of substrate allows the integration of microelectronic, photoelectronic or nanotechnology circuitry.
  • Many polymers are strongly opaque at visible and ultraviolet wavelengths, and the glass is remarkably opaque to the latter.
  • the majority of polymers do not allow the deposition of metals for electrodes or their platinization by standard techniques, reducing their ability.
  • the increase in mechanical strength is not excessively significant in glass, and is achieved in exchange for high flexibility in most polymers, making them poorly indicated for penetration into living tissues.
  • SiC is a semiconductor material with a long history as an abrasive material in the industry. However, it has not been until the last decade of the twentieth century when, thanks to the 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 the creation of high power, high frequency and high temperature devices.
  • the SiC has numerous properties that make it suitable for this type of applications: large electronic gap width, high thermal conductivity, high breaking voltage, high saturation speed of the load carriers, high thermal stability, low coefficient of thermal expansion, low density and high inactivity and chemical resistivity [4].
  • SiC also has other characteristics that make it suitable for use in the biomedical field. Both the Si substrate and SiC are considered as biocompatible materials such as titanium and therefore ideal for implantable systems, for example. But in addition, SiC has advantages over Si as it has lower protein adhesion and lower platelet aggregation, when it comes into 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 in-vascular prostheses due to its good hemocompatibility (lower adhesion of proteins and lower platelet aggregation)
  • SiC has superior mechanical and tribological properties (hardness, resistance to friction and prolonged use) that make it an ideal material for orthopedic use compared to other materials commonly used for these applications such as chromium alloys -cobalt and molybdenum (CoCrMo) or that of titanium-6 aluminum-4 vanadium T ⁇ -6A1-4V and even that of 316L stainless steel (SS 316L) [7].
  • 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 applications Biomedical For this reason, it can be used, for example, for use in artificial implantation of the pancreas, kidney or for oral implantable drug dispenser [8].
  • Semi-insulating SiC has other characteristics, in addition to those mentioned above (biocompatibility and resistance), which can be very useful in the biomedical field. Characteristics such as that it has a remarkably high intrinsic resistivity, although it can be doped to reach semiconduction levels typical of Si and although it presents a multitude of polytypes with different surface characteristics (eg, polar, non-polar), it is manipulable at nanometric scales , and allows the integration of active components of greater resistance and range of application than Si itself. Another feature is that the semi-insulating SiC is transparent in the visible and infrared range. All these features can be very useful depending on which biomedical microdevices. No reference has been found for its use as a substrate for devices for biomedical applications and specifically for the monitoring of biological signals. Its use can improve the benefits currently presented by devices made in Si substrate for biomedical monitoring and recording applications.
  • Patent ES 2 154 241 Al Multisensor microsystem based on Si.
  • Nanoporous SiC A Semi-Permeable Candidate Material for
  • 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 non-semi-insulating etc.
  • the advantages offered by semi-insulating SiC 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 visible and infrared wavelengths.
  • an object of the invention is a microsystem useful as a biological signal sensor, hereinafter microsystem of the invention, comprising semi-insulating SiC as a substrate for Biomedical applications for monitoring organs, tissues, cells or organic molecules.
  • microsystem of the invention may include other necessary elements, defined and known by a technician in the field of art, for the final application of the microsystem as a sensor.
  • a particular object of the present invention is the microsystem of the invention which includes one or more electrodes or other sensors, made with microelectronic technologies, for the monitoring of physical, chemical, optical, electrical and biological parameters. in different ranges and frequencies.
  • Another particular object of the present invention is the microsystem of the invention in which a device and / or nanotechnological processes are included to improve or increase the performance for the monitoring of physical, chemical, electrical and biological parameters (such as the incorporation of carbon nanotubes such as nanoelectrodes, adhesion of polymeters to functionalize the surface etc), 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.
  • a device and / or nanotechnological processes are included to improve or increase the performance for the monitoring of physical, chemical, electrical and biological parameters (such as the incorporation of carbon nanotubes such as nanoelectrodes, adhesion of polymeters to functionalize the surface etc), 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.
  • a specific embodiment of the present invention is a microneedle-shaped microsystem, as shown in example 1.
  • Another specific embodiment of the present invention is a plate-shaped microsystem for cell cultures or "in vitro" tissue cultures such and as shown in example 2.
  • Another particular object of the present invention is the microsystem of the invention in which an integrated or external battery power system, network connection or radio frequency carrier wave is included.
  • Another particular object of the present invention is the microsystem of the invention in which integrated circuitry is included in the same substrate for acquisition, treatment, amplification, process, multiplexing or telemetry sending of the captured signals.
  • Another object of the present invention is a method of manufacturing the microsystem of the invention 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 can be composed of one or several stacked dielectric materials; such as silicon oxide, silicon nitride, aluminum nitride, alumina, high K dielectrics, etc., c. Deposit of a metallic layer for the formation of the electrodes: this layer can be composed of one or several stacked metals such as Titanium, Platinum, Gold or Cobalt, d. Engraving of the metallic layer, e. Deposit of the passivation layer: this layer can be composed of one or several stacked dielectric materials. F. Opening contacts in the passivation layer, and g. Separation of the components by sawing the processed substrate.
  • Another particular object of the invention is the manufacturing process of the microsystem of the invention, described above, in which, given the intrinsic nature of the semi-insulating SiC substrate, step b) of depositing a dielectric layer in the process is obviated manufacturing, unlike other substrates semiconductors such as silicon.
  • the thickness of this layer can vary between 0 (in the case of absence of dielectric layer) and 3 micrometers.
  • Another particular object of the invention is the manufacturing process of the microsystem of the invention described above, in which the definition of the motifs of the electrodes and their interconnection tracks is carried out by a photolithographic process with photosensitive resin or using a metal mask . In the case of a lithographic process, this can be done before or after the deposit of the metals.
  • Another particular object of the invention is the manufacturing process of the microsystem of the invention described above, in which the engraving of the metal 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).
  • Another particular object of the present invention is the method of manufacturing the microsystem, the invention in which the stacking dielectric material described in e) belongs to the following group: silicon oxide, silicon nitride, aluminum nitride, alumina, dielectric high K, etc.
  • Another particular object of the invention is the manufacturing method of the microsystem of the invention described above, in which the definition of the contact areas of the Contact Opening stage in the passivation layer (f )) is performed by a photolithographic process with photosensitive resin.
  • the engraving can be of the wet type with acids, or dry type by plasma (RIE / ICP / DECR).
  • Another particular object of the present invention is the manufacturing process of the microsystem of the invention in which the stacking dielectric material of b) belongs to the following group: silicon oxide, silicon nitride, aluminum nitride, alumina, dielectrics of high K.
  • another object of the invention is the use of the microsystem of the invention in biological signal measurement procedures with biomedical applications for monitoring organic organs, tissues, cells or molecules.
  • Another particular object of the present invention is the use of the microsystem of the invention in an invasive or non-invasive manner on the biological sample.
  • Another particular object of the present invention is the use of the microsystem of the invention by implantation in living beings and / or tissues temporarily or permanently.
  • Another particular object of the present invention is the use of the microsystem of the invention by implantation in a human being.
  • Figure 1 Diagram of the needle designed to be manufactured with microelectronic technologies with semiconductor substrates (Si y ).
  • 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 iter" 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 iter" 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 microsystems or semi-insulating SiC devices for biomedical applications such as cell culture monitoring platforms (B) Detail of one of these platforms that in this example contains 16 electrodes of platinum. (C) Cutting scheme of the manufacturing process. (D) Experimental results of monitoring a cell culture at different frequencies.
  • FIG. 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.
  • 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 or more electrical, chemical or optical sensors can be integrated by micro or nano technological processes.
