WO2005003285A1 - Measuring system for measuring at least one characteristic of a biological tissue and method for fixing a biological tissue to a measuring system of this type - Google Patents

Measuring system for measuring at least one characteristic of a biological tissue and method for fixing a biological tissue to a measuring system of this type Download PDF

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Publication number
WO2005003285A1
WO2005003285A1 PCT/FR2003/001684 FR0301684W WO2005003285A1 WO 2005003285 A1 WO2005003285 A1 WO 2005003285A1 FR 0301684 W FR0301684 W FR 0301684W WO 2005003285 A1 WO2005003285 A1 WO 2005003285A1
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WO
WIPO (PCT)
Prior art keywords
biological tissue
plate
silicon
wing
rigid support
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PCT/FR2003/001684
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French (fr)
Inventor
Tijani Gharbi
Vincent Thomas Armbruster
Philippe Gérard Lucien HUMBERT
Original Assignee
Tijani Gharbi
Vincent Thomas Armbruster
Humbert Philippe Gerard Lucien
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Application filed by Tijani Gharbi, Vincent Thomas Armbruster, Humbert Philippe Gerard Lucien filed Critical Tijani Gharbi
Priority to PCT/FR2003/001684 priority Critical patent/WO2005003285A1/en
Priority to AU2003255643A priority patent/AU2003255643A1/en
Publication of WO2005003285A1 publication Critical patent/WO2005003285A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/06—Plates; Walls; Drawers; Multilayer plates

Definitions

  • the present invention relates to a system for measuring at least one characteristic of a biological tissue and a method of attaching biological tissue to such a measurement system.
  • the present invention also relates to a method of fixing a biological tissue using such an attachment device.
  • the growth of the biological tissue or of the dermis in situ is done by weaving a lattice (or lattice) of collagen via the fibroblasts.
  • This trellis retracts to then form the dermis or biological tissue intended to remain attached to a hanging device.
  • the measurement systems include hooking devices which are generally formed by supports comprising textile or polymer fibers on which the fibroblasts weave the collagen lattice thereby clinging to the supports.
  • the supports comprising the textile fibers can in particular be formed by velcros (registered trademark).
  • the measurements carried out are measurements of isometric force exerted by the biological tissues in situ in order in particular to determine their flexibility and their resistance or then to characterize their aging or else to detect diseases.
  • the measurement of the force exerted by the biological tissue on the measurement system largely depends on the intrinsic elasticity. textile fibers of the support. It is therefore understood that the elasticity of the textile fibers of the support significantly disturbs the reliability of the measurements carried out by means of the measurement system, which does not make it possible to obtain sufficient precision for reliable operation.
  • the object of the present invention is in particular to overcome the technical problems mentioned above by proposing a reliable, simple measurement device which makes it possible to collect precise information on certain physical or physico-chemical properties of the biological tissue to be measured.
  • the subject of the invention is a measurement system which extends between two ends, characterized in that it comprises a flexible silicon-based plate having a thickness much less than its width and its length, and which extends between, on the one hand, a first free end having a plurality of through openings which pass through said plate according to its thickness and on which is intended to be attached one of the ends of the biological tissue and, on the other hand, a second end secured to a rigid support, the flexible plate and the rigid support being adapted to present facing surfaces spaced from one another and to which are respectively attached conductive plates forming a capacitive sensor, said conductive plates being arranged so that the distance between them varies as a function of the traction exerted by the biological tissue on the first free end of the flexible plate.
  • the thickness of the silicon-based plate is between 150 ⁇ m and 500 ⁇ m; - the through openings are formed by slots parallel to each other; each slot has a width of between 400 ⁇ m and 600 ⁇ m and the distance separating two adjacent slots is substantially equal to the width of said slots;
  • the silicon-based plate comprises a surface protective layer obtained by oxidation of the silicon to allow compatibility of the plate with the cells of the biological tissue;
  • the rigid support has substantially an L-shape which comprises a first rigid wing parallel to the flexible plate and a second wing which extends perpendicularly from the first wing and on which the second end of the flexible plate is fixed;
  • the flexible plate has substantially an L shape which comprises a first flexible wing parallel to the rigid support and a second wing which extends perpendicularly from the first wing, said second wing being fixed on the rigid support; and - the rigid support is also made from silicon, or based on a dielectric
  • the invention also relates to a method for fixing a biological tissue, during its formation, on a system for measuring at least one characteristic of the biological tissue as defined above, characterized in that the method comprises the following steps: - the fibroblasts are placed in a container containing a liquid suitable for the formation of biological tissue, and - at least the first free end of the flexible plate is placed in the liquid to allow the fibroblasts to weave a collagen lattice through the through openings of the plate.
  • FIG. 1 is a schematic perspective view of a device for hanging the measurement system according to the invention according to a first embodiment
  • - Figure 2 is a schematic perspective view of a measurement system according to the invention
  • - Figures 3 and 4 show the measuring principle using a measuring system according to the invention
  • - Figure 5 is a schematic perspective view of a measurement system according to a second embodiment according to the invention.
  • the hanging device shown in the figure 1 is in the form of a substantially rectangular plate 1 having a thickness e much less than its width and its length. This rectangular plate 1 is made from silicon and it has a plurality of through slots 2 which pass through said rectangular plate according to its thickness e.
  • the realization of the through slots 2 is carried out by a chemical attack on a plate based on cutting silicon [100] along the crystal axes of said silicon plate. More particularly, chemical machining can be carried out by a wet anisotropic attack carried out at 45 °, that is to say along the crystalline axis ⁇ 011> relative to the cutting plane [100] of the silicon wafer, in such a way that the wet anisotropic attack is carried out orthogonally to the cutting surface of said plate, which allows a silicon attack in width with the same speed as in depth.
  • this wet anisotropic attack at 45 ° to the cutting silicon wafer [100] makes it possible to pierce the silicon wafer by making slots having perfectly vertical sides.
