US20030124583A1 - Biochip for the archiving and medical laboratory analysis of biological sample material - Google Patents

Biochip for the archiving and medical laboratory analysis of biological sample material Download PDF

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Publication number
US20030124583A1
US20030124583A1 US10/257,661 US25766102A US2003124583A1 US 20030124583 A1 US20030124583 A1 US 20030124583A1 US 25766102 A US25766102 A US 25766102A US 2003124583 A1 US2003124583 A1 US 2003124583A1
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Prior art keywords
biochip
sample carrier
sample
micro
areas
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Hans-Jurgen Staab
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Bioref GmbH
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Bioref GmbH
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Publication of US20030124583A1 publication Critical patent/US20030124583A1/en
Priority to US11/984,611 priority Critical patent/US8592224B2/en
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    • 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
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
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Definitions

  • the invention relates to a biochip suitable for diagnostic purposes, which is coated with the biological sample material to be analysed, and which is suitable both for space-saving archiving of sample material and for the laboratory-medical diagnostic analysis thereof.
  • the invention further relates to sample carriers suitable for the production of such biochips, and to processes for the production of the sample carriers or biochips mentioned.
  • the invention further relates to diagnostic methods using the biochips of the present invention, as well as to the use of the biochips of the present invention or of the diagnostic methods in various medicinal areas.
  • Laboratory-medical diagnostics constitutes an important basis for medical treatment. Due to the rising number of available diagnostic marker molecules, the possibilities of laboratory-medical diagnostics are being continuously expanded. Because of the volume of the detection reactions to be carried through, their great urgency, as well as for economical reasons, automated analysis methods, which are able to cope with a large number of different analyses within a short time, are employed with preference.
  • the raw material for the laboratory-medical analysis of a patient's state of health is typically a body fluid such as whole blood, plasma, serum, urine, ascites, amniotic fluid, saliva, liquor, etc., or tissue samples of different organs.
  • the treating physician collects the sample from the patient, possibly subjects the same to a specific treatment, e.g. centrifugation, and then transfers the patient sample into a test tube, in which the sample is sent out or stored until the analysis is performed.
  • the sample may either be stored at room temperature, or it has to be cooled, or stored in frozen condition.
  • the patient samples In the case of long-term storage, i.e. if the storage is for a period of several weeks, months or years, the patient samples must be frozen at ⁇ 20° C. or at lower temperatures in order to prevent degradation of the analytes.
  • the main cause for the degradation occurring at room temperature is the enzyme activities inherent in the liquid sample material.
  • Typical sample volumes for long-term storage amount to at least 500 ⁇ l. If, after a first analysis, further analytical determinations are to be made at a later point in time, or at various later points in time, several 500 ⁇ l samples have to be prepared starting from the original collection of blood, and stored, or stored in deep-frozen condition. These samples take up a relatively large space, which renders storage over a prolonged period of time relatively expensive. For this reason, long-term storage of patient samples is as a rule not applied. This, however, means that one has to forgo the possibility of at a later time falling back upon a sample collected earlier.
  • this is desirable or even necessary, namely when it is important to compare a patient's current condition, in terms of certain diagnostic parameters, with an earlier states of the same patient.
  • Such comparisons are, however, not possible where the relevant diagnostic test(s) were not, or could not be, made at the earlier point(s) in time in question and the original sample(s) was/were not stored.
  • methods of the most different kind are currently utilized in laboratory medicine.
  • the currently utilized immunochemical analysis systems are based on antigen-antibody reactions, which mostly take place in a volume of ca. 10-500 ⁇ l.
  • the patient sample (body fluid, etc.), which contains the analyte to be detected, in this case an antigen, is incubated together with an antibody which is specific for this parameter and recognizes and binds to only this analyte.
  • the product of this antigen-antibody reaction is a complex containing antibody-bound antigens. The higher the antigen concentration in a patient sample, the higher the concentration of antigen-antibody complexes formed.
  • these antigen-antibody reactions take place either freely in solution (detection by turbidimetry or nephelometry), or they are performed on antigen-specific surfaces (e.g. RIA, ELISA).
  • antigen-specific surfaces e.g. RIA, ELISA.
  • the detection and quantification of antigen-antibody complexes is performed in the case of turbidimetry or nephelometry by measuring the turbidity, in the case of RIA (radioimmunoassay) by radio-isotope-marked antibodies in conjunction with radiometric detection, in the case of ELISA (enzyme-linked immunosorbent assay) and LIA with enzyme-marked antibodies in conjunction with the detection of enzyme-catalysed colour-reactions.
  • RIA radioimmunoassay
  • ELISA enzyme-linked immunosorbent assay
  • LIA enzyme-marked antibodies in conjunction with the detection of enzyme-catalysed colour-reactions.
  • Biochips in analogy to computer chips.
  • the size of such biochips is typically between 0.25 and 9 cm 2 .
  • Biochips described in the literature consist of a solid matrix of glass (S. P. A. Fodor et al.: Light-directed, spatially addressable parallel chemical synthesis; Science 251 (February 1991), p. 767-773); C. A. Rowe et al.: An array immunosensor for simultaneous detection of clinical analytes; Analytical Chemistry Vol. 71 (Jan.