  • a needle-type microdevice is shown, made with semi-insulating SiC microelectronic processes with the following dimensions: 15 mm in length, 525 ⁇ m in width and
  • FIG. 2 shows the scheme of the technological process for the realization of this device.
  • the microdevice has been developed with the procedure described in the detailed description.
  • Figure 3 shows the results of the behavior of needles with semi-insulating SiC substrate immersed in physiological serum simulating a biological medium.
  • Figure 4 shows the results of the behavior of needles with semi-insulating SiC substrate immersed in physiological serum simulating a biological medium. Both results show that the semi-insulating SiC offers the following advantages over the Si in the needle-shaped micro system to monitor the bioimpedance of living organs, tissues or cells:
  • the novelty presented in this second example is the realization of a semi-insulating SiC substrate micro device for cell culture monitoring.
  • They are microsystems that consist of a semi-insulating SiC platform of dimensions adapted to culture media, with one or more electrical, chemical or optical sensors incorporated by micro or nano technological processes on which the cell culture is based.
  • the cultures can be of different cell types and toxic chemicals, drugs or other substances of interest can be added to them to analyze their influence on the culture medium. This influence will be monitored through the micro device.
  • 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.
  • the possibility of applying large voltages and its ease of assembly with glass by ⁇ nodic bonding is added.
  • the system presented in this example corresponds to a microsystem for electrophoresis by cross injection.
  • the system is filled with buffer solution and / or electrophoresis gel (eg acrylamide, agarose, etc.) by injection through the different receptacles.
  • the substance to be analyzed is deposited in well 1 and is typically injected by applying a voltage between electrodes 1 and 2.
  • a high voltage is then applied (from 0.2 to 5 kV) between electrodes 3 and 4 for the electrophoretic separation of solute in the separation channel.
  • the usual dimensions of the 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 m 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 m 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.
  • 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 typically performed at the end of the separation channel.
  • a laser-induced fluorescence system has been used, marking the molecules to be separated and then detecting them with a confocal microscope and photomultiplier.
  • the sample can be labeled in many other ways (eg radioactivity) and detected with optical, radioactive, electromechanical or electrical measurement systems.
  • 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.
  • 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.
  • 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.
  • the microsystem described here can be expanded and improved to give rise to a microsystem of total analysis (m-TAS), in which other reactions (apart from electrophoresis) of importance for the analysis or preparation of the sample take place, such as PCR or other amplification, hybridization, ligation, restriction, magneto- capture, phosphorylation, radioactive, fluorescent or other types of marking, and much more.
  • m-TAS microsystem of total analysis
  • semi-insulating SiC semi-insulating silicon carbide
  • 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 gives rise to high-resolution electrophoresis and very fast.
  • the semi-insulating SiC is transparent to the wavelengths typically used in detection and this greatly improves the quality of this compared to opaque substrates such as silicon. Its low thermal resistivity allows a 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 the applied electric field that distort electrophoresis badnas.
  • the semi-insulating SiC has the advantage of being fully integrable in a microtechnological process environment, which allows the integration of active and control devices on the same substrate, as well as all types of sensors, such as photodiodes or chemical sensors for the detection of the molecules to be separated.
  • microsystems or microdevices that manufactured with semi-insulating SiC substrates have novel advantages over the current ones, which makes it possible to improve and expand their biomedical applicability as monitoring of living beings.

Abstract

The invention relates to devices which are made using microelectronic technologies on a semi-insulating silicon carbide substrate and which are used to monitor the biological behaviour of organs, tissues, cells or organic molecules. The invention also relates to the associated production method.

Description

TÍTULOTITLE
SISTEMA SENSOR EN CARBURO DE SILICIO (SIC) SEMIAISLANTE,SILICON CARBIDE SENSOR SYSTEM (SIC) SEMIAISLANTE,
PROCEDIMIENTO DE ELABORACIÓN Y SUS APLICACIONESELABORATION PROCEDURE AND ITS APPLICATIONS
SECTOR DE LA TÉCNICASECTOR OF THE TECHNIQUE
Esta invención se encuadra en el sector de tecnologías de semiconductores en lo que al material y proceso de fabricación se refiere y en el sector biomédico en cuanto a la aplicación.This invention is part of the semiconductor technology sector in terms of material and manufacturing process and in the biomedical sector in terms of application.
El objetivo de la presente invención es la utilización del SiC Semiaislante como sustrato de cualquier microsistema o microdispositivo para aplicaciones biomédicas de monitorización y registro y que resuelva al menos en parte los inconvenientes y limitaciones de los sistemas realizados sobre otros sustratos semiconductores para aplicaciones biomédicas.The objective of the present invention is the use of Semi-Insulating SiC as a substrate of any microsystem or microdevice for biomedical monitoring and recording applications and that at least partially resolves the inconveniences and limitations of the systems made on other semiconductor substrates for biomedical applications.
ESTADO DE LA TÉCNICASTATE OF THE TECHNIQUE
La presente invención hace relación a sistemas de registro y monitorización de señales biológicas originadas en entes vivos, ya sean células o cultivos celulares, tejidos, órganos u organismos enteros. En particular, la presente invención hace referencia al uso de nuevos materiales en los dispositivos físicos para la captación simultánea y/ o multifrecuencial de diferentes señales biológicas.The present invention relates to systems for recording and monitoring biological signals originating in living entities, whether cells or cell cultures, tissues, organs or entire organisms. In particular, the present invention refers to the use of new materials in physical devices for simultaneous and / or multi-frequency uptake of different biological signals.
El registro de señales biológicas es una actividad de suma importancia en el desarrollo de dispositivos médicos y para la exploración de los seres vivos. Existen multitud de técnicas y métodos para el registro de señales biológicas. Estos difieren entre sí principalmente en función de (1) la naturaleza de la señal biológica a registrar, (2) el principio de aplicación para la captación de la señal, (3) el periodo de registro y (4) el sistema de aplicación del dispositivo sobre la entidad biológica. En los últimos años, y gracias a los avances realizados en tecnologías de microelectrónica y microsistemas, se han desarrollado microsistemas capaces de monitorizar diferentes parámetros fisicoquímicos en una única plataforma y de forma simultanea. Utilizando múltiples microsensores dispuestos sobre un mismo sustrato, este tipo de dispositivos permiten medir diversos parámetros fisiológicos (e.g. temperatura, impedancia eléctrica, pH y [K+]) de un cultivo celular o de un órgano de forma simultanea, mínimamente invasiva y espacialmente localizada, facilitando la extracción de correlaciones útiles para el diagnóstico y la prognosis entre los parámetros monitorizados [1] [2] [3].The registration of biological signals is a very important activity in the development of medical devices and for the exploration of living beings. There are many techniques and methods for recording biological signals. These differ from each other mainly in terms of (1) the nature of the biological signal to be recorded, (2) the principle of application for the capture of the signal, (3) the period of registration and (4) the system of application of the device on the biological entity. In recent years, and thanks to the advances made in microelectronics and microsystems technologies, microsystems have been developed capable of monitoring different physicochemical parameters on a single platform and simultaneously. Using multiple microsensors arranged on the same substrate, these types of devices allow measuring various physiological parameters (eg 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].