  • a protective layer is used for the wet anisotropic attack, this layer being produced from silica (Si0 2 ) obtained by oxidation of the surface of the silicon plate. This oxidation occurs approximately at a temperature between 900 ° and 1300 ° under gaseous flow of pure oxygen or oxygen charged with water. Pure oxygen makes it possible to obtain an oxidation surface state identical to the initial state of silicon, and therefore leads to a much slower oxidation of the material.
  • the through slots 2 are parallel to each other and have an angle of inclination of about 45 ° relative to the edges longitudinal and transverse of the silicon-based plate 1.
  • the angle of inclination of the through slots 2 can be arbitrary, and said slots can in particular be parallel to the longitudinal edges of the plate or else be parallel to its transverse edges.
  • the thickness of the silicon plate 1 is comprised, for example between 150 ⁇ m and 500 ⁇ m.
  • each slot 2 has a width of between 400 ⁇ m and 600 ⁇ m while the distance which separates two adjacent slots 2 is substantially equal to the width of said slots.
  • the through slots 2 can also be arranged only on a portion, for example a lower part of the silicon wafer for attachment to a support to constitute a measurement system as shown in FIG. 2.
  • This measurement system includes a support rigid 3 which has substantially an L shape and which comprises a first rigid wing 31 substantially parallel to the silicon-based plate 1, as well as a second wing 32 which extends perpendicularly from the first wing 31.
  • the second wing 32 of the rigid support 3 is fixed to the upper end 11 of the silicon plate 1 by means, for example, of a silicon-based adhesive.
  • the lower portion of the silicon plate delimited by its lower end 12 is in turn provided with a plurality of through slots 2 on which are intended to hang the biological tissues during their formation in culture, as will be described in detail later.
  • the silicon plate 1 as well as the rigid support 3 also has surfaces 13 and 33 which are arranged facing each other and on which are respectively added conductive armatures la and 3a forming a capacitive sensor.
  • the length of the wing 32 of the support 3 which delimits the space between the conductive armatures 3a and la is determined as a function of the sensitivity sought for the capacitive sensor.
  • the conductive plates 1a and 3a are connected to a processing unit 4 by respective electrical connections 5 and 6. This processing unit 4 is adapted to determine the isometric forces exerted by a biological tissue attached to the through slots 2 of the plate in silicon 1 by measuring the variation in the capacitance of the capacitive sensor.
  • This variation in the capacitance of the sensor is a function of the variation in the distance which separates the conductive armature 3a from the support 3 of the conductive armature 1a from the silicon plate 1, this plate made of silicon 1 being intended to deform under the action of the forces exerted by the biological tissue in formation.
  • FIGS. 3 and 4 the method of fixing a biological tissue 7, during its formation, on a silicon plate, to allow, via the measuring device, the measurement of at least one characteristic of said biological tissue 7.
  • fibroblasts for the formation of biological tissue are firstly placed in a container such as a cup 8 containing a suitable liquid 9. at least one characteristic is intended to be measured by the measuring device.
  • the measuring device formed by the rigid support 3 and the silicon plate 1 is then placed in the cup 8 and a second silicon plate 10 also provided on its lower portion with through slots 10a to allow the attachment of biological tissue during its formation.
  • the rigid support 3 of the measuring device is disposed inside the cup 8 and in the liquid 9, but it can of course be located outside of said cup 8 while the plate made of silicon 1 or more precisely its lower portion comprising the through slots 2, must it always be placed in the liquid 9 of the container 8.
  • the silicon plate 10 is, in turn, fixed in any manner to the cup 8 so not to undergo any deformation during the formation of the tissue.
  • the growth of biological tissue or dermis in situ is therefore done by weaving a lattice (or lattice) of collagen via fibroblasts.
  • the fibroblasts weave the collagen lattice through the network of slots 2 and 10a of the silicon plates 2 and 10.
  • the collagen lattice tightens, it then clings naturally to the slots 2 and 10a of the silicon plates 2 and 10.
  • the biological tissue shrinks, thereby exerting traction on the lower portion of the silicon plate 1 (see FIG. 4).
  • This traction exerted on the silicon plate 1 causes the conductive plates 1a and 3a to move away, thereby varying the capacitance of the capacitor formed by said conductive plates 1a and 3a.
  • the processing unit 4 determines the isometric force exerted by the biological tissue, and therefore the mechanical properties of said biological tissue by the relation existing between the variation of the capacitance of the capacitor formed by the reinforcements la and 3a and the knowledge of the intrinsic properties and the dimensions of the silicon plate 1 (modulus of elasticity, modulus of deformation).
  • the measurement of the variation of the capacity of the capacitor formed by the reinforcements 1a and 3a indirectly gives the measurement of the variation of the force exerted by the biological tissue during its formation.
  • the relationship between the variation of the capacitance of the capacitor and the isometric force exerted by the biological tissue is a function of the intrinsic properties and of the dimensions of the flexible silicon plate 1.
  • the rigid support 3 which is substantially in an L-shape can also be produced at p from a silicon plate, obtaining the two wings 31 and 32 can be carried out from chemical machining.
  • the flexible silicon plate 1 can for example have a length of the order of 25 mm and a width of approximately 20 mm. for a thickness of 200 ⁇ m.
  • the conductive armatures may for example have a length of 22 mm for a width of 20 mm while being separated from each other by a distance of approximately 50 ⁇ m, when no force is exerted on the lower end of the flexible silicon plate. Under these conditions, the capacitance of the capacitor varies approximately 200pF at rest to 500pF for a traction exerted by the biological tissue of approximately 10 milli newtons.
  • the flexible silicon plate 1 can have a substantially L-shape while the rigid support 3 has a substantially parallelepiped shape.
  • the silicon plate 1 comprises a first flexible wing 14 parallel to the rigid support 3 and a second wing 15 which extends perpendicularly from the first wing 14, this second wing 15 being fixed to the rigid support 3 by means of a glue for example based on silicon.