  • the analytes to be analysed which are contained in the patient samples, can subsequently be bound and detected with suitable detection systems.
  • CCD charge-coupled-device
  • M. Eggers et al. M. Eggers et al.; loc cit.
  • T. Vo-Dinh et al. DNA biochip using a photo-transistor integrated circuit; Analytical Chemistry 71 (1999) p. 358-363
  • fluorescence detectors S. P. A. Fodor et al.; loc cit.
  • biochips are currently being used exclusively for research purposes, e.g. for DNA sequencing, gene expression analysis, gene mutation analysis and protein-binding studies, i.e. antibody-binding studies.
  • gene expression analysis M. Schena et al.: Quantitative monitoring of gene expression patterns with a complementary DNA microarray; Science 270 (20 Oct. 1995) p. 467-470
  • DNA sequences which are complementary to certain genes are spotted on with the aid of a pipetting robot onto the matrix of a chip blank, with every single spot representing a certain gene.
  • mRNA is isolated from the tissue sample to be analysed, marked with a fluorescent dye and applied on the entire biochip. Then, the binding of marked mRNA molecules to certain sites of the biochip can be detected.
  • the biochip is discarded as it is contaminated with the mRNA sample.
  • biochips can be utilized for DNA sequence analysis and for gene mutation analysis.
  • biochips known from the prior art are restricted to such embodiments where specific, selected, or especially synthesized molecules are applied and bound to a solid matrix in a defined, miniaturized arrangement. These molecules serve to detect the presence of certain analytes in a heterogeneous mixture, e.g. the patient sample. This means that these biochips are test-specific, i.e. they allow only for those detection reactions which are pre-determined by the detection molecules present on the chip.
  • the task underlying the invention was therefore to provide a miniaturized analysis system in the form of a biochip for diagnostic purposes, which analysis system was to enable repeated execution of analytical detection methods, even at longer intervals of time, on the same patient sample material. Furthermore, the biochip was to enable the space-saving storage and archiving of the sample material for a prolonged period of time.
  • the task underlying the invention was to provide a method enabling the automated implementation of detection reactions with a biochip complying with the aforementioned prerequisites.
  • the method should be highly flexible, i.e. it should be easily adaptable to other, originally not intended detection reactions.
  • the process was to enable repeated examination of the same sample material at intervals of time.
  • the biochip according to the invention comprises a sample carrier made of a solid matrix, to the surface of which is linked the sample material to be analysed, which sample material originates from a biological organism.
  • the sample material to be analysed is linked to a solid phase.
  • the biochip according to the present invention represents a patient-specific or patient sample-specific chip, whereas the hitherto known biochips are test-specific, i.e. detection-specific biochips.
  • the binding of the sample material can be directly to the surface of the sample carrier matrix.
  • the matrix or surface of the sample carrier is pre-treated by chemical or physical methods in order to improve the binding capacity of the surface for the sample material. Methods suitable for this purpose, e.g. etching or roughening, are known to those skilled in the art.
  • FIG. 1A represents a biochip (a) in section comprising a sample carrier (b) and a sample material ( 2 ) bound thereto.
  • the sample carrier substantially consists of a solid matrix ( 1 ).
  • the binding of the sample material may optionally also be carried out by means of a layer of linker molecules (linker layer) applied to the surface of the sample carrier.
  • linker layer a layer of linker molecules
  • FIG. 1B represents a sample carrier (b) in section consisting of a solid matrix ( 1 ) and a linker layer ( 3 ) located thereon; the sample material ( 2 ) is bound on the surface of the sample carrier via the linker layer.
  • the diagnostic detection reaction is principally carried through in such a manner that the molecules suitable for the detection are applied to very small areas of the biochip, which is coated with the sample material, as will be described in detail below. In this way, it is possible to treat different areas of the surface of the biochip with different diagnostic detection reagents either simultaneously or successively.
  • the sample material to be analysed is bound to the surface of the sample carrier.
  • the sample material is present in dried condition and is therefore stable in storage even at room temperature. Since the biochips of the invention are miniaturized systems, in this way a space-saving and economical storage and archiving of patient sample material is made possible. In this manner, a large number of the patient-specific biochips according to the present invention can be stored in a small space and is available for performing multiple analytical detection reactions.
  • the archivability of the biochips in conjunction with the possibility of performing several detection reactions on various sites of the chip surface independently from each other, enables the examination of a specific diagnostic marker in a specific patient, or in a specific sample of a patient, at different intervals of time. It is especially advantageous that such diagnostic examinations are possible at a later point in time even in such cases where they have not been planned originally, i.e. at the time of collecting the sample. This applies especially to such detection reactions which have been developed at a later point in time after the collection.
  • each individual specimen of a biochip according to this invention contains sample material which has in each case been collected from a certain, individual biological organism, e.g. sample material originating from a certain patient.
  • sample material e.g. sample material originating from a certain patient.
  • sample material e.g. sample material originating from a certain patient.
