EP2142911A2 - Biopuce pour l'analyse par fluorescence de transporteurs individuels - Google Patents

Biopuce pour l'analyse par fluorescence de transporteurs individuels

Info

Publication number
EP2142911A2
EP2142911A2 EP08748708A EP08748708A EP2142911A2 EP 2142911 A2 EP2142911 A2 EP 2142911A2 EP 08748708 A EP08748708 A EP 08748708A EP 08748708 A EP08748708 A EP 08748708A EP 2142911 A2 EP2142911 A2 EP 2142911A2
Authority
EP
European Patent Office
Prior art keywords
biochip
membrane
recesses
carrier
transport
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08748708A
Other languages
German (de)
English (en)
Inventor
Stefan Hummel
Matthias Pirsch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synentec GmbH
Original Assignee
Synentec GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synentec GmbH filed Critical Synentec GmbH
Publication of EP2142911A2 publication Critical patent/EP2142911A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence

Definitions

  • the invention relates to a biochip for the optical measurement of the properties of individual transport systems.
  • Biological membranes separate cells from the outer medium and the individual cell compartments of the cells. Transport systems such as transport proteins and channels selectively control the mass transfer through these membranes. Dysfunctions of these transporters and channels are responsible for many common diseases.
  • membrane transporters were the most abundant target group. There are at least 1,302 transporter pharmaceuticals, both imported and under development, in the portfolios of 326 companies worldwide. Overall, more than 100 transporter targets are currently being researched by the pharmaceutical companies, which shows what immense economic importance they have.
  • the object of the invention is therefore to propose a device by means of which the properties of transporter molecules can be measured with high measurement accuracy and high throughput.
  • a biochip for the optical measurement of the properties of individual transport systems, which consists essentially of a transparent support and a plurality of recesses open at the top, wherein the Biochip is formed such that its openings are covered by a membrane, and so closed measuring chambers are formed and the transport of substrate molecules via the membrane in the wells is detectable.
  • the membrane is clamped over the recesses in the biochip, so that they are closed.
  • Evaluation yields parameters such as the transport rate, the conclusions about the transport protein / channel or e.g. allow an influence of a drug candidate. Both the method and the evaluation can be automated and used in high throughput.
  • a conductive layer preferably made of metal, is applied to the biochip, then it can additionally be used as an electrode, preferably for measurements of the impedance spectroscopy or else for the application of an electric field.
  • a second electrode in the solution over the membrane, e.g. statements about the electrical tightness of an applied lipid layer or a cell layer are taken by means of impedance spectroscopy. This can be used as a quality control for the quality of the lipid layer or even evaluation of the viability of the cells.
  • An applied electric field can be used for the control of voltage dependent channel proteins, e.g. To switch an ion channel to the open state and then perform as described a transport measurement by means of fluorescence measurement of an ion-dependent fluorescence indicator.
  • Proteo liposomes so artificial, hollow membrane vesicles containing inserted into the membrane transport proteins to use. These can either be coupled directly to the activated surface of the biochip or applied by fusion with a preformed lipid membrane.
  • the vesicle is reshaped to a membrane containing the transporter, which closes the measuring chambers formed in the wells in the biochip and thus enables a fluorescence measurement for characterizing the transporters and determining the transport rates.
  • the carrier is made of a material with a high
  • Refractive index such as glass, silicon or silicon dioxide.
  • refractive index is higher than the refractive index of the measuring solution used, total reflection and thus an evanescent field at the phase boundary of the material and the measuring solution can be generated by irradiating the excitation light at an angle and used for fluorescence detection.
  • the carrier (10) may have one or more layers (20) connected to its top.
  • the upwardly opened depressions (30) are provided in the layer or layers (20).
  • the diameter of the recesses is smaller than the wavelength of the excitation light, so that the recesses are formed as zero-mode waveguides.
  • the intensity of the excitation light then decreases exponentially within the measuring chamber, whereby a highly selective excitation is possible.
  • the biochip on the upper side is substantially opaque. As a result, the excitation light is shielded from the membrane. Fluorescent substrate molecules that are located in the membrane or above the membrane, ie outside the
  • a particularly suitable metal is gold because it is chemically inert, can be securely bonded to the substrate, and also has suitable light-reflecting properties. Titanium is also suitable.
  • the metal layer is firmly connected to the carrier by means of a bonding agent. It has been found that a metal, in particular chromium or titanium, is very well suited as adhesion promoter.
  • An improvement in the measurement accuracy can be achieved in that the metal layer is designed to be reflective on its underside in order to mirror the excitation light and thus excite the substrate molecules several times.
  • the opening of the recess may be partially covered by the overlying metal layer by having the opening in the metal layer selected to be smaller than the recess opening.
  • the metal layer lying over the openings can be used as an electrode for electrical measurements of the membrane or can also be used to generate an electric field. If the layer consists of silicon dioxide, fluorescence detection of the transport substrates in the recesses of the layer is possible.
  • the layer bearing the transparent support is made of a fluoropolymer, such as Teflon or Cytop, then this allows the detection of the fluorescence in the measuring chambers, e.g. using confocal laser scanning microscopy.
  • a fluoropolymer such as Teflon or Cytop
  • a further improvement can be achieved in that the diameter of the recesses decreases continuously from the bottom to the top, so that the recesses have approximately a conical shape.
  • the larger diameter of the chambers towards the carrier then make it possible to detect the fluorescence in the measuring spaces thus formed with greater accuracy.