  • the deformation of the silicon plate 1 will take place approximately at the junction between the first flexible wing 14 and the second wing 15 connected to the support 3.
  • the L-shape of the silicon plate 1 can also be obtained by appropriate chemical machining.
  • the silicon plate 1 and the rigid support 3 can both have a substantially parallelepiped shape and be separated from each other by a wedge or spacer arranged at their upper ends.

Abstract

The invention relates to a biological tissue adhering device that enables the fixing of biological tissue during its formation in a culture. The device comprises a silicon baseplate (1) having a thickness much less than its width and length, and the plate (1) has a number of traversing openings (2) that traverse said plate along the thickness thereof.

Description

SYSTEME DE MESURE D'AU MOINS UNE CARACTERISTIQUE D'UN TISSU BIOLOGIQUE ET PROCEDE DE FIXATION D'UN TISSU BIOLOGIQUE SUR UN TEL SYSTEME DE MESURE La présente invention se rapporte à un système de mesure d'au moins une caractéristique d'un tissu biologique et à un procédé de fixation d'un tissu biologique sur un tel système de mesure . La présente invention se rapporte également à un procédé de fixation d'un tissu biologique utilisant un tel dispositif d'accrochage. Lorsque l'on souhaite observer et procéder à des mesures de certaines propriétés physiques et physicochimiques d'un tissu biologique in situ, il est préalablement nécessaire que le tissu biologique, lors de sa formation en culture, s'accroche à un support. La croissance du tissu biologique ou du derme in situ se fait par tissage d'un treillis (ou lattice) de collagène par l'intermédiaire des fibroblastes . Ce treillis, au cours de sa croissance, se rétracte pour former ensuite le derme ou tissu biologique destiné à rester accroché sur un dispositif d'accrochage. A cet effet, les systèmes de mesure comprennent des dispositifs d'accrochage qui sont généralement formés par des supports comprenant des fibres textiles ou polymères sur lesquelles les fibroblastes tissent le treillis de collagène en venant ainsi s'accrocher aux supports. Les supports comprenant les fibres textiles peuvent notamment être formés par des velcros (marque déposée) . Lorsque l'on procède ensuite à des mesures des propriétés mécaniques du derme en culture, il est nécessaire de fixer le support réalisé à partir de fibres textiles sur le système de mesure appropriée. Généralement les mesures effectuées sont des mesures de force isométrique exercée par les tissus biologiques in situ afin notamment de déterminer leur souplesse et leur résistance ou alors de caractériser leur vieillissement ou bien de détecter des maladies. Ainsi, lorsque l'on utilise des systèmes de mesure pourvus de supports à fibres textiles pour accrocher in situ le tissu biologique, la mesure de la force exercée par le tissu biologique sur le système de mesure dépend pour une grande partie de l'élasticité intrinsèque des fibres textiles du support. On comprend donc que l'élasticité des fibres textiles du support perturbe de manière importante la fiabilité des mesures opérées par le biais du système de mesure, ce qui ne permet pas d'obtenir une précision suffisante pour une exploitation fiable. La présente invention a notamment pour but de pallier les problêmes techniques mentionnés ci-dessus en proposant un dispositif de mesure fiable, simple et qui permet de recueillir des informations précises sur certaines propriétés physiques ou physico-chimiques du tissu biologique à mesurer. A cet effet, l'invention a pour objet un système de mesure qui s'étend entre deux extrémités, caractérisé en ce que qu'il comprend une plaque flexible à base de silicium présentant une épaisseur très inférieure à sa largeur et à sa longueur, et qui s'étend entre, d'une part, une première extrémité libre présentant une pluralité d'ouvertures traversantes qui traversent ladite plaque suivant son épaisseur et sur laquelle est destinée à être rapportée l'une des extrémités du tissu biologique et, d'autre part, une deuxième extrémité solidaire d'un support rigide, la plaque flexible et le support rigide étant adaptés pour présenter des surfaces en regard espacées l'une de l'autre et sur lesquelles sont respectivement rapportées des armatures conductrices formant un capteur capacitif, lesdites armatures conductrices étant disposées pour que la distance qui les sépare varie en fonction de la traction exercée par le tissu biologique sur la première extrémité libre de la plaque flexible. Dans des formes de réalisations préférées de l'invention, on a recours, en outre, à l'une et ou à l'autre des dispositions suivantes : - l'épaisseur de la plaque à base de silicium est comprise entre 150μm et 500μm ; - les ouvertures traversantes sont formées par des fentes parallèles les unes aux autres ; - chaque fente présente une largeur comprise entre 400μm et 600μm et la distance séparant deux fentes adjacentes est sensiblement égale à la largeur desdites fentes ; - la plaque à base de silicium comprend une couche de protection superficielle obtenue par oxydation du silicium pour permettre une compatibilité de la plaque avec les cellules du tissu biologique ; le support rigide présente sensiblement une forme en L qui comprend une première aile rigide parallèle à la plaque flexible et une deuxième aile qui s'étend perpendiculairement à partir de la première aile et sur laquelle est fixée la deuxième extrémité de la plaque flexible ; - la plaque flexible présente sensiblement une forme en L qui comprend une première aile flexible parallèle au support rigide et une deuxième aile qui s'étend perpendiculairement à partir de la première aile, ladite deuxième aile étant fixée sur le support rigide ; et - le support rigide est également réalisé à base de silicium, ou à base d'un matériau diélectrique. L'invention a également pour objet un procédé de fixation d'un tissu biologique, lors de sa formation, sur un système de mesure d'au moins une caractéristique du tissu biologique tel que défini ci-dessus, caractérisé en ce que le procédé comprend les étapes suivantes : - on dispose des fibroblastes dans un récipient contenant un liquide approprié pour la formation du tissu biologique, et - on dispose au moins la première extrémité libre de la plaque flexible dans le liquide pour permettre aux fibroblastes de tisser un treillis de collagène au travers des ouvertures traversantes de la plaque . D'autres caractéristiques et avantages de 1 ' invention apparaîtront au cours de la description qui va suivre de plusieurs de ces formes de réalisations, données à titre d'exemples non