  • further biological organisms from which suitable sample material may be obtained are animals, plants, fungi and microorganisms.
  • body fluids such as, for instance, whole blood, plasma, serum, urine, ascites, amniotic fluid, saliva, liquor, lavage material from body cavities or bronchoalveolar lavage.
  • tissue samples or organ samples, or components, cells, fractions, cell-disintegration material, concentrates or extracts from the mentioned fluids or from tissue or organ samples may be used.
  • the solid components of the blood sample are separated by centrifugation; subsequently the serum obtained in this manner can be applied and bound to the surface of the sample carrier.
  • the surface of the sample carrier according to this invention which surface is loaded with sample material, is partitioned into micro-areas. These are very small surface areas which are arranged close together, but are separated from each other. Usually, the surface is subdivided into a plurality of such micro-areas, preferably at least 100 micro-areas per cm 2 . For certain application purposes, a smaller number of micro-areas per unit area may be sufficient, e.g. 10 to 100 micro-areas per cm 2 .
  • the micro-areas may preferably be configured as depressions or separated from each other by hydrophobic or non-wettable border regions.
  • sample carrier By providing the sample carrier with hydrophobic or non-wettable border regions it is possible to prevent the linkage of sample material in these regions, so that these border regions, which are located between the individual border regions, are free from sample material.
  • the configuration of the micro-areas will be illustrated further below, by way of example, in FIGS. 2 and 3.
  • the implementation of analytical detection reactions is improved since this measure facilitates the detection and treatment of single sites by a pipetting robot.
  • the micro-areas are applied in the form of a regular grid or screen, it is possible to identify and address individual micro-areas by means of their coordinates. Thereby, the selective application of detection reagents to individual sites of the biochip using a pipetting robot is simplified.
  • the partitioning of the chip surface coated with the sample material increases the detection reliability, respectively prevents the risk of unwanted reactions or contaminations, as the individual micro-areas are separated from each other by border regions or are present in the form of depressions.
  • the sample carrier of the biochip according to the present invention substantially consists of a solid matrix.
  • Suitable base materials for the matrix of the sample carrier are, for instance, silicone, plastics (e.g. polyvinyl chloride, polyester, polyurethane, polystyrene, polypropylene, polyethylene, polyethylene terephthalate, polyamide, nitrocellulose) or glass, but other solid materials may be used as well. Transparent solid materials are used with preference. However, when selecting the matrix material, on must take care that it be suitable for durably binding the intended sample material.
  • the sample carrier may also be a laminate of at least two different matrix materials, with preferably one of the two layers forming a rigid carrier layer and the other layer serving as the surface for binding the sample material.
  • the outer dimensions of the biochips according to the present invention are selected such that the requirement of miniaturisation is fulfilled.
  • the surface of such a biochip, or of a sample carrier for production of such a biochip should be at most 10 cm 2 , preferably at most 4 cm 2 , and especially preferred at most 1 cm 2 .
  • the sample carrier is configured as a flat-shaped body, with particular preference having a square or rectangular outline. But other geometric shapes may be suitable too, e.g. round or circular sample carriers or biochips.
  • the thickness of the flat-shaped sample carrier is preferably less than 3 mm, especially preferred less than 1 mm.
  • the outer dimensions of the biochip are selected such that they are compatible with already available pipetting robots or analysis automatons and enable the use of the biochips according to the invention in such appliances.
  • the surface of a sample carrier is coated with the biological sample material, and this material is bound to the surface of the sample carrier; this bond may be covalent or non-covalent.
  • this bond may be covalent or non-covalent.
  • chemical or physical pretreatment the surface of the sample carrier can be enlarged, which leads to an increase in the binding capacity. Methods suitable for this purpose are known to those skilled in the art.
  • the surface of the sample carrier may be provided with a linker layer prior to application of the sample material in order to improve the binding of the sample material, respectively of the analytes (e.g. biomolecules or cells) contained therein, to the surface of the sample carrier, or to bring about a selective or preferred binding of certain analytes or groups or classes of analytes.
  • linkers are understood to mean such chemical compounds which on the one hand are capable of entering into a firm bond with the surface of the sample carrier, i.e. with its matrix material, and on the other hand are capable of binding biological sample material, or binding the latter selectively or in a preferred manner.
  • the surface of the sample carrier may be provided with a layer of linker molecules which enable the selective binding or concentration of certain groups of biological macromolecules, preferably of proteins, peptides, glycoproteins, sugars, lipids, nucleic acids, or the binding or concentration of cells or certain cell types or cell populations.
  • linker molecules which enable the selective binding or concentration of certain groups of biological macromolecules, preferably of proteins, peptides, glycoproteins, sugars, lipids, nucleic acids, or the binding or concentration of cells or certain cell types or cell populations.