  • the coupling that is to say the fixation of the biological membranes or artificial vesicles to the biochip, can take place in such a way that its surface has linker molecules which are in particular amino-reactive and / or lipid derivatives and which bind covalently or noncovalently to suitable constituents of the membrane.
  • the membrane has one or more proteins, in particular pore, channel or carrier proteins, whose transport activity is detected via the vesicle membrane.
  • Another application of the biochip is the characterization of production cell lines for recombinant proteins and antibodies.
  • cells or cell components are measured for the production of recombinant proteins or antibodies.
  • the cells are bound to the biochip, so that they close with their membrane, the wells of the chip. It is also possible to grow cells on the biochips.
  • Upon secretion of the produced proteins into the measuring chambers becomes generates a fluorescence signal via a reporter system. This fluorescence signal provides information on the amount of recombinant protein or antibody generated and thus allows the discovery of many producing cells that can be used for the biotechnological production of these proteins and antibodies.
  • the membranes used in the measurement may be biological or artificial lipid membranes. If biological membranes are used, particularly natural measuring conditions result.
  • the measurement is with a vesicle membrane containing reconstituted transporter molecules therein.
  • a vesicle membrane containing reconstituted transporter molecules therein. This allows fast, reproducible measurements. By embedding in the vesicle membrane, the transporter protein also regains its functional conformation.
  • the membrane stretched over a depression contains as few as possible, preferably one to three, transporter molecules.
  • the detection of the substrate transported by the transporter molecules is made possible by the fact that the substrate molecules fluoresce, preferably by being bound to a fluorescent dye, but also by binding to a substrate-dependent fluorescence indicator, e.g. for the measurement of ion currents.
  • the fluorescent substrate molecules are transported by the transporter molecule across the membrane into the wells of the biochip. There they are detected by means of a suitable fluorescence detection device. A particularly accurate measurement is made by the detection device measuring the fluorescence in a confocal plane within the well.
  • a further improvement in accuracy is achieved in that the diameter of the recesses, taking into account the wavelength of the excitation light, is selected such that an evanescent field is generated, which is used for fluorescence detection.
  • an evanescent field is generated by irradiating the excitation light at a total reflecting angle and thus used for fluorescence detection.
  • a layer is electrically conductive and designed as an electrode so as to electrically measure or excite the membrane.
  • a suitable layer may be, for example, the metal layer of gold arranged above the carrier.
  • the layer can thus additionally be used as an electrode for characterizing the electrical properties of membranes, cell layers or the transport systems present in the membrane.
  • the biochip can be used in such a way that the impedance of the membrane or epithelial cell layer stretched across the biochip is measured with transport systems, for example transport proteins. As a result, the tightness of the membrane can be determined.
  • the biochip can also be used by means of the electrode in addition to generate an electric field, in particular for the control of voltage-sensitive transport systems.
  • These are, for example, voltage-dependent ion channels, ie ion channels which open at a certain limit value of the membrane voltage or shut down.
  • By changing the applied electric field so functional switching processes can be triggered, which have a change in the transport of substrate through the membrane result.
  • the transport substrate can then be detected in the wells by means of fluorescence indicators.
  • an exemplary application of the biochip is that the top metal layer of the biochip is covered with a lipid membrane containing ion channels.
  • an electric field is applied to the electrically conductive layer, ie the electrode.
  • the applied voltage leads to the activation of the ion channels. This creates an ion current across the membrane into the wells, which is then detected quantitatively by fluorescence.
  • the proposed biochip thus surprisingly has the additional advantage that it can switch biological transport systems electrically functional and at the same time be able to measure the transport generated thereby via the membrane optically by means of fluorescence.
  • FIG. 1 shows a vertical section of the biochip according to the invention
  • FIG. 2 shows a vertical section as in FIG. 1 with a vesicle
  • FIG. 3 shows a vertical section as in FIG. 2 with a resting biological cell
  • Figure 4 is a plan view of an array of the biochip
  • FIG. 5a shows a detail view of the biochip with a depression in vertical section
  • Figure 5b is a detail view of the biochip with a cone-shaped recess of the biochip in vertical section and
  • Figure 6 is a detail view of a preferred embodiment of the biochip with a recess in vertical section.
  • FIG. 1 shows a vertical section through the biochip according to the invention.
  • the biochip 1 consists of a carrier 10, which is transparent to the excitation light or the fluorescent light. At his
  • the biochip 1 which serve as measuring chambers for the detection of a substrate 60.
  • the biochip 1 consists of a composite of different materials.
  • the basis is the optically transparent carrier 10 made of cover glass.
  • a layer of silicon dioxide 20 is arranged on the top of the carrier.
  • a layer of titanium is applied, which serves both as a reflector for the excitation light 80 and as a bonding agent for a further layer of gold.
  • the gold layer can be contacted and used as an electrode.
  • the three layers 20 contain through recesses 30 through which an upwardly open measuring chamber is formed in each case.
  • a membrane 40 is applied for the measurement, so that the measurement spaces 30 are closed.
  • the membrane 40 can be made from artificial proteo-liposomes 5 which contain transport proteins or pore proteins as a transport system.
  • the membrane 40 the Cell membrane of production cell lines for recombinant proteins or antibodies.
  • the membrane 40 contains transport systems 50, such as transport proteins or pore proteins.
  • transport systems 50 such as transport proteins or pore proteins.
  • transporters of the ABC transporter group which are relevant for many diseases, such as e.g. adrenoleukodystrophy ABCD 1 transporter with fatty acids as substrate or e.g. the glutamate transporter with the substrate glutamate, whose metabolism is disturbed in mental illness.