A pesar de sus enormes ventajas, un problema común en estos dispositivos reside en su herencia tecnológica. El Si cristalino ultrapuro es el material por antonomasia en microelectrónica y, por ende, también en el desarrollo de microsistemas. A pesar de sus numerosas ventajas, como la posibilidad de incorporar circuitería microelectrónica y fotoelectrónica e incluso nanotecnologías, el Si presenta también fuertes desventajas. Su opacidad a las radiaciones ultravioleta y visible, por ejemplo, dificulta la inspección óptica y su acoplamiento con sistemas de detección por fluorescencia en aplicaciones como los cultivos celulares. Por otra parte, su relativa fragilidad dificulta enormemente su manejo en aplicaciones clínicas y supone un riesgo en su introducción e/o implante en seres vivos. Finalmente, la resistividad del sustrato de Si distorsiona el registro eléctrico a ciertas frecuencias, ya que las corrientes aplicadas para el registro fugan parcialmente a través del sustrato. Este fenómeno disminuye también la efectividad de técnicas necesarias en la creación de electrodos de registro, como la platinización por electromigración, e impide su uso como dispositivo en otras técnicas analíticas de interés que requieren voltajes significativos, como la electroforesis.Despite their enormous advantages, a common problem in these devices lies in their technological heritage. The ultrapure crystalline Si is the material par excellence in microelectronics and, therefore, also in the development of microsystems. Despite its numerous advantages, such as the possibility of incorporating microelectronic and photoelectronic circuitry and even nanotechnologies, Si also has strong disadvantages. Its opacity to ultraviolet and visible radiation, for example, makes optical inspection difficult and its coupling with fluorescence detection systems in applications such as cell cultures. On the other hand, its relative fragility greatly hinders its management in clinical applications and poses a risk in its introduction and / or implantation in living beings. Finally, the resistivity of the Si substrate distorts the electrical register at certain frequencies, since the currents applied to the register partially leak through the substrate. This phenomenon also reduces the effectiveness of necessary techniques in the creation of recording electrodes, such as electromigration platinization, and prevents their use as a device in other analytical techniques of interest that require significant voltages, such as electrophoresis.
Actualmente existen alternativas frente al Si para solventar estos problemas. Diferentes materiales, como el vidrio o varios tipos de polímeros plásticos y siliconas como el PMMA, el PMMS o las polymidas, y combinaciones entre ellos han sido utilizados como sustratos para, por ejemplo, la creación de microsistemas de electroforesis, la fabricación de dispositivos para cultivo celular o para monitorización local de diversos parámetros en tejido vivo. Estos sustratos requieren de diversas técnicas para su fabricación, como el proceso fotolitográfico de gravado húmedo en vidrio, técnicas de hot- embossing y moldeado en polímeros, etc. Aun así, y pese a su demostrada funcionalidad, estos dispositivos no resuelven algunos de los problemas del Si e incluso introducen algunos propios. Ni el vidrio ni los polímeros permiten crear todo el abanico de estructuras tridimensionales disponible en tecnologías de Si. Además, ninguno de estos dos tipos de sustrato permite la integración de circuitería microelectrónica, fotoelectrónica o de nanotecnologías. Muchos polímeros son fuertemente opacos a longitudes de ondas visibles y ultravioletas, y el vidrio es notablemente opaco a estas últimas. La mayoría de polímeros, además, no permiten la deposición de metales para electrodos ni su platinización mediante técnicas estándar, disminuyendo la Habilidad de los mismos. El aumento en resistencia mecánica no es excesivamente significativo en vidrio, y se consigue a cambio de una alta flexibilidad en la mayoría de polímeros, haciéndolos poco indicados para su penetración en tejidos vivos.Currently there are 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 among them have been used as substrates for, for example, the creation of electrophoresis microsystems, the manufacture of devices for cell culture or for local monitoring of various parameters in living tissue These substrates require various manufacturing techniques, such as the photolithographic process of wet glass etching, hot-embossing and polymer molding techniques, etc. Even so, and despite their proven functionality, these devices do not solve some of the Si problems and 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, photoelectronic or nanotechnology circuitry. Many polymers are strongly opaque at visible and ultraviolet wavelengths, and the glass is remarkably opaque to the latter. The majority of polymers, in addition, do not allow the deposition of metals for electrodes or their platinization by standard techniques, reducing their ability. The increase in mechanical strength is not excessively significant in glass, and is achieved in exchange for high flexibility in most polymers, making them poorly indicated for penetration into living tissues.
El SiC es un material semiconductor con una larga historia como material abrasivo en la industria. Sin embargo, no ha sido hasta la última década del siglo XX cuando, gracias al desarrollo de nuevos procesos de obtención de SiC ultra puro (calidad microelectrónica), este material ha alcanzado una notable relevancia en el área de la microelectrónica como nuevo sustrato para la creación de dispositivos de alta potencia, alta frecuencia y alta temperatura. El SiC posee numerosas propiedades que lo hacen indicado para este tipo de aplicaciones: gran anchura de gap electrónico, alta conductividad térmica, alta tensión de ruptura, alta velocidad de saturación de los portadores de carga, alta estabilidad térmica, bajo coeficiente de expansión térmica, baja densidad y elevada inactividad y resistividad química [4].SiC is a semiconductor material with a long history as an abrasive material in the industry. However, it has not been until the last decade of the twentieth century when, thanks to the 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 the creation of high power, high frequency and high temperature devices. The SiC has numerous properties that make it suitable for this type of applications: large electronic gap width, high thermal conductivity, high breaking voltage, high saturation speed of the load carriers, high thermal stability, low coefficient of thermal expansion, low density and high inactivity and chemical resistivity [4].
Estas características del SiC como sustrato en microtecnologías ha hecho que se utilizara mucho en el área de aplicaciones aeroespaciales y de la industria automovilística por ejemplo [5].These characteristics of SiC as a substrate in microtechnologies have made it widely used in the area of aerospace applications and the automotive industry for example [5].
Aparte de estas características, como material semiconductor, el SiC posee también otras características que lo hacen idóneo para su uso en el ámbito biomédico. Tanto el sustrato de Si como el SiC son considerados materiales tan biocompatibles como el titanio y por tanto ideales para sistemas implantables, por ejemplo. Pero además el SiC tiene ventajas sobre el Si en cuanto presenta una menor adhesión de proteínas y menor agregación de plaquetas, cuando se pone en contacto con la sangre) [6]. Debido a que además es muy inerte químicamente y muy resistente en condiciones extremas mecánicas y de medio ambiente se ha comenzado mucho a utilizar para recubrimientos de superficies para prótesis articulares implantables y últimamente como recubrimiento para stents y otras prótesis intarvasculares por su buena hemocompatibilidad (menor adhesión de proteínas y menor agregación de plaquetas)Apart from these characteristics, as a semiconductor material, SiC also has other characteristics that make it suitable for use in the biomedical field. Both the Si substrate and SiC are considered as biocompatible materials such as titanium and therefore ideal for implantable systems, for example. But in addition, SiC has advantages over Si as it has lower protein adhesion and lower platelet aggregation, when it comes into 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 in-vascular prostheses due to its good hemocompatibility (lower adhesion of proteins and lower platelet aggregation)
Un estudio reciente concluye que SiC posee propiedades superiores mecánicas y tribológicas (dureza, resistencia a la fricción y al uso prolongado) que lo hacen un material idóneo para uso en ortopedia respecto a otros materiales habitualmente mas utilizados para estas aplicaciones como son las aleaciones de cromo-cobalto y molibdeno (CoCrMo) o la de titanio-6 aluminio-4 vanadio TÍ-6A1-4V e incluso la de acero inoxidable 316L (SS 316L) [7].A recent study concludes that SiC has superior mechanical and tribological properties (hardness, resistance to friction and prolonged use) that make it an ideal material for orthopedic use compared to other materials commonly used for these applications such as chromium alloys -cobalt and molybdenum (CoCrMo) or that of titanium-6 aluminum-4 vanadium TÍ-6A1-4V and even that of 316L stainless steel (SS 316L) [7].
En el campo biomédico y ya con tecnologías microelectrónicas se han creado estructuras nanoporosas de SiC que permiten sus utilización como material semi-permeable para la creación de membranas que puedan actuar como interfase in vivo en aplicaciones biomédicas. Por ello, puede utilizarse, por ejemplo, para su utilización en implante artificial de páncreas, de riñon o para dispensador implantable oral de medicamentos [8].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 applications Biomedical For this reason, it can be used, for example, for use in artificial implantation of the pancreas, kidney or for oral implantable drug dispenser [8].