  • analytes e.g. different classes of biological macromolecules
  • linker molecules may be used, for example (L. C.shriver-Lake; Antibody immobilization using heterobifunctional crosslinkers; Biosensors & Bioelectronics Vol. 12 (1997), p. 1101-1106): N-succinimidyl-4-maleimidobutyrate (GMBS; for binding of amino groups), 4-(N-maleimidomethyl)-cyclohexane-1-carboxylhydrazide-HCl (M2C2H; for binding of residual sugar), or antibodies with known binding specificities for binding the most different macromolecules or cells or types of cells.
  • GMBS N-succinimidyl-4-maleimidobutyrate
  • M2C2H 4-(N-maleimidomethyl)-cyclohexane-1-carboxylhydrazide-HCl
  • M2C2H 4-(N-maleimidomethyl)-cyclohexane-1-carboxylhydrazide-HCl
  • the surface of the sample carrier or biochip is partitioned into microareas.
  • this partitioning may also be achieved by a discontinuously configured linker layer.
  • micro-areas of linker-containing surface areas, and linker-free zones located therebetween are formed, with preferably at least 100 micro-areas being present per cm 2 .
  • a sample carrier the surface of which is suitable for binding sample material thereto and is preferably subdivided into micro-areas
  • the sheet-like matrix raw material glass, plastics, etc.
  • the corresponding matrix raw material may be liquefied and subsequently cast into appropriate moulds, e.g. by injection moulding, to produce sample carriers.
  • micro-areas mentioned, respectively the intermediate border regions can be produced, for example, by employing physical methods such as engraving, punching, embossing or printing, or by chemical methods such as etching or applying hydrophobic layers. It is furthermore possible to apply linker layers in the form of micro-areas to the surface of the sample carriers with the aid of a pipetting robot. Also, various known printing methods may be adapted to enable the production of the micro-areas of the present invention. Finally, the aforementioned methods can also be utilized in combination. Furthermore, it is possible to carry through the subdivision into micro-areas already in the matrix raw material, which is present in sheet-like form, said matrix raw material subsequently being separated into individual sample carriers in the manner described.
  • the biochips according to the present invention are especially suitable for archiving and multiple diagnostic analysis of sample material from one particular patient per biochip (“patient-specific” biochip).
  • patient-specific biochip a biochip
  • the biochip or a corresponding sample carrier be provided with means which enable the identification of the biochips, or the storage of patient-related data, or the storage of analysis data. This can preferably be done by means of a machine-readable bar code, a machine-readable magnetic strip, a digital storage element or another computer-readable storage medium.
  • the above described embodiment is of advantage.
  • the presence of a means for data storage on the biochips makes it possible, for example, for the physician or the laboratory physician collecting the sample and possibly applying the sample material to the sample carrier, to store, for example, patient-related data, or data relating to the collection of the sample on the biochip. Furthermore, it is thereby also possible to store analysis results or their evaluation, so that information on analyses which have already been performed earlier can also be stored.
  • the invention further comprises diagnostic detection methods comprising process steps for manufacturing a biochip using sample material, as well as comprising process steps for carrying out diagnostic detection reactions and for the evaluation thereof.
  • body fluids, tissue samples or the like are obtained from a patient or from another organism, and, if required, subjected to pre-treatment (e.g. centrifugation, concentration, etc.). If required, the sample material is suspended or dissolved in a suitable buffer or solvent.
  • this sample material preferably in liquid form, is applied to the surface of a sample carrier according to the present invention, e.g. by means of a pipette or by dipping. After a short incubation time of a few minutes, e.g. 1 to 10 min., any excess sample material is removed (e.g. by suction).
  • drying takes place, preferably at slightly elevated temperatures (30-60° C.), thereby causing the sample material, respectively the analytes (e.g. biomolecules) contained therein, to be linked to the surface of the sample carrier, or, as the case may be, to the linker layer.
  • the aforementioned process steps may be carried out by the physician collecting the sample material, or by auxiliary medical staff.
  • the patient-specific or sample-specific biochips thus obtained can subsequently be stored at room temperature under dry conditions, and are ready for immediate or later analysis.
  • Suitable as detection reagents are, for example, antibodies, antigens, sequence-specific antibodies, lectins, DNA probes, low-molecular ligands, hormones, biomolecule-binding dyes or other specifically binding molecules.
  • the mentioned sites or micro-areas of the biochip are incubated, for a certain time and at a certain temperature, with the selected detection reagents at certain concentrations, the experiment parameters in each case being dependent on the kind of detection reagents used and on the respective sample material. Those skilled in the art will normally be familiar with the selection of suitable experimental parameters.
  • the liquid detection reagent is removed by suction, using a pipetting robot. Subsequently, in a next step, likewise utilizing a pipetting robot, wash solvents and, if required, further detection reagents are applied in sequential order to the sites or micro-areas to be analysed and thereafter sucked off.
  • wash solutions and the detection reagents to be used in addition, e.g. fluorescence-marked antibodies, as well as the suitable reaction conditions are in principle known to those skilled in the art.
  • those sites or micro-areas where a positive detection reaction has taken place are identified by a suitable detector. Registration of these measurement signals is preferably accomplished with the aid of CCD cameras, photo-transistors, or radioactivity, luminescence or fluorescence detectors, the selection of the detection method being dependent on the kinds of detection reagents used. The primary measurement data supplied by the detectors can then be subjected to a computer-aided evaluation.