limitatifs, en regard des dessins joints. Sur les dessins : - la figure 1 est une vue schématique en perspective d'un dispositif d'accrochage du système de mesure conforme à l'invention selon une première forme de réalisation ; - la figure 2 est une vue schématique en perspective d'un système de mesure conforme a l'invention ; - les figures 3 et 4 représentent le principe de mesure utilisant un système de mesure conforme à l'invention ; et - la figure 5 est une vue schématique en perspective d'un système de mesure selon un second mode de réalisation conforme à l'invention. Sur les différentes figures,' les mêmes références désignent des éléments identiques ou similaires. Le dispositif d'accrochage représenté sur la figure 1 se présente sous la forme d'une plaque sensiblement rectangulaire 1 ayant une épaisseur e très inférieure à sa largeur et à sa longueur. Cette plaque rectangulaire 1 est réalisée à base de silicium et elle présente une pluralité de fentes traversantes 2 qui traversent ladite plaque rectangulaire suivant son épaisseur e. La réalisation des fentes traversantes 2 est réalisée par une attaque chimique d'une plaque à base de silicium de coupe [100] suivant les axes cristallins de ladite plaque de silicium. Plus particulièrement, l'usinage chimique peut être réalisé par une attaque anisotrope humide effectuée à 45°, c'est-à-dire suivant l'axe cristallin <011> par rapport au plan de coupe [100] de la plaque en silicium, de telle manière que l'attaque anisotrope humide s'effectue orthogonalement à la surface de coupe de ladite plaque, ce qui permet une attaque du silicium en largeur avec la même vitesse qu'en profondeur. Ainsi cette attaque anisotrope humide à 45° de la plaque de silicium de coupe [100] permet de percer la plaque de silicium en réalisant des fentes ayant des flancs parfaitement verticaux. Une couche de protection est utilisée pour l'attaque anisotrope humide, cette couche étant réalisée à partir de silice (Si02) obtenu par oxydation de la surface de la plaque en silicium. Cette oxydation se produit environ à une température comprise entre 900° et 1300° sous flux gazeux d ' oxygène pur ou d ' oxygène chargé en eau. L ' oxygène pur permet l'obtention d'un état de surface de l'oxydation identique à l'état initial du silicium, et conduit donc à une oxydation beaucoup moins rapide du matériau. Sur la figure 1, les fentes traversantes 2 sont parallèles les unes aux autres et elles présentent un angle d'inclinaison d'environ 45° par rapport aux bords longitudinaux et transversaux de la plaque à base de silicium 1. Toutefois, l'angle d'inclinaison des fentes traversantes 2 peut être quelconque, et lesdites fentes peuvent notamment être parallèles aux bords longitudinaux de la plaque ou alors être parallèles à ses bords transversaux. L'épaisseur de la plaque en silicium 1 est comprise, par exemple entre 150 μm et 500 μm. A titre d'exemple, chaque fente 2 présente une largeur comprise entre 400 μm et 600 μm tandis que la distance qui sépare deux fentes 2 adjacentes est sensiblement égale à la largeur desdites fentes . Les fentes traversantes 2 peuvent également être uniquement disposées sur une portion, par exemple inférieure de la plaque en silicium en vue de son accrochage sur un support pour constituer un système de mesure tel que représenté sur la figure 2. Ce système de mesure comprend un support rigide 3 qui présente sensiblement une forme en L et qui comprend une première aile rigide 31 sensiblement parallèle à la plaque à base de silicium 1, ainsi qu'une deuxième aile 32 qui s'étend perpendiculairement à partir de la première aile 31. La deuxième aile 32 du support rigide 3 est fixée sur l'extrémité supérieure 11 de la plaque en silicium 1 au moyen, par exemple, d'une colle à base de silicium. La portion inférieure de la plaque en silicium délimitée par son extrémité inférieure 12 est quant à elle pourvue d'une pluralité de fentes traversantes 2 sur lesquelles sont destinés à s'accrocher les tissus biologiques lors de leur formation en culture, comme cela sera décrit en détail ultérieurement. Par ailleurs, la plaque en silicium 1 ainsi que le support rigide 3 présente également des surfaces 13 et 33 qui sont disposées en regard et sur lesquelles sont respectivement rapportées des armatures conductrices la et 3a formant un capteur capacitif. Bien entendu, la longueur de l'aile 32 du support 3 qui délimite l'espace entre les armatures conductrices 3a et la est déterminée en fonction de la sensibilité recherchée pour le capteur capacitif. Les armatures conductrices la et 3a sont reliées à une unité de traitement 4 par des liaisons électriques respectives 5 et 6. Cette unité de traitement 4 est adaptée pour déterminer les forces isométriques exercées par un tissu biologique accroché sur les fentes traversantes 2 de la plaque en silicium 1 par mesure de la variation de la capacité du capteur capacitif. Cette variation de la capacité du capteur, comme on va le voir ci-après, est fonction de la variation de la distance qui sépare l'armature conductrice 3a du support 3 de l'armature conductrice la de la plaque en silicium 1, cette plaque en silicium 1 étant destinée à se déformer sous l'action des forces exercées par le tissu biologique en formation. Nous allons maintenant décrire, en regard des figures 3 et 4 , le procédé de fixation d'un tissu biologique 7, lors de sa formation, sur une plaque en silicium, pour permettre par l'intermédiaire du dispositif de mesure, la mesure d'au moins une caractéristique dudit tissu biologique 7. Selon le procédé de fixation conforme à l'invention on dispose tout d'abord dans un récipient tel qu'une coupelle 8 contenant un liquide approprié 9, des fibroblastes pour la formation du tissu biologique dont au moins une caractéristique est destinée à être mesurée par le dispositif de mesure. On dispose ensuite le dispositif de mesure formé par le support rigide 3 et la plaque en silicium 1 dans la coupelle 8 ainsi qu'une deuxième plaque en silicium 10 également pourvue sur sa portion inférieure de fentes traversantes 10a pour permettre l'accrochage du tissu biologique lors de sa formation. Sur les figures 3 et 4, le support rigide 3 du dispositif de mesure est disposé à l'intérieur de la coupelle 8 et dans le liquide 9, mais il peut bien entendu être situé à l'extérieur de ladite coupelle 8 tandis que la plaque en silicium 1 ou plus exactement sa portion inférieure comprenant les fentes traversantes 2, doit elle être toujours disposée dans le liquide 9 du récipient 8. La plaque en silicium 10 est, quant à elle, fixée d'une manière quelconque à la coupelle 8 afin de ne subir aucune