El SiC semiaislante presenta otras características, además de las anteriormente mencionadas (biocompatibilidad y resistencia), que pueden ser de gran utilidad en el campo biomédico. Características como que presenta una resistividad intrínseca notablemente elevada, si bien puede ser dopado para llegar a niveles de semiconducción propios del Si y aunque presenta una multitud de politipos con diferentes características superficiales (e.g., polar, no-polar), es manipulable a escalas nanométricas, y permite la integración de componentes activos de mayor resistencia y rango de aplicación que el propio Si. Otra característica es que el SiC semiaislante es transparente en el rango visible e infrarrojo. Todas estas características pueden ser muy útiles en según que microdispositivos biomédicos. No se ha encontrado ninguna referencia de su utilización como sustrato para dispositivos para aplicaciones biomédicas y en concreto para la monitorización de señales biológicas. Su utilización puede mejorar las prestaciones que actualmente presentan los dispositivos realizados en sustrato de Si para aplicaciones biomédicas de monitorización y registro. Semi-insulating SiC has other characteristics, in addition to those mentioned above (biocompatibility and resistance), which can be very useful in the biomedical field. Characteristics such as that it has a remarkably high intrinsic resistivity, although it can be doped to reach semiconduction levels typical of Si and although it presents a multitude of polytypes with different surface characteristics (eg, polar, non-polar), it is manipulable at nanometric scales , and allows the integration of active components of greater resistance and range of application than Si itself. Another feature is that the semi-insulating SiC is transparent in the visible and infrared range. All these features can be very useful depending on which biomedical microdevices. No reference has been found for its use as a substrate for devices for biomedical applications and specifically for the monitoring of biological signals. Its use can improve the benefits currently presented by devices made in Si substrate for biomedical monitoring and recording applications.
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Ke; R.P. Devaty; W.J. Choyke. Biomedical Microdeυices, December 2004, υol. 6, no. 4, pp. 261-267(7) DESCRIPCIÓN DB LA INVENCIÓNKe; RP Devaty; WJ Choyke. Biomedical Microdeυices, December 2004, υol. 6, no. 4, pp. 261-267 (7) DESCRIPTION DB THE INVENTION
La presente invención se refiere a la fabricación y uso de dispositivos realizados con tecnologías microelectrónicas sobre un sustrato de SiC semi-aislante para la monitorización del comportamiento biológico de órganos, tejidos, células o moléculas orgánicas. Lo novedoso de esta invención es que mediante tecnologías de microelectrónicas y la utilización del SiC semiaislante como sustrato se han obtenido microsistemas tipo sensores para dispositivos médicos que ofrecen mejores prestaciones respecto a otros sustratos actualmente utilizados como Si, SiC no semiaislante etc.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 non-semi-insulating etc.
En particular, las ventajas que ofrece el SiC semiaislante, como nuevo material biocompatible para uso en dispositivos para monitorización del comportamiento biológico de órganos, tejidos, células o moléculas orgánicas, son las siguientes: • Transparencia a longitudes de onda visibles e infrarrojos.In particular, the advantages offered by semi-insulating SiC, 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 visible and infrared wavelengths.
• Alta resistencia mecánica respecto al Si• High mechanical resistance with respect to Si
• Alta resistividad que hace que mejore significativamente el registro eléctrico multifrecuencial y permitiendo además una deposición mejorada de metales para electrodos, es decir se optimiza el proceso de platinización. Además el mayor campo eléctrico critico permite una aplicación de voltajes mas elevados.• High resistivity that significantly improves the multifrequency electrical register and also allows an improved deposition of electrode metals, that is, the platinization process is optimized. In addition, the greater critical electric field allows an application of higher voltages.
• Mayor biocompatibilidad que la que proporciona el Si• Greater biocompatibility than that provided by Si
• Permite procesado usando tecnologías de microsistemas adaptadas y entornos de fabricación propios del Si. • Permite la integración de tecnología microelectrónica con fotoelectrónica a la vez.• Allows processing using adapted microsystem technologies and manufacturing environments typical of Si. • Allows the integration of microelectronic technology with photoelectronics at the same time.
• Permite la integración de nanotecnologías como nanotubos de carbono.• Allows the integration of nanotechnologies such as carbon nanotubes.
Así, un objeto de la invención lo constituye un microsistema útil como sensor de señales biológicas, en adelante microsistema de la invención, que comprende SiC semiaislante como sustrato para aplicaciones biomédicas de monitorización de órganos, tejidos, células o moléculas orgánicas.Thus, an object of the invention is a microsystem useful as a biological signal sensor, hereinafter microsystem of the invention, comprising semi-insulating SiC as a substrate for Biomedical applications for monitoring organs, tissues, cells or organic molecules.
Además, el microsistema de la invención puede incluir otros elementos necesarios, definidos y conocidos por un técnico medio del sector de la técnica, para la aplicación final del microsistema como sensor.In addition, the microsystem of the invention may include other necessary elements, defined and known by a technician in the field of art, for the final application of the microsystem as a sensor.
Así, un objeto particular de la presente invención lo constituye el microsistema de la invención en el que se incluye uno o más electrodos u otro tipo de sensores, realizados con tecnologías microelectrónicas, para la monitorización de parámetros físicos, químicos, ópticos, eléctricos y biológicos en diferentes rangos y frecuencias.Thus, a particular object of the present invention is the microsystem of the invention which includes one or more electrodes or other sensors, made with microelectronic technologies, for the monitoring of physical, chemical, optical, electrical and biological parameters. in different ranges and frequencies.
Otro objeto particular de la presente invención lo constituye el microsistema de la invención en el que se incluye un dispositivo y/ o procesos nanotecnológicos para mejorar o incrementar la prestaciones para la monitorización de parámetros físicos, químicos, eléctricos y biológicos (como p.e. la incorporación de nanotubos de carbono como nanoelectrodos, adhesión de polímetros para funcionalizar la superficie etc ), o un sistema de alimentación por batería integrada o externa, conexión a red u onda portadora de radiofrecuencia; o circuitería integrada en el mismo sustrato para adquisición, tratamiento, amplificación, proceso, multiplexado o envío telemétrico de las señales captadas.Another particular object of the present invention is the microsystem of the invention in which a device and / or nanotechnological processes are included to improve or increase the performance for the monitoring of physical, chemical, electrical and biological parameters (such as the incorporation of carbon nanotubes such as nanoelectrodes, adhesion of polymeters to functionalize the surface etc), 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.
Otro objeto particular de la presente invención lo constituye el microsistema de la invención en el que, en función de la aplicación concreta y de las necesidades técnicas, dicho microsistema presenta diferentes formas, dimensiones y mecanismos de proceso y encapsulado. Una realización concreta de la presente invención es un microsistema en forma de microaguja, tal y como se muestra en el ejemplo 1. Otra realización concreta de la presente invención es un microsistema en forma de placa para cultivos celulares o de tejidos "in vitro" tal y como se muestra en el ejemplo 2. Otro objeto particular de la presente invención lo constituye el microsistema de la invención en el que se incluye un sistema de alimentación por batería integrada o externa, conexión a red u onda portadora de radiofrecuencia. Otro objeto particular de la presente invención lo constituye el microsistema de la invención en el que se incluye circuitería integrada en el mismo sustrato para adquisición, tratamiento, amplificación, proceso, multiplexado o envío telemétrico de las señales captadas.Another particular object of the present invention is the microsystem of the invention in which, depending on the specific application and technical needs, said microsystem has different forms, dimensions and mechanisms of process and encapsulation. A specific embodiment of the present invention is a microneedle-shaped microsystem, as shown in example 1. Another specific embodiment of the present invention is a plate-shaped microsystem for cell cultures or "in vitro" tissue cultures such and as shown in example 2. Another particular object of the present invention is the microsystem of the invention in which an integrated or external battery power system, network connection or radio frequency carrier wave is included. Another particular object of the present invention is the microsystem of the invention in which integrated circuitry is included in the same substrate for acquisition, treatment, amplification, process, multiplexing or telemetry sending of the captured signals.