  • Positive detection reactions are in principle brought about by a specific interaction or linkage between the analytes (e.g. certain antigens in the patient sample) and the detection reagent used, e.g. by forming antigen-antibody complexes. These are made detectable by further reaction steps or reagents, which are known to those skilled in the art.
  • analytes e.g. certain antigens in the patient sample
  • the detection reagent used e.g. by forming antigen-antibody complexes.
  • biochips according to the invention are analysed simultaneously or parallelly in the manner described, i.e. if the detection reactions and the detection are performed simultaneously or parallelly on a plurality of biochips.
  • biochip or biochips is/are treated parallelly (at the same time) or sequentially one after the other, with different detection reagents possessing different detection specificities, said detection reagents in each case being applied to sites or micro-areas which have not previously been examined.
  • detection reagents in each case being applied to sites or micro-areas which have not previously been examined.
  • it is possible to test, within an extremely short period of time, on the presence or absence of certain diagnostic marker molecules in a plurality of patient-specific biochips.
  • the biochips can be returned for archiving and storing. They are then available for further detection reactions.
  • different micro-areas of the biochip are treated with different detection reagents.
  • the biochips according to the present invention together with the raw material bound thereon are, at room temperature, storable for a several years, at least for a period of 5 years, and during this storage time can be used repeatedly for carrying out the detection reactions described.
  • the biochips of the present invention are therefore advantageous in all those cases where it is important to store or archive sample material from patients affording the possibility of performing diagnostic detection reactions.
  • the biochips may also be stored at lower temperatures, e.g. at 0° C. to 15° C. or at even lower temperatures, e.g. below 0° C.
  • lower temperatures e.g. at 0° C. to 15° C.
  • lower temperatures e.g. below 0° C.
  • the biochips of the invention can expediently be stored or archived in a closable case or box which has guide rails on its inner side walls along which the biochips can be inserted into the case and by means of which they are locked therein.
  • guide rails By providing a plurality of such guide rails, it is possible to accommodate more than 100 biochips in a space-saving manner in a single case. A large number of those cases can in turn be integrated as an immovable or movable component in a drawer system or cupboard system.
  • the biochips according to the present invention are suitable for a plurality of practical applications. In the following, some possibilities of application will be described.
  • the biochips according to the present invention can be used in the field of tumour diagnostics to monitor, for example, the appearance of certain tumour markers in the serum or in tissue samples.
  • tumour markers are formed by tumours and secreted in body fluids of a sick person, or they are formed by the organism as a result of its reaction to the tumour.
  • these marker molecules are absent in the serum or other body fluids of healthy persons, or are present therein only in small amounts.
  • an increase in the serum concentration of the marker may occur.
  • the assessment of “medium” serum concentrations is problematic in respect of establishing a diagnosis since that finding can both point to a normal value which although being anomalous is nevertheless harmless (e.g. genetically caused), as well as to the beginning of tumour growth.
  • the decisive question is therefore whether there has been an increase in the serum concentration of such a tumour marker at a certain time.
  • This question can be answered if the serum concentration of that tumour marker is examined at certain time intervals. Only in this way is it possible to recognize a beginning tumour growth at an early point and with relative certainty.
  • marker detections must be carried out for each test person at intervals of time (i.e. a sequential determination), so that a trend analysis can be performed.
  • the trend analyses or sequential determinations of tumour markers using the biochips of the present invention may also be utilized for development control or follow-up of tumours, e.g. for postoperative relapse control or for the control of a cytostatic therapy.
  • the biochips of the present invention are suitable for clinical research, where archiving patient sample material likewise plays a big part. This is of significance especially where—for instance when the formulation of the scientific problem is changed—later ascertainment becomes necessary on earlier patient samples.
  • the biochips according to the present invention are much more suitable since they enable a considerably larger number of detection reactions while at the same time requiring considerably less space and affording facilitated storage. Because of the large number of detection reactions made possible by one biochip there is also no longer any necessity of preparing and storing several parallel samples of a patient at a particular point in time.
  • a further application field of the biochips according to this invention are blood banks or firms or other organisations which process human donor material (e.g. body fluids, cells, tissues) and where samples of the donor material and possibly of products made therefrom must or should be stored for diagnostic detection reactions for purposes of control. Usually only the analysis results but not the samples themselves are stored as this would require too much space. However, in connection with occurring contaminations, it may also be advantageous to subject such samples again to an analysis, possibly using other detection methods, for example for legal safeguarding. A renewed analysis of such samples may also be of advantage if it is to be proved that a raw, intermediate or end product of human material in terms of its composition complied with the regulations or the provisions of the law.
  • human donor material e.g. body fluids, cells, tissues
  • the biochips according to the invention may advantageously be used for archiving and subsequent analysis of samples of donor blood or other donor material from blood banks, companies and other organisations. If a contamination has occurred or there is a suspicion of non-conformity, the archived biochips make it possible to subsequently analyse the suspicious donor samples or samples of products based thereon. In this way it is possible to subsequently provide proof that a donor sample or product sample conformed to regulations, standards, or provisions of the law. This can be of great significance and assistance in particular in legal disputes. Furthermore, the inventive biochips or sample carriers may be used for storing and archiving patient sample material for purposes of routine diagnostic of patient samples.