déformation lors de la formation du tissu. La croissance du tissu biologique ou du derme in situ se fait donc par tissage d'un treillis (ou lattice) de collagène par l'intermédiaire des fibroblastes. Ainsi, lors de la formation du tissu, les fibroblastes tissent le treillis de collagène à travers le réseau de fentes 2 et 10a des plaques en silicium 2 et 10. Lorsque le treillis de collagène se resserre, il s'accroche alors naturellement aux fentes 2 et 10a des plaques en silicium 2 et 10. Au fur et à mesure de sa croissance, le tissu biologique se rétracte en exerçant ainsi une traction sur la portion inférieure de la plaque en silicium 1 (voir figure 4) . Cette traction exercée sur la plaque en silicium 1 provoque 1 ' éloignement des armatures conductrices la et 3a en faisant ainsi varier la capacité du condensateur formé par lesdites armatures conductrices la et 3a. L'unité de traitement 4 détermine alors la force isométrique exercée par le tissu biologique, et donc les propriétés mécaniques dudit tissu biologique par la relation existant entre la variation de la capacité du condensateur formé par les armatures la et 3a et la connaissance des propriétés intrinsèques et des dimensions de la plaque en silicium 1 (module d'élasticité, module de déformation) . Ainsi, la mesure de la variation de la capacité du condensateur formé par les armatures la et 3a donne indirectement la mesure de la variation de la force exercée par le tissu biologique au cours de sa formation. Bien entendu, on comprend que la relation entre la variation de la capacité du condensateur et la force isométrique exercée par le tissu biologique, est fonction des propriétés intrinsèques et des dimensions de la plaque flexible en silicium 1. Ainsi, pour optimiser les mesures, il suffit de modifier la longueur et/ou l'épaisseur de ladite plaque en silicium, et de procéder à des mesures préalables de la variation de la capacité du condensateur formé par les armatures la 3a en fonction d'une force déterminée et connue qui est exercée sur l'extrémité inférieure de la plaque en silicium 1, pour pouvoir établir un tableau ou une courbe de correspondances entre ladite force exercée au niveau de l'extrémité de la plaque en silicium et la valeur capacitive du condensateur, ce tableau ou cette courbe de correspondances étant mémorisé par l'unité de traitement 4. Le support rigide 3 qui se présente sensiblement sous une forme en L peut également être réalisé à partir d'une plaque en silicium, l'obtention des deux ailes 31 et 32 pouvant être réalisée à partir d'un usinage chimique. Les forces exercées par le tissu biologique in situ étant généralement de l'ordre de la dizaine de milli- newtons, la plaque flexible en silicium 1 peut par exemple avoir une longueur de l'ordre de 25 mm et une largeur d'environ 20 mm pour une épaisseur de 200 μm. Par ailleurs, les armatures conductrices pourront par exemple avoir une longueur de 22 mm pour une largeur de 20 mm tout en étant séparées l'une de l'autre d'une distance d'environ 50μm, lorsque aucun effort n'est exercé sur l'extrémité inférieure de la plaque flexible en silicium. Dans ces conditions, la capacité du condensateur varie a peu près de 200pF au repos à 500pF pour une traction exercée par le tissu biologique d'environ 10 milli newtons. Selon un second mode de réalisation du système de mesure conforme à l'invention, représenté sur la figure 5, la plaque flexible en silicium 1 peut présenter sensiblement une forme en L tandis que le support rigide 3 présente une forme sensiblement parallélépipédique . La plaque en silicium 1 comprend une première aile flexible 14 parallèle au support rigide 3 et une deuxième aile 15 qui s'étend perpendiculairement à partir de la première aile 14, cette deuxième aile 15 étant fixée sur le support rigide 3 au moyen d'une colle par exemple à base de silicium. Dans ce cas, la déformation de la plaque en silicium 1 se fera approximativement au niveau de la jonction entre la première aile 14 flexible et la deuxième aile 15 reliée au support 3. Bien entendu, la forme en L de la plaque en silicium 1 peut également être obtenue par un usinage chimique approprié. De même, selon un autre mode de réalisation non représenté sur les figures, la plaque en silicium 1 et le support rigide 3 peuvent tous les deux présenter une forme sensiblement parallélépipédique et être séparés l'un de l'autre par une cale ou entretoise disposée au niveau de leurs extrémités supérieures . SYSTEM FOR MEASURING AT LEAST ONE CHARACTERISTIC OF A BIOLOGICAL TISSUE AND METHOD FOR FIXING A BIOLOGICAL TISSUE ON SUCH A MEASUREMENT SYSTEM The present invention relates to a system for measuring at least one characteristic of a biological tissue and a method of attaching biological tissue to such a measurement system. The present invention also relates to a method of fixing a biological tissue using such an attachment device. When it is desired to observe and make measurements of certain physical and physicochemical properties of a biological tissue in situ, it is first necessary that the biological tissue, during its formation in culture, clings to a support. The growth of the biological tissue or of the dermis in situ is done by weaving a lattice (or lattice) of collagen via the fibroblasts. This trellis, during its growth, retracts to then form the dermis or biological tissue intended to remain attached to a hanging device. To this end, the measurement systems include hooking devices which are generally formed by supports comprising textile or polymer fibers on which the fibroblasts weave the collagen lattice thereby clinging to the supports. The supports comprising the textile fibers can in particular be formed by velcros (registered trademark). When the mechanical properties of the cultured dermis are then measured, it is necessary to fix the support produced from textile fibers to the appropriate measurement system. Generally the measurements carried out are measurements of isometric force exerted by the biological tissues in situ in order in particular to determine their flexibility and their resistance or then to characterize their aging or else to detect diseases. Thus, when measurement systems provided with textile fiber supports are used to hang the biological tissue in situ, the measurement of the force exerted by the biological tissue on the measurement system largely depends on the intrinsic elasticity. textile fibers of the support. It is therefore understood that the elasticity of the textile fibers of the support significantly disturbs the reliability of the measurements carried out by means of the measurement system, which does