Otro objeto de la presente invención es un procedimiento de fabricación del microsistema de la invención caracterizado por las siguientes etapas: a. Limpieza del substrato de SiC semiaislante con disolventes y ácidos adecuados, b. Depósito de una capa dieléctrica: esta capa puede estar compuesta de uno o varios materiales dieléctricos apilados; como óxido de silicio, nitruro de silicio, nitruro de aluminio, alúmina, dieléctricos de alto K, etc., c. Depósito de una capa metálica para la formación de los electrodos: esta capa puede ser compuesta de uno o varios metales apilados como Titanio, Platino, Oro o Cobalto, d. Grabado de la capa metálica, e. Depósito de la capa de pasivación: esta capa puede estar compuesta de uno o varios materiales dieléctricos apilados. f. Apertura de contactos en la capa de pasivación, y g. Separación de los componentes mediante el serrado del substrato procesado.Another object of the present invention is a method of manufacturing the microsystem of the invention 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 can be composed of one or several stacked dielectric materials; such as silicon oxide, silicon nitride, aluminum nitride, alumina, high K dielectrics, etc., c. Deposit of a metallic layer for the formation of the electrodes: this layer can be composed of one or several stacked metals such as Titanium, Platinum, Gold or Cobalt, d. Engraving of the metallic layer, e. Deposit of the passivation layer: this layer can be composed of one or several stacked dielectric materials. F. Opening contacts in the passivation layer, and g. Separation of the components by sawing the processed substrate.
Otro objeto particular de la invención lo constituye el procedimiento de fabricación del microsistema de la invención, descrito anteriormente, en el que, dado el carácter intrínseco del substrato de SiC semiaislante, se obvia la etapa b) de depósito de una capa dieléctrica en el proceso de fabricación, a diferencia de otros substratos semiconductores como el Silicio. El espesor de esta capa puede variar entre 0 (en el caso de ausencia de capa dieléctrica) y 3 micrómetros.Another particular object of the invention is the manufacturing process of the microsystem of the invention, described above, in which, given the intrinsic nature of the semi-insulating SiC substrate, step b) of depositing a dielectric layer in the process is obviated manufacturing, unlike other substrates semiconductors such as silicon. The thickness of this layer can vary between 0 (in the case of absence of dielectric layer) and 3 micrometers.
Otro objeto particular de la invención lo constituye el procedimiento de fabricación del microsistema de la invención descrito anteriormente, en el que la definición de los motivos de los electrodos y sus pistas de interconexión se realiza mediante un proceso fotolitográfico con resina fotosensible o usando una máscara metálica. En el caso de un proceso litográfico, éste se puede realizar antes o después del depósito de los metales. Otro objeto particular de la invención lo constituye el procedimiento de fabricación del microsistema de la invención descrito anteriormente, en el que el grabado de la capa metálica d) se puede hacer por la técnica de "lift-off", mediante un grabado húmedo con ácidos o bien por grabado seco por plasma (RIE / ICP / DECR). Otro objeto particular de la presente invención lo constituye el procedimiento de fabricación del microsistema la invención en el que el material dieléctrico de apilación descrito en e) pertenece al siguiente grupo: óxido de silicio, nitruro de silicio, nitruro de aluminio, alúmina, dieléctricos de alto K, etc., Otro objeto particular de la invención lo constituye el procedimiento de fabricación del microsistema de la invención descrito anteriormente, en el que la definición de las zonas de contactos de la etapa de Apertura de contactos en la capa de pasivación (f)) se realiza mediante un proceso fotolitográfico con resina fotosensible. El grabado puede ser del tipo húmedo con ácidos, o bien tipo seco por plasma (RIE / ICP / DECR).Another particular object of the invention is the manufacturing process of the microsystem of the invention described above, in which the definition of the motifs of the electrodes and their interconnection tracks is carried out by a photolithographic process with photosensitive resin or using a metal mask . In the case of a lithographic process, this can be done before or after the deposit of the metals. Another particular object of the invention is the manufacturing process of the microsystem of the invention described above, in which the engraving of the metal 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). Another particular object of the present invention is the method of manufacturing the microsystem, the invention in which the stacking dielectric material described in e) belongs to the following group: silicon oxide, silicon nitride, aluminum nitride, alumina, dielectric high K, etc., Another particular object of the invention is the manufacturing method of the microsystem of the invention described above, in which the definition of the contact areas of the Contact Opening stage in the passivation layer (f )) is performed by a photolithographic process with photosensitive resin. The engraving can be of the wet type with acids, or dry type by plasma (RIE / ICP / DECR).
Otro objeto particular de la presente invención lo constituye el procedimiento de fabricación del microsistema de la invención en el que el material dieléctrico de apilación de b) pertenece al siguiente grupo: óxido de silicio, nitruro de silicio, nitruro de aluminio, alúmina, dieléctricos de alto K. Finalmente, otro objeto de la invención es el uso del microsistema de la invención en procedimientos de medidas de señales biológicas con aplicaciones biomédicas de monitorización de órganos, tejidos, células o moléculas orgánicas.Another particular object of the present invention is the manufacturing process of the microsystem of the invention in which the stacking dielectric material of b) belongs to the following group: silicon oxide, silicon nitride, aluminum nitride, alumina, dielectrics of high K. Finally, another object of the invention is the use of the microsystem of the invention in biological signal measurement procedures with biomedical applications for monitoring organic organs, tissues, cells or molecules.
Otro objeto particular de la presente invención es el uso del microsistema de la invención de forma invasiva o no invasiva sobre la muestra biológica.Another particular object of the present invention is the use of the microsystem of the invention in an invasive or non-invasive manner on the biological sample.
Otro objeto particular de la presente invención es el uso del microsistema de la invención mediante el implante en seres y/ o tejidos vivos de forma temporal o permanente.Another particular object of the present invention is the use of the microsystem of the invention by implantation in living beings and / or tissues temporarily or permanently.
Otro objeto particular de la presente invención es el uso del microsistema de la invención mediante el implante en un ser humano.Another particular object of the present invention is the use of the microsystem of the invention by implantation in a human being.
DESCRIPCIÓN DB LAS FIGURASDESCRIPTION DB THE FIGURES
Figura 1.- Esquema de la aguja diseñada para ser fabricada con tecnologías microelectrónicas con substratos semiconductores (Si yFigure 1.- Diagram of the needle designed to be manufactured with microelectronic technologies with semiconductor substrates (Si y
SiC).Sic).
Figura 2.- Proceso de fabricación y sección de corte de la aguja realizada con substrato de SiC. El diagrama indica la arquitectura del proceso tecnológico.Figure 2.- Manufacturing process and cutting section of the needle made with SiC substrate. The diagram indicates the architecture of the technological process.
Figura 3: Estudio "in υitro" de las agujas con substrato de Si. Se muestran los resultados del comportamiento de las agujas con sustrato de SiC semiaislante inmersas en suero fisiológico simulando un medio biológicoFigure 3: "In iter" 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
Figura 4: Estudio "in υitro" con sustrato de SiC Semiaislante. Se muestran los resultados del comportamiento de las agujas con sustrato de Si inmersas en suero fisiológico simulando un medio biológico. Figura 5.- (A) Mascara para la fabricación de microsistemas o dispositivos en SiC semiaislante para aplicaciones biomédicas como plataformas de monitorización de cultivos celulares (B) Detalle de una de estas plataformas que en este ejemplo contiene 16 electrodos de platino. (C) Esquema de corte del proceso de fabricación. (D) Resultados experimentales de la monitorización de un cultivo celular a distintas frecuencias.Figure 4: "In iter" 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 microsystems or semi-insulating SiC devices for biomedical applications such as cell culture monitoring platforms (B) Detail of one of these platforms that in this example contains 16 electrodes of platinum. (C) Cutting scheme of the manufacturing process. (D) Experimental results of monitoring a cell culture at different frequencies.