  • the biochips according to this invention can also be advantageously utilised in epidemiological studies, to examine the proliferation of infectious diseases, for example. Hitherto such examinations frequently failed because the sample material from the past was no longer available since, for practical reasons, it was not possible to store the required numbers of blood samples or the like.
  • the biochips described here enable a space-saving and economical long-term storage and archiving. It is thereby possible to archive a large number of samples. These samples are then available for later epidemiological studies; hence these studies are able to take into account a much larger patient collective as they can fall back on archived samples from the past.
  • biochips and the methods according to the present invention can be utilised to advantage in connection with different formulations of problems in the field of medicine or veterinary medicine.
  • applications for purposes of tissue typing or in the field of forensic medicine are also possible.
  • FIG. 1A shows a section through a biochip (a) according to the invention which consists of a sample carrier (b) and the sample material ( 2 ) bound to the surface thereof.
  • the sample carrier (b) substantially consists of a solid matrix ( 1 ).
  • FIG. 1B shows, in section, an embodiment of the biochip (a) according to the present invention, wherein the sample carrier (b) comprises a solid matrix ( 1 ) and additionally a linker layer ( 3 ) located thereon.
  • the sample material ( 2 ) is linked to the matrix via the linker layer ( 3 ) of the sample carrier.
  • FIG. 2 shows sectional representations of different embodiments of the biochip according to the present invention, which embodiments comprise the afore-mentioned micro-areas (c).
  • FIGS. 2A to H there is depicted a region of a biochip in which such a micro-area is situated.
  • FIG. 2A shows a section through a biochip in the region of a micro-area (c), with (b) again designating the sample carrier consisting of a solid matrix ( 1 ).
  • the biological sample material ( 2 ) is bound to the surface of the sample carrier only in the region of the micro-area (c).
  • the adjacent regions of the sample carrier surface are free of sample material.
  • FIG. 2B likewise shows a section through a biochip in the region of a micro-area (c), similarly to FIG. 2A, however, with the sample material ( 2 ) being bound to the matrix ( 1 ) of the sample carrier (b) via a linker layer ( 3 ).
  • the linker layer is present only in the region of each micro-area; the adjacent regions are free of linker molecules.
  • FIG. 2C likewise shows a section through a biochip in the region of a micro-area (c), similarly to FIG. 2A.
  • the border regions ( 4 ) surrounding each micro-area are provided with hydrophobic properties, or they are non-wettable, so that in these border regions no sample material ( 2 ) can be bound.
  • FIG. 2D shows an embodiment in a representation as in FIG. 2A wherein the measures shown in FIGS. 2B and 2C are combined with each other.
  • the sample material ( 2 ) is linked via a linker layer ( 3 ), which is situated in the region of the micro-area (c), to the matrix of the sample carrier.
  • the border regions ( 4 ), which surround each micro-area, have been provided with hydrophobic properties or made non-wettable.
  • FIG. 2E shows a further embodiment in a representation as in FIG. 2A.
  • a micro-area (c) is shown which is configured in the form of a depression ( 5 ) in which the sample material ( 2 ) is bound to the matrix ( 1 ) of the sample carrier (b).
  • FIG. 2F shows a variant of the embodiment depicted in FIG. 2E, in which a micro-area (c) is shown which is configured in the form of a depression ( 5 ) the bottom of which is coated with a linker layer ( 3 ) by means of which the sample material ( 2 ) is bound to the matrix ( 1 ) of the sample carrier (b).
  • a micro-area (c) is shown which is configured in the form of a depression ( 5 ) the bottom of which is coated with a linker layer ( 3 ) by means of which the sample material ( 2 ) is bound to the matrix ( 1 ) of the sample carrier (b).
  • FIG. 2G shows a variant of the embodiment depicted in FIG. 2E, with the depression ( 5 ) of the micro-area (c) being configured in the form of a rounded trough.
  • FIG. 2H shows a variant of the embodiment depicted in FIG. 2F, with the depression ( 5 ) of the micro-area (c) being configured in the form of a rounded trough.
  • FIG. 3 shows, by way of example, some embodiments of the biochip or sample carrier according to the invention, in plan view.
  • FIG. 3A shows the basic shape of a biochip or sample carrier (b) according to the invention, with the surface area to be coated with the sample material being designated as ( 6 ).
  • the regions outside the surface area ( 6 ), especially the border regions, may be rendered hydrophobic or non-wettable.
  • FIG. 3B shows a variant of the sample carrier (b) depicted in FIG. 3A, which, in addition ( 8 ), is equipped with a bar code, magnetic strip or another storage medium.
  • FIG. 3C shows a sample carrier (b) or biochip in plan view, with the arrangement of the mentioned micro-areas (c) being represented by way of example.
  • the border regions may be rendered hydrophobic or non-wettable.