not make it possible to obtain sufficient precision for reliable operation. The object of the present invention is in particular to overcome the technical problems mentioned above by proposing a reliable, simple measurement device which makes it possible to collect precise information on certain physical or physico-chemical properties of the biological tissue to be measured. To this end, the subject of the invention is a measurement system which extends between two ends, characterized in that it comprises a flexible silicon-based plate having a thickness much less than its width and its length, and which extends between, on the one hand, a first free end having a plurality of through openings which pass through said plate according to its thickness and on which is intended to be attached one of the ends of the biological tissue and, on the other hand, a second end secured to a rigid support, the flexible plate and the rigid support being adapted to present facing surfaces spaced from one another and to which are respectively attached conductive plates forming a capacitive sensor, said conductive plates being arranged so that the distance between them varies as a function of the traction exerted by the biological tissue on the first free end of the flexible plate. In preferred embodiments of the invention, use is also made of one or more of the following provisions: the thickness of the silicon-based plate is between 150 μm and 500 μm; - the through openings are formed by slots parallel to each other; each slot has a width of between 400 μm and 600 μm and the distance separating two adjacent slots is substantially equal to the width of said slots; the silicon-based plate comprises a surface protective layer obtained by oxidation of the silicon to allow compatibility of the plate with the cells of the biological tissue; the rigid support has substantially an L-shape which comprises a first rigid wing parallel to the flexible plate and a second wing which extends perpendicularly from the first wing and on which the second end of the flexible plate is fixed; - The flexible plate has substantially an L shape which comprises a first flexible wing parallel to the rigid support and a second wing which extends perpendicularly from the first wing, said second wing being fixed on the rigid support; and - the rigid support is also made from silicon, or based on a dielectric material. The invention also relates to a method for fixing a biological tissue, during its formation, on a system for measuring at least one characteristic of the biological tissue as defined above, characterized in that the method comprises the following steps: - the fibroblasts are placed in a container containing a liquid suitable for the formation of biological tissue, and - at least the first free end of the flexible plate is placed in the liquid to allow the fibroblasts to weave a collagen lattice through the through openings of the plate. Other characteristics and advantages of the invention will become apparent from the following description of several of these embodiments, given by way of nonlimiting examples, with reference to the accompanying drawings. In the drawings: - Figure 1 is a schematic perspective view of a device for hanging the measurement system according to the invention according to a first embodiment; - Figure 2 is a schematic perspective view of a measurement system according to the invention; - Figures 3 and 4 show the measuring principle using a measuring system according to the invention; and - Figure 5 is a schematic perspective view of a measurement system according to a second embodiment according to the invention. In the different figures, ' the same references designate identical or similar elements. The hanging device shown in the figure 1 is in the form of a substantially rectangular plate 1 having a thickness e much less than its width and its length. This rectangular plate 1 is made from silicon and it has a plurality of through slots 2 which pass through said rectangular plate according to its thickness e. The realization of the through slots 2 is carried out by a chemical attack on a plate based on cutting silicon [100] along the crystal axes of said silicon plate. More particularly, chemical machining can be carried out by a wet anisotropic attack carried out at 45 °, that is to say along the crystalline axis <011> relative to the cutting plane [100] of the silicon wafer, in such a way that the wet anisotropic attack is carried out orthogonally to the cutting surface of said plate, which allows a silicon attack in width with the same speed as in depth. Thus this wet anisotropic attack at 45 ° to the cutting silicon wafer [100] makes it possible to pierce the silicon wafer by making slots having perfectly vertical sides. A protective layer is used for the wet anisotropic attack, this layer being produced from silica (Si0 2 ) obtained by oxidation of the surface of the silicon plate. This oxidation occurs approximately at a temperature between 900 ° and 1300 ° under gaseous flow of pure oxygen or oxygen charged with water. Pure oxygen makes it possible to obtain an oxidation surface state identical to the initial state of silicon, and therefore leads to a much slower oxidation of the material. In Figure 1, the through slots 2 are parallel to each other and have an angle of inclination of about 45 ° relative to the edges longitudinal and transverse of the silicon-based plate 1. However, the angle of inclination of the through slots 2 can be arbitrary, and said slots can in particular be parallel to the longitudinal edges of the plate or else be parallel to its transverse edges. The thickness of the silicon plate 1 is comprised, for example between 150 μm and 500 μm. By way of example, each slot 2 has a width of between 400 μm and 600 μm while the distance which separates two adjacent slots 2 is substantially equal to the width of said slots. The through slots 2 can also be arranged only on a portion, for example a lower part of the silicon wafer for attachment to a support to constitute a measurement system as shown in FIG. 2. This measurement system includes a support rigid 3 which has substantially an L shape and which comprises a first rigid wing 31 substantially parallel to the silicon-based plate 1, as well as a second wing 32 which extends perpendicularly from the first wing 31. The second wing 32 of the rigid support 3 is fixed to the upper end 11 of the silicon plate 1 by means, for example, of a silicon-based adhesive. The lower portion of the silicon plate delimited by its lower end 12 is in turn provided with a plurality of