Figura 6.- Esquema del dispositivo genérico propuesto. Dispositivo de electroforesis con inyección en T, cuatro cubetas y dos canales.Figure 6.- Scheme of the proposed generic device. Electrophoresis device with T-injection, four cuvettes and two channels.
Figura 7.- Detalle de una zona de la cruz en los canales de electroforesis realizados en SiC semiaislante mediante ataque en seco por RIE.Figure 7.- Detail of an area of the cross in the electrophoresis channels made in semi-insulating SiC by dry attack by RIE.
EJEMPLOS DE REALIZACIÓN DE LA INVENCIÓNEXAMPLES OF EMBODIMENT OF THE INVENTION
Como descripción de modos de realización de la presente invención se detallan tres ejemplos de dispositivos, no limitantes del alcance de la invención, realizados en sustrato de SiC semiaislante para monitorización del comportamiento biológico de órganos, tejidos, células o moléculas orgánicas:As a description of embodiments of the present invention, three examples of devices, not limiting the scope of the invention, are made in semi-insulating SiC substrate for monitoring the biological behavior of organic organs, tissues, cells or molecules:
Ejemplo 1.- Sensor tipo microaguja en sustrato de SiC semiaislante.Example 1.- Microneedle sensor in semi-insulating SiC substrate.
La novedad que se presenta en este primer ejemplo es la realización en SiC semiaislante de un microdispositivo en forma de aguja en la que pueden integrarse uno o más sensores eléctricos, químicos o ópticos mediante procesos micro o nano tecnológicos.The novelty presented in this first example is the semi-insulating realization in SiC of a needle-shaped microdevice in which one or more electrical, chemical or optical sensors can be integrated by micro or nano technological processes.
En el ejemplo de la figura 1 se muestra un microdispositivo tipo aguja realizado con procesos microelectrónicos en SiC semiaislante con las siguientes dimensiones: 15 mm de longitud, 525 μm de anchura yIn the example of figure 1 a needle-type microdevice is shown, made with semi-insulating SiC microelectronic processes with the following dimensions: 15 mm in length, 525 μm in width and
350 μm de espesor, con 4 electrodos de platino de 300x300 μm cada uno y de 1.800 Á de espesor.350 μm thick, with 4 platinum electrodes of 300x300 μm each and 1,800 Á thick.
Materiales de partida:Starting Materials:
- Oblea de SiC 4" y Oblea Si semiaislante 4" - Ia etapa: depósito del óxido de campo (FOX, Field Oxide): 1.5 μm de SiO2.- Wafer of SiC 4 "and Wafer Si semi-insulating 4" - I to stage: deposit of the field oxide (FOX, Field Oxide): 1.5 μm of SiO2.
- 2a etapa: Depósito de Ti/ Pt: metal para electrodo. - 3a etapa: Lift-off de la capa Ti/ Pt- 2 nd stage: Deposit Ti / Pt metal electrode. - step 3: Lift-off of Ti / Pt layer
- 4o etapa: depósito de la pasivación (SiO2-Si3N4).- 4 or step: deposit passivation (SiO2-Si3N4).
En la figura 2 se muestra el esquema del proceso tecnológico para la realización de este dispositivo. El microdispositivo se ha elaborado con el procedimiento que se describe en la descripción detallada.Figure 2 shows the scheme of the technological process for the realization of this device. The microdevice has been developed with the procedure described in the detailed description.
En este ejemplo concreto, su aplicación es para la monitorización de la bioimpedancia intratisular de órganos o tejidos. Ejemplos de aplicaciones biomédicas pueden ser, monitorización de la isquemia y isquemia-reperfusión de órganos o tejidos en experimentación animal, cirugía cardiaca, transplante de órganos etc.In this specific example, its application is for the monitoring of intra-tissue bioimpedance of organs or tissues. Examples of biomedical applications can be, monitoring of ischemia and ischemia-reperfusion of organs or tissues in animal experimentation, cardiac surgery, organ transplantation etc.
En la Figura 3 se muestran los resultados del comportamiento de las agujas con sustrato de SiC semiaislante inmersas en suero fisiológico simulando un medio biológico. En la Figura 4 se muestran los resultados del comportamiento de las agujas con sustrato de SiC semi-aislante inmersas en suero fisiológico simulando un medio biológico. Ambos resultados muestran que el SiC semiaislante ofrece las siguientes ventajas respecto al Si en los micro sistema en forma de aguja para monitorizar la bioimpedancia de órganos, tejidos o células vivas:Figure 3 shows the results of the behavior of needles with semi-insulating SiC substrate immersed in physiological serum simulating a biological medium. Figure 4 shows the results of the behavior of needles with semi-insulating SiC substrate immersed in physiological serum simulating a biological medium. Both results show that the semi-insulating SiC offers the following advantages over the Si in the needle-shaped micro system to monitor the bioimpedance of living organs, tissues or cells:
• Alta resistividad que mejoran significativamente: - El registro eléctrico multifrecuencial.• High resistivity that significantly improve: - The multifrequency electrical register.
- El rendimiento del proceso de platinización de los electrodos- The performance of the electrode platinization process
- La aplicación de mayores voltajes- The application of higher voltages
• Mayor resistencia mecánica• Greater mechanical resistance
Ejemplo 2.- Microdispositivo para cultivos celularesExample 2.- Microdevice for cell cultures
La novedad que se presenta en este segundo ejemplo es la realización de un microdispositivo en sustrato de SiC semiaislante para monitorización de cultivos celulares. Son microsistemas que consisten en una plataforma de SiC semiaislante de dimensiones adaptadas a medios de cultivos, con uno o más sensores eléctricos, químicos u ópticos incorporados mediante procesos micro o nano tecnológicos sobre los que se asienta el cultivo celular. Los cultivos pueden ser de diferentes tipos celulares y a ellos se pueden añadir productos químicos tóxicos, fármacos o otras sustancias que interesen para analizar su influencia sobre el medio de cultivo. Esta influencia será monitorizada a través del microdispositivo.The novelty presented in this second example is the realization of a semi-insulating SiC substrate micro device for cell culture monitoring. They are microsystems that consist of a semi-insulating SiC platform of dimensions adapted to culture media, with one or more electrical, chemical or optical sensors incorporated by micro or nano technological processes on which the cell culture is based. The cultures can be of different cell types and toxic chemicals, drugs or other substances of interest can be added to them to analyze their influence on the culture medium. This influence will be monitored through the micro device.
Estas plataformas realizadas sobre sustratos de SiC semiaislante tienen las ventajas anteriormente enunciadas para monitorización de cultivos celulares y además otra que resulta de mucha utilidad para esta aplicación y es su transparencia lo que permite la utilización a la vez de técnicas de microscopía (Ver figura 5).These platforms made on semi-insulating SiC substrates have the advantages listed above for cell culture monitoring and also another that is very useful for this application and it is its transparency that allows the use of microscopy techniques at the same time (See figure 5) .