  • FIG. 3D finally shows a variant of the embodiment depicted in FIG. 3C, in which—as in FIG. 3B—additionally a means for data storage is provided, e.g. a bar code, magnetic strip or another storage medium.
  • a means for data storage e.g. a bar code, magnetic strip or another storage medium.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070254308A1 (en) * 1999-10-29 2007-11-01 Perkinelmer Las, Inc. Amplified array analysis method and system
US10082660B2 (en) 2014-01-16 2018-09-25 Euroimmun Medizinische Labordiagnostika Ag Transparent microscope slide having a marking
US11554376B2 (en) 2016-12-15 2023-01-17 Ricoh Company, Ltd. Container and calibration standard plate

Families Citing this family (20)

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Publication number Priority date Publication date Assignee Title
DE69737883T2 (de) 1996-04-25 2008-03-06 Bioarray Solutions Ltd. Licht-regulierte, elektrokinetische zusammensetzung von partikeln an oberflächen
US9709559B2 (en) 2000-06-21 2017-07-18 Bioarray Solutions, Ltd. Multianalyte molecular analysis using application-specific random particle arrays
DE10113711A1 (de) * 2001-03-16 2002-09-26 Lifebits Ag Verfahren zum Nachweis biochemischer Reaktionen und Messträger zur Durchführung des Verfahrens
WO2002088388A1 (fr) * 2001-04-26 2002-11-07 Ruebben Albert Procede et dispositif de quantification de charges de mutation
US7262063B2 (en) 2001-06-21 2007-08-28 Bio Array Solutions, Ltd. Directed assembly of functional heterostructures
JP4377689B2 (ja) 2001-10-15 2009-12-02 バイオアレイ ソリューションズ リミテッド 同時尋問及び酵素仲介検出による多型遺伝子座の複合分析
DE10163514A1 (de) * 2001-12-14 2003-07-03 Inst Polymerforschung Dresden Speichersystem für Nukleinsäure-Proben
US7335153B2 (en) 2001-12-28 2008-02-26 Bio Array Solutions Ltd. Arrays of microparticles and methods of preparation thereof
JP2004069559A (ja) 2002-08-07 2004-03-04 Seiko Epson Corp 製造システム、その制御装置、制御方法、制御システム及び制御プログラム
US7526114B2 (en) 2002-11-15 2009-04-28 Bioarray Solutions Ltd. Analysis, secure access to, and transmission of array images
WO2004112946A2 (fr) * 2003-06-05 2004-12-29 Bioprocessors Corp. Reacteur a composant a memoire
US7595279B2 (en) 2003-09-22 2009-09-29 Bioarray Solutions Ltd. Surface immobilized polyelectrolyte with multiple functional groups capable of covalently bonding to biomolecules
CA2544041C (fr) 2003-10-28 2015-12-08 Bioarray Solutions Ltd. Optimisation de l'analyse de l'expression genique a l'aide de sondes de capture immobilisees
US7848889B2 (en) 2004-08-02 2010-12-07 Bioarray Solutions, Ltd. Automated analysis of multiplexed probe-target interaction patterns: pattern matching and allele identification
DE102006020625B3 (de) * 2006-05-02 2007-08-16 Dr. Lauk & Dr. Breitling Gmbh Verfahren zur Gewinnung und Lagerung von zellhaltigen bzw. DNA-haltigen Proben für molekulargenetische Untersuchungen
CH704757B1 (de) * 2011-03-29 2015-09-30 Werner Döbelin Verfahren und Probenträgerkarte zur automatischen Extraktion und direkten Analyse von Proben.