through slots 2 on which are intended to hang the biological tissues during their formation in culture, as will be described in detail later. Furthermore, the silicon plate 1 as well as the rigid support 3 also has surfaces 13 and 33 which are arranged facing each other and on which are respectively added conductive armatures la and 3a forming a capacitive sensor. Of course, the length of the wing 32 of the support 3 which delimits the space between the conductive armatures 3a and la is determined as a function of the sensitivity sought for the capacitive sensor. The conductive plates 1a and 3a are connected to a processing unit 4 by respective electrical connections 5 and 6. This processing unit 4 is adapted to determine the isometric forces exerted by a biological tissue attached to the through slots 2 of the plate in silicon 1 by measuring the variation in the capacitance of the capacitive sensor. This variation in the capacitance of the sensor, as will be seen below, is a function of the variation in the distance which separates the conductive armature 3a from the support 3 of the conductive armature 1a from the silicon plate 1, this plate made of silicon 1 being intended to deform under the action of the forces exerted by the biological tissue in formation. We will now describe, with reference to FIGS. 3 and 4, the method of fixing a biological tissue 7, during its formation, on a silicon plate, to allow, via the measuring device, the measurement of at least one characteristic of said biological tissue 7. According to the fixing method according to the invention, fibroblasts for the formation of biological tissue are firstly placed in a container such as a cup 8 containing a suitable liquid 9. at least one characteristic is intended to be measured by the measuring device. The measuring device formed by the rigid support 3 and the silicon plate 1 is then placed in the cup 8 and a second silicon plate 10 also provided on its lower portion with through slots 10a to allow the attachment of biological tissue during its formation. In FIGS. 3 and 4, the rigid support 3 of the measuring device is disposed inside the cup 8 and in the liquid 9, but it can of course be located outside of said cup 8 while the plate made of silicon 1 or more precisely its lower portion comprising the through slots 2, must it always be placed in the liquid 9 of the container 8. The silicon plate 10 is, in turn, fixed in any manner to the cup 8 so not to undergo any deformation during the formation of the tissue. The growth of biological tissue or dermis in situ is therefore done by weaving a lattice (or lattice) of collagen via fibroblasts. Thus, during the formation of the tissue, the fibroblasts weave the collagen lattice through the network of slots 2 and 10a of the silicon plates 2 and 10. When the collagen lattice tightens, it then clings naturally to the slots 2 and 10a of the silicon plates 2 and 10. As it grows, the biological tissue shrinks, thereby exerting traction on the lower portion of the silicon plate 1 (see FIG. 4). This traction exerted on the silicon plate 1 causes the conductive plates 1a and 3a to move away, thereby varying the capacitance of the capacitor formed by said conductive plates 1a and 3a. The processing unit 4 then determines the isometric force exerted by the biological tissue, and therefore the mechanical properties of said biological tissue by the relation existing between the variation of the capacitance of the capacitor formed by the reinforcements la and 3a and the knowledge of the intrinsic properties and the dimensions of the silicon plate 1 (modulus of elasticity, modulus of deformation). Thus, the measurement of the variation of the capacity of the capacitor formed by the reinforcements 1a and 3a indirectly gives the measurement of the variation of the force exerted by the biological tissue during its formation. Of course, it is understood that the relationship between the variation of the capacitance of the capacitor and the isometric force exerted by the biological tissue, is a function of the intrinsic properties and of the dimensions of the flexible silicon plate 1. Thus, to optimize the measurements, it it suffices to modify the length and / or the thickness of said silicon plate, and to carry out preliminary measurements of the variation of the capacitance of the capacitor formed by the reinforcements la 3a as a function of a determined and known force which is exerted on the lower end of the silicon plate 1, in order to be able to establish a table or a correspondence curve between said force exerted at the end of the silicon plate and the capacitive value of the capacitor, this table or this curve correspondences being memorized by the processing unit 4. The rigid support 3 which is substantially in an L-shape can also be produced at p from a silicon plate, obtaining the two wings 31 and 32 can be carried out from chemical machining. The forces exerted by the biological tissue in situ being generally of the order of ten milli-newtons, the flexible silicon plate 1 can for example have a length of the order of 25 mm and a width of approximately 20 mm. for a thickness of 200 μm. Otherwise, the conductive armatures may for example have a length of 22 mm for a width of 20 mm while being separated from each other by a distance of approximately 50 μm, when no force is exerted on the lower end of the flexible silicon plate. Under these conditions, the capacitance of the capacitor varies approximately 200pF at rest to 500pF for a traction exerted by the biological tissue of approximately 10 milli newtons. According to a second embodiment of the measurement system according to the invention, shown in FIG. 5, the flexible silicon plate 1 can have a substantially L-shape while the rigid support 3 has a substantially parallelepiped shape. The silicon plate 1 comprises a first flexible wing 14 parallel to the rigid support 3 and a second wing 15 which extends perpendicularly from the first wing 14, this second wing 15 being fixed to the rigid support 3 by means of a glue for example based on silicon. In this case, the deformation of the silicon plate 1 will take place approximately at the junction between the first flexible wing 14 and the second wing 15 connected to the support 3. Of course, the L-shape of the silicon plate 1 can also be obtained by appropriate chemical machining. Similarly, according to another embodiment not shown in the figures, the silicon plate 1 and the rigid support 3 can both have a substantially parallelepiped shape and be separated from each other by a wedge or spacer arranged at their upper ends.