Ejemplo 3.- Microdispositivo con microcanales para electroforesisExample 3.- Microchannel with microchannels for electrophoresis
La novedad que se presenta en este tercer ejemplo es la realización de un microdispositivo en sustrato de SiC semiaislante con microcanales y cubetas realizados con procesos micro o nanotecnológicos para ser aplicados como sistemas de análisis de biomoléculas. Además de las ventajas anteriormente enunciadas se añade la posibilidad de aplicar grandes voltajes y su facilidad de ensamblaje con el vidrio por αnodic bonding.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 above-mentioned advantages, the possibility of applying large voltages and its ease of assembly with glass by αnodic bonding is added.
En concreto, el sistema que se presenta en este ejemplo corresponde a un microsistema para electroforesis mediante inyección en cruz. Para su uso, el sistema se rellena con solución tampón y/ o gel de electroforesis (e.g. acrilamida, agarosa, etc.) mediante inyección a través de los distintos receptáculos. La sustancia a analizar se deposita en el pocilio 1 y se inyecta típicamente mediante la aplicación de un voltaje entre los electrodos 1 y 2. Una vez el soluto de interés ha sido insertado en la cruz, se aplica después un voltaje alto (de 0.2 a 5 kV) entre los electrodos 3 y 4 para la separación electroforética del soluto en el canal de separación. Las dimensiones habituales de los canales son de 1-2 cm para el de inyección y 3-6 cm para el de separación, y las cubetas acostumbran a tener un diámetro aproximado de 1 cm, aunque ninguna de estas dimensiones es limitante.Specifically, the system presented in this example corresponds to a microsystem for electrophoresis by cross injection. For use, the system is filled with buffer solution and / or electrophoresis gel (eg acrylamide, agarose, etc.) by injection through the different receptacles. The substance to be analyzed is deposited in well 1 and is typically injected by applying a voltage between electrodes 1 and 2. Once the solute of interest has been inserted into the cross, a high voltage is then applied (from 0.2 to 5 kV) between electrodes 3 and 4 for the electrophoretic separation of solute in the separation channel. The usual dimensions of the 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.
El sistema está realizado en SiC semiaislante. El SiC semiaislante se ha grabado para definir los canales hasta una profundidad de ~20 m mediante grabado en seco por RIE (Reactive Ion Etching), aunque se pueden obtener los canales también mediante técnicas de grabado húmedo. La profundidad de los canales ha sido establecida en este caso para una aplicación propuesta (electroforesis de proteínas) pero puede variar dependiendo de la aplicación entre 0.5 y 200 m y en ningún caso está limitada por el proceso tecnológico aquí usado. El sistema está cubierto por un sustrato también aislante (vidrio) que se ha pegado de forma hermética (para evitar fugas) al SiC semiaislante mediante la técnica de soldado anódico. Se pueden usar también otras técnicas y materiales para realizar el sellado, como vidrio pegado con diferentes tipos de resinas y pegamentos, soldado térmico del vidrio al SiC semiaislante, usar SiC semiaislante como cobertura mediante soldado térmico o pegado con capas intermedias, o usar cualquier otro material aislante eléctrico susceptible de ser soldado/pegado al SiC semiaislante de forma que cubra de forma hermética los canales de separación. El vidrio se ha agujereado en las zonas que quedan inmediatamente encima de las cubetas para permitir el acceso a los pocilios, aunque existe la alternativa de usar un trozo de vidrio cortado para no cubrir las cubetas si el diseño (como en este caso) lo permite. La técnica usada para agujerear el vidrio en este caso ha sido un ataque en solución HF, aunque se pueden usar técnicas alternativas (como sandblasting, taladro ultrasónico o láser). Es también posible, aunque no recomendable, realizar este tipo de sistemas en abierto (sin cobertura).The system is made of semi-insulating SiC. The semi-insulating SiC has been recorded to define the channels to a depth of ~ 20 m 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 m 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).
La detección de la muestra separada se realiza típicamente al final del canal de separación. En este caso se ha usado un sistema de fluorescencia inducida por láser, marcando las moléculas a separar y detectándolas luego con un microscopio confocal y fotomutiplicador. No obstante, la muestra se puede marcar de muchas otras maneras (e.g. radioactividad) y detectar con sistemas ópticos, de medición radioactiva, electromecánicos o eléctricos.Detection of the separated sample is typically performed at the end of the separation channel. In this case a laser-induced fluorescence system has been used, marking the molecules to be separated and then detecting them with a confocal microscope and photomultiplier. However, the sample can be labeled in many other ways (eg radioactivity) and detected with optical, radioactive, electromechanical or electrical measurement systems.
El diseño mostrado en la figura corresponde a un microsistema sencillo para electroforesis de proteínas, que podría ser también usado para la separación de DNA insertando un gel de separación, o de cualquier otra molécula susceptible de ser separada electroforéticamente. Este diseño básico puede ser ampliado y mejorado de muchas formas. Por ejemplo, se pueden añadir canales de inyección/ separación para realizar múltiples electroforesis paralelas o electroforesis bidimensionales, también se puede modificar el canal de separación para convertirlo en una zona ancha de separación tipo slab-gel.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.
Además, el sistema puede ser modificado ampliamente para adaptarse a las diferentes necesidades que presente la muestra. Por ejemplo, los pocilios de inyección pueden ser modificados para convertirse en pocilios donde tenga lugar una reacción en cadena de la polimerasa (PCR), una ligación, una restricción, una fosforilación o una lisis celular (entre otras reacciones), mediante la inclusión de electrodos y/ o resistencias para llevar a cabo ciclos térmicos o aplicar voltajes localmente, y mediante la adición de los reactivos requeridos al pocilio. Asimismo, los canales también pueden adaptarse para convertirse en canales de captura inmuno-magnética de células o moléculas, canales de distribución de solutos como marcadores fluorescentes, etc. También se pueden integrar detectores para realizar la detección in situ, tales como fotodiodos, electrodos o contadores de radioactividad.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.
Así pues, partiendo del ejemplo aquí propuesto como desmostrador y usando microtecnologías convencionales, el microsistema aquí descrito puede ser ampliado y mejorado para dar lugar a un microsistema de análisis total (m-TAS), en el que tengan lugar otras reacciones (aparte de la electroforesis) de importancia para el análisis o preparación de la muestra, tales como la PCR u otras técnicas de amplificación, hibridación, ligación, restricción, magneto-captura, fosforilación, mareaje radioactivo, fluorescente o de otros tipos, y un largo etcétera.Thus, based on the example proposed here as a demonstrator and using conventional microtechnologies, the microsystem described here can be expanded and improved to give rise to a microsystem of total analysis (m-TAS), in which other reactions (apart from electrophoresis) of importance for the analysis or preparation of the sample take place, such as PCR or other amplification, hybridization, ligation, restriction, magneto- capture, phosphorylation, radioactive, fluorescent or other types of marking, and much more.
La realización de esta invención en carburo de silicio semiaislante (SiC semiaislante) resulta innovadora y presenta numerosas ventajas frente a tecnologías alternativas. Respecto al silicio, el SiC semiaislante es netamente superior en su resistencia eléctrica, lo que permite la aplicación de altos voltajes (e.g. 1 kV), hecho que da lugar a electroforesis de alta resolución y muy rápidas. Además, el SiC semiaislante es transparente a las longitudes de onda usadas típicamente en detección y esto permite mejorar mucho la calidad de esta comparándola con sustratos opacos como el silicio. Su baja resistividad térmica permite una disipación de calor más efectiva que en silicio y mucho más eficaz que en vidrio y en polímeros, minimizando los efectos Joule de calentamiento local debidos al campo eléctrico aplicado que distorsionan las badnas de electroforesis. Esto permite de nuevo la aplicación de altos potenciales eléctricos sin perdida de resolución por distorsión de efectos Joule. Respecto también al vidrio y a otros polímeros, el SiC semiaislante presenta la ventaja de ser completamente integrable en un entorno de proceso microtecnológico, lo que permite la integración de dispositivos activos y de control sobre el mismo sustrato, así como todo tipo de sensores, tales como fotodiodos o sensores químicos para la detección de las moléculas a separar.The realization of this invention in semi-insulating silicon carbide (semi-insulating SiC) is innovative and has numerous advantages over alternative technologies. Regarding 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 gives rise to high-resolution electrophoresis and very fast. In addition, the semi-insulating SiC is transparent to the wavelengths typically used in detection and this greatly improves the quality of this compared to opaque substrates such as silicon. Its low thermal resistivity allows a 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 the applied electric field that distort electrophoresis badnas. This allows the application of high electrical potentials again without loss of resolution due to distortion of Joule effects. With respect to glass and other polymers, the semi-insulating SiC has the advantage of being fully integrable in a microtechnological process environment, which allows the integration of active and control devices on the same substrate, as well as all types of sensors, such as photodiodes or chemical sensors for the detection of the molecules to be separated.