  • Fluorescence method detectable transport substrates 60 added. This is made possible, for example, by covalently marking the substrate with a fluorescent dye.
  • the transport 70 of the transport substrates through the transport systems 50 contained in the membrane 40 into the recesses 30 of the biochip is specific to the transport system 50 contained and can be quantified by fluorescence measurements in the measurement spaces 30. This makes it possible to draw conclusions about parameters specific to the transport system 50, such as transport rates and permeability, and thus the evaluation of drug candidates or the production rates of production cell lines.
  • the biochip may consist of a fluoropolymer 20 such as Teflon or Cytop, which contains the measurement spaces 30 and is applied to a light-transmissive carrier 10. This allows the detection of fluorescence in the measurement spaces, e.g. using confocal laser scanning microscopy.
  • a fluoropolymer 20 such as Teflon or Cytop
  • the biochip can also consist of a metal layer 20, into which the holes 30 are introduced, and which are applied to a light-transmitting carrier 10. If the diameter of the Holes 30 a certain size in the nanometer range, so the incident light can no longer penetrate completely into the measuring chambers, instead forms an evanescent field at the transition of the carrier and filled with measuring solution measuring space. The pits then represent "Zero Mode Waveguides" and thus allow the detection of the fluorescence in the measuring chambers formed.
  • Another way to make the biochip is to anisotropically etch conical holes 30 in silicon dioxide 20 and then apply this to a permeable support 10. The larger diameter of the holes towards the carrier 10 then permits detection of the fluorescence in these depressions.
  • the biochip may be formed by forming recesses 30 in a high refractive index material, such as a glass sheet. Glass 10 + 20, refractive index 1.53 can be produced. This refractive index is significantly higher than that of the measuring solution located in the measuring chambers 30 with a refractive index of 1.33. If the excitation light is irradiated obliquely from below, an evanescent field is generated at a transition from the carrier to the measurement solution at total reflection of the light, which can be used to detect the fluorescence in the measuring chambers 30.
  • a high refractive index material such as a glass sheet. Glass 10 + 20, refractive index 1.53 can be produced. This refractive index is significantly higher than that of the measuring solution located in the measuring chambers 30 with a refractive index of 1.33. If the excitation light is irradiated obliquely from below, an evanescent field is generated at a transition from the carrier to the measurement solution at total reflection of the light, which can be used to detect the flu
  • FIG. 2 shows a vertical section as in FIG. 1 with a vesicle (5). Pore-forming proteins (50) are reconstituted in the vesicle membrane.
  • FIG. 3 shows a vertical section as in FIG. 2 with a resting biological cell 15. This may be a complete cell 15 or just a part thereof. The cell extends over several recesses 30 and covers them. This makes it possible to measure under natural biological conditions.
  • FIG. 4 shows a plan view of an array 36 of the biochip 1. This is formed by virtue of the fact that four depressions 30, which are square in plan view, are arranged close to one another and thus form a group 35. The group 35 has a length c or width d of about 100 microns. Sixteen recessed groups 35 or sixty-four recesses 30 are arranged in each case to form an array 36 which has a length a or width b of about 500 ⁇ m in each case.
  • FIG. 5a shows a detail view of an embodiment of the biochip 1 with a depression 30 in vertical section.
  • a metal layer of gold is applied to a carrier 10 made of cover glass by means of a bonding agent made of chromium or titanium (not shown).
  • the measuring chamber 30 is thus formed in this embodiment only through the opening 31 in the metal, while the glass carrier 10 itself has no recess.
  • FIG. 5 b shows a similar embodiment as in FIG. 5 a, but the metal layer 20 has a conical or conical depression 30.
  • the opening 31 also has a diameter of 60 to 120 nm on its upper side, but widens downwards. This increases the measurement accuracy because the measurement chamber 30 contains more substrate 60 (not shown) and thus the signal / noise ratio is improved.
  • FIG. 6 shows a detailed view of a preferred embodiment of the biochip 1 with a depression 30 in vertical section.
  • a further metal layer of gold is applied by means of an adhesion promoter made of chromium or titanium (not shown) to a carrier 10 made of cover glass and a layer of silicon dioxide 20 connected thereto.
  • the two metal layers together have a thickness of about 100 nm.
  • the silicon dioxide and metal layers are provided with a layer opening 31 and a continuous recess 30 having a diameter of 200 nm.
  • the pitch is 500 nm. For the measurement of cellular membranes, the pitch is 1 to 2.5 ⁇ m.
  • the measuring chamber is formed by the depression 30 within the layer
  • the recess has a length e of about 1 .mu.m and an opening diameter 31 of about 200 nm.
  • the thickness f of the metal layer is preferably about 100 nm, the diameter of the layer opening 21 about 200 nm.
  • an advantage of this embodiment is that the measuring space formed in the glass carrier 10 by the depression 30 has a greater extent in the vertical direction.
  • the substrate molecules 50 (not shown) transported via the membrane are further removed on the average from the membrane and thus from the non-transported substrate molecules 50.
  • only the substrate molecules 50 below the lipid membrane (not shown) should be excited to fluoresce, facilitated by the greater spatial distance. This increases the signal / noise ratio.
  • the signal-to-noise ratio can be further improved by covering the upper recess opening 31 in part by the metal layer 20.
  • the excitation light is thus effectively shielded from the non-transported substrate molecules 50 (not shown) above the membrane.
  • FIG. 6 shows a schematic representation of the beams 80 of the excitation light.
  • a parallel light beam 80 is obliquely angled into the bottom of the glass carrier 10.
  • the beam path is arranged as in a commercially available TIRF microscope.
  • the beams 80 are reflected by the metal layer 20 and repeatedly irradiate the measuring volume 30 with the sample 60 (not shown).
  • the signal excitation is amplified many times, which further improves the measurement accuracy considerably.
  • the evanescent wave forming next to the excitation light is not shown in FIG. Due to the oblique incidence and thickness of the metal layer 20, the diameter is insufficient for zero mode excitation, which is desirable for signal suppression.