Claims

REVENDICATIONS
1. Système de mesure d'au moins une caractéristique d'un tissu biologique (7) qui s'étend entre deux extrémités, caractérisé en ce que qu'il comprend une plaque flexible (1) à base de silicium présentant une épaisseur (e) très inférieure à sa largeur et à sa longueur, et qui s'étend entre, d'une part, une première extrémité libre (12) présentant une pluralité d'ouvertures traversantes (2) qui traversent ladite plaque (1) suivant son épaisseur (e) et sur laquelle est destinée à être rapportée l'une des extrémités du tissu biologique (7) et, d'autre part, une deuxième extrémité (11) solidaire d'un support rigide (3) , la plaque flexible (1) et le support rigide (3) étant adaptés pour présenter des surfaces en regard (13, 33) espacées l'une de l'autre et sur lesquelles sont respectivement rapportées des armatures conductrices (la, 3a) formant un capteur capacitif, lesdites armatures conductrices (la, 3a) étant disposées pour que la distance qui les sépare varie en fonction de la traction exercée par le tissu biologique (7) sur la première extrémité libre (12) de la plaque flexible (1) . 1. System for measuring at least one characteristic of a biological tissue (7) which extends between two ends, characterized in that it comprises a flexible plate (1) based on silicon having a thickness (e ) much less than its width and its length, and which extends between, on the one hand, a first free end (12) having a plurality of through openings (2) which pass through said plate (1) according to its thickness (E) and on which is intended to be attached one of the ends of the biological tissue (7) and, on the other hand, a second end (11) secured to a rigid support (3), the flexible plate (1 ) and the rigid support (3) being adapted to present facing surfaces (13, 33) spaced from one another and on which are respectively attached conductive armatures (la, 3a) forming a capacitive sensor, said armatures conductive (la, 3a) being arranged so that the distance between them the barrier varies as a function of the traction exerted by the biological tissue (7) on the first free end (12) of the flexible plate (1).
2. Système selon la revendication 1, dans lequel l'épaisseur (e) de la plaque à base de silicium est comprise entre 150 μm et 500 μm. 2. System according to claim 1, in which the thickness (e) of the silicon-based plate is between 150 μm and 500 μm.
3. Système selon l'une ou l'autre des revendications 1 et 2, dans lequel les ouvertures traversantes (2) sont formées par des fentes parallèles les unes aux autres. 3. System according to either of claims 1 and 2, wherein the through openings (2) are formed by slots parallel to each other.
4. Système selon la revendication 3, dans lequel chaque fente (2) présente une largeur comprise entre 400 μm et 600 μm et la distance séparant deux fentes adjacentes est sensiblement égale à la largeur desdites fentes (2) . 4. The system of claim 3, wherein each slot (2) has a width between 400 microns and 600 microns and the distance between two adjacent slots is substantially equal to the width of said slots (2).
5. Système selon l'une quelconque des revendications précédentes, dans lequel la plaque à base de silicium (1) comprend une couche de protection superficielle obtenue par oxydation du silicium pour permettre une compatibilité de la plaque (2) avec les cellules du tissu biologique. 5. System according to any one of the preceding claims, in which the silicon-based plate (1) comprises a surface protective layer obtained by oxidation of the silicon to allow compatibility of the plate (2) with the cells of the biological tissue.
6. Système selon l'une quelconque des revendications précédentes, dans lequel le support rigide (3) présente sensiblement une forme en L qui comprend une première aile rigide (31) parallèle à la plaque flexible (1) et une deuxième aile (32) qui s'étend perpendiculairement à partir de la première aile (31) et sur laquelle est fixée la deuxième extrémité (11) de la plaque flexible (1) . 6. System according to any one of the preceding claims, in which the rigid support (3) has substantially an L-shape which comprises a first rigid wing (31) parallel to the flexible plate (1) and a second wing (32) which extends perpendicularly from the first wing (31) and on which the second end (11) of the flexible plate (1) is fixed.
7. Système selon l'une quelconque des revendications 1 à 5, dans lequel la plaque flexible (1) présente sensiblement une forme en L qui comprend une première aile flexible (14) parallèle au support rigide (3) et une deuxième aile (15) qui s'étend perpendiculairement à partir de la première aile (14) , ladite deuxième aile (15) étant fixée sur le support rigide (3) . 7. System according to any one of claims 1 to 5, in which the flexible plate (1) has substantially an L-shape which comprises a first flexible wing (14) parallel to the rigid support (3) and a second wing (15 ) which extends perpendicularly from the first wing (14), said second wing (15) being fixed on the rigid support (3).
8. Système selon l'une quelconque des revendications précédentes, dans lequel le support rigide (3) est réalisé en silicium. 8. System according to any one of the preceding claims, in which the rigid support (3) is made of silicon.
9. Procédé de fixation d'un tissu biologique (7), lors de sa formation, sur un système de mesure d'au moins une caractéristique du tissu biologique selon l'une quelconque des revendications précédentes, caractérisé en ce que le procédé comprend les étapes suivantes : - on dispose des fibroblastes dans un récipient (8) contenant un liquide approprié (9) pour la formation du tissu biologique (7) , et - on dispose au moins la première extrémité libre (12) de la plaque flexible (1) dans le liquide (9) pour permettre aux fibroblastes de tisser un treillis de collagène au travers des ouvertures traversantes (2) de la plaque . 9. Method for fixing a biological tissue (7), during its formation, on a system for measuring at least one characteristic of the biological tissue according to any one of the preceding claims, characterized in that the method comprises following steps: - the fibroblasts are placed in a container (8) containing an appropriate liquid (9) for the formation of biological tissue (7), and - there is at least the first free end (12) of the flexible plate (1 ) in the liquid (9) to allow the fibroblasts to weave a collagen lattice through the through openings (2) of the plate.
PCT/FR2003/001684 2003-06-05 2003-06-05 Measuring system for measuring at least one characteristic of a biological tissue and method for fixing a biological tissue to a measuring system of this type WO2005003285A1 (en)

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EP2671077A2 (en) * 2011-01-31 2013-12-11 Imperial Innovations Limited Diagnostic method

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EP2671077A2 (en) * 2011-01-31 2013-12-11 Imperial Innovations Limited Diagnostic method
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