Estos son tres ejemplos de microsistema o microdispositivos que fabricados con sustratos de SiC semiaislante presentan unas ventajas novedosas respecto a los actuales lo que permite mejorar y ampliar su aplicabilidad biomédica en cuanto monitorización de seres vivos. These are three examples of microsystems or microdevices that manufactured with semi-insulating SiC substrates have novel advantages over the current ones, which makes it possible to improve and expand their biomedical applicability as monitoring of living beings.

Claims

REIVINDICACIONES
L- Microsistema útil como sensor de señales biológicas caracterizado porque comprende SiC semiaislante como sustrato para aplicaciones biomédicas de monitorización de órganos, tejidos, células o moléculas orgánicas.L- 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.- Microsistema según la reivindicación 1 caracterizado porque se incluye uno o más electrodos u otro tipo de sensores, realizados con tecnologías microelectrónicas, para la monitorización de parámetros físicos, químicos, ópticos, eléctricos y biológicos en diferentes rangos y frecuencias.2. Microsystem according to claim 1 characterized in that one or more electrodes or other sensors are included, made with microelectronic technologies, for the monitoring of physical, chemical, optical, electrical and biological parameters in different ranges and frequencies.
3.- Microsistema según las reivindicaciones 1 y 2 caracterizado porque se incluye un dispositivo y/ o procesos nanotecnológicos para la monitorización de parámetros físicos, químicos, eléctricos y biológicos. 3. Microsystem according to claims 1 and 2 characterized in that a device and / or nanotechnological processes are included for the monitoring of physical, chemical, electrical and biological parameters.
4.- Microsistema según las reivindicaciones 1 a la 3 caracterizado porque presenta diferentes formas, dimensiones y mecanismos de proceso y encapsulado en función de las aplicaciones finales. 4. Microsystem according to claims 1 to 3 characterized in that it has different shapes, dimensions and process mechanisms and encapsulated depending on the final applications.
5.- Microsist ema según la reivindicación 4 caracterizado porque tiene forma de aguja. 5. Microsist ema according to claim 4 characterized in that it has a needle shape.
6.- Microsistema según las reivindicaciones 1 a la 5 caracterizado porque incluye un sistema de alimentación por batería integrada o externa, conexión a red u onda portadora de radiofrecuencia. 6. Microsystem according to claims 1 to 5, characterized in that it includes an integrated or external battery supply system, network connection or radio frequency carrier wave.
7.- Microsistema según las reivindicaciones 1 a la 6 caracterizado porque incluye circuitería integrada en el mismo sustrato para adquisición, tratamiento, amplificación, proceso, multiplexado o envío telemétrico de las señales captadas.7. 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.
8.- Procedimiento de fabricación de un microsistema según las reivindicaciones 1 a la 7 caracterizado por las siguientes etapas: a). Limpieza del substrato de SiC semiaislante con disolventes y ácidos adecuados, b) Depósito de una capa dieléctrica: esta capa puede estar compuesta de uno o varios materiales dieléctricos apilados, c) Depósito de una capa metálica para la formación de los electrodos: esta capa puede ser compuesta de uno o varios metales apilados como Titanio, Platino, Oro o Cobalto, d) Grabado de la capa metálica, e) Depósito de la capa de pasivación: esta capa puede estar compuesta de uno o varios materiales dieléctricos apilados , f) Apertura de contactos en la capa de pasivación, y g) Separación de los componentes mediante el serrado del substrato procesado. 8. 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 may be composed of one or more stacked dielectric materials, c) Deposit of a metallic layer for the formation of the electrodes: this layer can be composed of one or several stacked metals such as Titanium, Platinum, Gold or Cobalt, d) Engraving of the metallic layer, e) Deposit of the passivation layer : this layer can be composed of one or several stacked dielectric materials, f) Opening of contacts in the passivation layer, and g) Separation of the components by sawing the processed substrate.
9.- Procedimiento según la reivindicación 8 caracterizado porque la etapa b) se ha obviado.9. Method according to claim 8 characterized in that step b) has been omitted.
10.- Procedimiento según la reivindicación 8 caracterizado porque la definición de los motivos de los electrodos y sus pistas de interconexión para el depósito de la capa metálica de c) se realiza mediante un proceso fotolitográfico con resina fotosensible o usando una máscara metálica o mediante un proceso litográfico que se puede realizar antes o después del depósito de los metales.10. 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 photolithographic process with photosensitive resin or by using a metal mask or by means of a Lithographic process that can be performed before or after the deposit of metals.
11.- Procedimiento según la reivindicación 8 caracterizado porque el grabado de la capa metálica d) se puede hacer por la técnica de "lift-off", mediante un grabado húmedo con ácidos o bien por grabado seco por plasma (RIE / ICP / DECR).11. Method according to claim 8 characterized in that the engraving of the metal 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 ).
12.- Procedimiento según la reivindicación 8 caracterizado porque el material dieléctrico de apilado de e) pertenece al siguiente grupo: óxido de silicio, nitruro de silicio, nitruro de aluminio, alúmina y dieléctricos de alto K.12. 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.
13.- Procedimiento según la reivindicación 8 caracterizado porque la definición de las zonas de contactos de la etapa de apertura de contactos en la capa de pasivación (f)) se realiza mediante un proceso fotolitográfico con resina fotosensible y donde el grabado puede ser del tipo húmedo con ácidos, o bien tipo seco por plasma (RIE / ICP / DECR). 13. 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 type wet with acids, or dry plasma type (RIE / ICP / DECR).
14.- Procedimiento según la reivindicación 8 caracterizado porque el material dieléctrico de apilado de b) pertenece al siguiente grupo: óxido de silicio, nitruro de silicio, nitruro de aluminio, alúmina y dieléctricos de alto K. 14. 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.
15.- Uso del microsistema según las reivindicaciones l a la 7 en procedimientos de medidas de señales biológicas con aplicaciones biomédicas de monitorización de órganos, tejidos, células o moléculas orgánicas. 15. Use of the microsystem according to claims 1 to 7 in biological signal measurement procedures with biomedical applications for monitoring organic organs, tissues, cells or molecules.
16.- Uso según la reivindicación 14 caracterizado porque se aplica de forma invasiva o no invasiva sobre la muestra biológica.16. Use according to claim 14 characterized in that it is applied invasively or non-invasively on the biological sample.
17.- Uso según la reivindicación 14 caracterizado porque el microdispositivo se implanta en seres y/ o tejidos vivos de forma temporal o permanente. 17. Use according to claim 14 characterized in that the microdevice is implanted in living beings and / or tissues temporarily or permanently.
18.- Uso según la reivindicación 16 caracterizado porque el ser vivo es un ser humano. 18. Use according to claim 16 characterized in that the living being is a human being.
PCT/ES2006/070104 2005-07-15 2006-07-13 Semi-insulating silicon carbide (sic) sensor system, production method thereof and use of same WO2007010076A1 (en)

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