Abstract

L'invention concerne une biopuce (1) pour la mesure optique des propriétés de systèmes de transport individuels (50). Pour pouvoir mesurer les propriétés de molécules transporteuses (50) avec une précision et un débit élevés, ladite biopuce (1) de mesure optique des propriétés de systèmes de transport individuels (50) est essentiellement composée d'un support transparent (10) et de plusieurs cavités (30) ouvertes vers le haut. Ladite biopuce (1) est conçue de telle manière que ses ouvertures (31) peuvent être recouvertes par une membrane (40) de manière à former des chambres de mesure fermées (30) et à permettre la détection du transport de molécules de substrat (60) vers les cavités (30), au moyen de la membrane (40).
EP08748708A 2007-04-04 2008-04-02 Biopuce pour l'analyse par fluorescence de transporteurs individuels Withdrawn EP2142911A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007016699A DE102007016699A1 (de) 2007-04-04 2007-04-04 Biochip für die Fluoreszenzanalyse von einzelnen Transportern
PCT/DE2008/000532 WO2008122267A2 (fr) 2007-04-04 2008-04-02 Biopuce pour l'analyse par fluorescence de transporteurs individuels

Publications (1)

Publication Number Publication Date
EP2142911A2 true EP2142911A2 (fr) 2010-01-13

Family

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EP08748708A Withdrawn EP2142911A2 (fr) 2007-04-04 2008-04-02 Biopuce pour l'analyse par fluorescence de transporteurs individuels

Country Status (5)

Country Link
US (1) US20100092341A1 (fr)
EP (1) EP2142911A2 (fr)
JP (1) JP5370864B2 (fr)
DE (1) DE102007016699A1 (fr)
WO (1) WO2008122267A2 (fr)

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Also Published As

Publication number Publication date
JP5370864B2 (ja) 2013-12-18
JP2010523987A (ja) 2010-07-15
DE102007016699A1 (de) 2008-10-09
WO2008122267A3 (fr) 2008-12-11
US20100092341A1 (en) 2010-04-15
WO2008122267A2 (fr) 2008-10-16

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