JP6030633B2 (ja) * 2011-04-19 2016-11-24 ポーレックス コーポレイション 焼結多孔性プラスチックを含む試料貯蔵および送達のためのカード
JP2014515108A (ja) * 2011-04-19 2014-06-26 ポーレックス コーポレイション 液体試料の採取、保存、輸送および送達用器具
KR101339927B1 (ko) 2012-05-31 2013-12-10 한국원자력연구원 자기센서를 이용한 방사선에 의한 바이오 물질의 손상을 탐지하는 방법 및 이를 이용한 바이오 도시미터용 자기센서 바이오칩
WO2015105114A1 (fr) * 2014-01-10 2015-07-16 コニカミノルタ株式会社 Procédé et système de dosage immunologique

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4959308A (en) * 1987-08-27 1990-09-25 Board Of Regents, The University Of Texas System Immunoassay for antibodies binding platelets
US5741462A (en) * 1995-04-25 1998-04-21 Irori Remotely programmable matrices with memories
US5972626A (en) * 1997-07-30 1999-10-26 University Of Massachusetts Cancer detection by centrosome abnormality
US6066448A (en) * 1995-03-10 2000-05-23 Meso Sclae Technologies, Llc. Multi-array, multi-specific electrochemiluminescence testing
US6372185B1 (en) * 1997-05-16 2002-04-16 Aurora Biosciences Corporation Liquid chemical distribution method and apparatus
US6406840B1 (en) * 1999-12-17 2002-06-18 Biomosaic Systems, Inc. Cell arrays and the uses thereof
US6475808B1 (en) * 1998-07-14 2002-11-05 Zyomyx, Incorporated Arrays of proteins and methods of use thereof
US6479301B1 (en) * 1996-12-31 2002-11-12 Genometrix Genomics Incorporated Methods for fabricating an array for use in multiplexed biochemical analysis

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5474796A (en) * 1991-09-04 1995-12-12 Protogene Laboratories, Inc. Method and apparatus for conducting an array of chemical reactions on a support surface
US6468742B2 (en) * 1993-11-01 2002-10-22 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip
JPH07209399A (ja) * 1994-01-25 1995-08-11 Toyobo Co Ltd リガンド・レセプター反応測定用プラスチックス容器
US5807522A (en) * 1994-06-17 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods for fabricating microarrays of biological samples
JPH09187300A (ja) * 1995-11-06 1997-07-22 Sumitomo Pharmaceut Co Ltd ヒトｃｙｐ２ａ６遺伝子を用いた遺伝子診断方法
WO1997045730A1 (fr) * 1996-05-30 1997-12-04 Biodx Procedes et appareil a groupement miniaturise de cellules pour le criblage sur la base de cellules
DE19628928A1 (de) * 1996-07-18 1998-01-22 Basf Ag Feste Träger für analytische Meßverfahren, ein Verfahren zu ihrer Herstellung sowie ihre Verwendung
DE29616373U1 (de) * 1996-09-19 1996-11-07 Furtmayr, Ludwig, Dr., 82152 Planegg Teststreifen für analytische Nachweisverfahren
JP3610231B2 (ja) * 1997-08-01 2005-01-12 キヤノン株式会社 反応場アレー、反応場アレーの製造方法、反応場アレーを用いた反応方法及び反応場アレーを用いた試料溶液中の物質の定量方法
DE19736470C2 (de) * 1997-08-21 2001-02-22 Ulrich Schenck Datenverarbeitungsfähiger Mikroskopie-Probenträger und Verfahren zur Analyse von mikroskopierbaren Proben
US6087102A (en) * 1998-01-07 2000-07-11 Clontech Laboratories, Inc. Polymeric arrays and methods for their use in binding assays
DE29906382U1 (de) * 1998-04-14 1999-09-30 BioTul/Bio Instruments GmbH, 80339 München Probenträger mit Kennzeichnung
US6306589B1 (en) * 1998-05-27 2001-10-23 Vysis, Inc. Biological assays for analyte detection
DE69916421T2 (de) * 1998-09-09 2005-03-24 Hitachi Software Engineering Co., Ltd., Yokohama Biochip und verfahren zur verwendung des biochips
US20010049111A1 (en) * 1999-08-13 2001-12-06 Norbert Windhab Methods, procedures, and formats for using microelectronic array devices to perform multiplex immunoassay analyses

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4959308A (en) * 1987-08-27 1990-09-25 Board Of Regents, The University Of Texas System Immunoassay for antibodies binding platelets
US6066448A (en) * 1995-03-10 2000-05-23 Meso Sclae Technologies, Llc. Multi-array, multi-specific electrochemiluminescence testing
US5741462A (en) * 1995-04-25 1998-04-21 Irori Remotely programmable matrices with memories
US6479301B1 (en) * 1996-12-31 2002-11-12 Genometrix Genomics Incorporated Methods for fabricating an array for use in multiplexed biochemical analysis
US6372185B1 (en) * 1997-05-16 2002-04-16 Aurora Biosciences Corporation Liquid chemical distribution method and apparatus
US5972626A (en) * 1997-07-30 1999-10-26 University Of Massachusetts Cancer detection by centrosome abnormality
US6475808B1 (en) * 1998-07-14 2002-11-05 Zyomyx, Incorporated Arrays of proteins and methods of use thereof
US6475809B1 (en) * 1998-07-14 2002-11-05 Zyomyx, Incorporated Protein arrays for high-throughput screening
US6630358B1 (en) * 1998-07-14 2003-10-07 Zyomyx, Incorporated Arrays of proteins and methods of use thereof
US6406840B1 (en) * 1999-12-17 2002-06-18 Biomosaic Systems, Inc. Cell arrays and the uses thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070254308A1 (en) * 1999-10-29 2007-11-01 Perkinelmer Las, Inc. Amplified array analysis method and system
US8153367B2 (en) * 1999-10-29 2012-04-10 Perkinelmer Las, Inc. Amplified array analysis system
US10082660B2 (en) 2014-01-16 2018-09-25 Euroimmun Medizinische Labordiagnostika Ag Transparent microscope slide having a marking
US11554376B2 (en) 2016-12-15 2023-01-17 Ricoh Company, Ltd. Container and calibration standard plate

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ATE393913T1 (de) 2008-05-15
EP1277055B1 (fr) 2008-04-30
AU3929801A (en) 2001-11-12
US8592224B2 (en) 2013-11-26
JP4695812B2 (ja) 2011-06-08
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DE10020704A1 (de) 2001-11-08
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