WO2004012856A1 - Hybrid chip for the miniaturization of chemical, biomedical, and biological processes and method of application - Google Patents

Hybrid chip for the miniaturization of chemical, biomedical, and biological processes and method of application Download PDF

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Publication number
WO2004012856A1
WO2004012856A1 PCT/HU2003/000063 HU0300063W WO2004012856A1 WO 2004012856 A1 WO2004012856 A1 WO 2004012856A1 HU 0300063 W HU0300063 W HU 0300063W WO 2004012856 A1 WO2004012856 A1 WO 2004012856A1
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compounds
chip
biological
transport
chemical
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PCT/HU2003/000063
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French (fr)
Inventor
Ferenc Darvas
László ÜRGE
György Dormán
Tamás KARANCSI
Lajos GÖDÖRHÁZY
Dániel SZALAY
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Comgenex Rt.
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Priority to AU2003249102A priority Critical patent/AU2003249102A1/en
Publication of WO2004012856A1 publication Critical patent/WO2004012856A1/en

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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/08—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B30/00—Methods of screening libraries
    • C40B30/10—Methods of screening libraries by measuring physical properties, e.g. mass
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00418—Means for dispensing and evacuation of reagents using pressure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00599—Solution-phase processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00686—Automatic
    • B01J2219/00689—Automatic using computers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00695—Synthesis control routines, e.g. using computer programs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/007—Simulation or vitual synthesis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00822—Metal
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00871—Modular assembly
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/0095—Control aspects
    • B01J2219/00986—Microprocessor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/02—Identification, exchange or storage of information

Definitions

  • the four main elements of lead optimization are: (1 ) synthesis and work-up of compounds, (2) chemical analysis of the compounds, (3) biological assay of the compounds and (4) establishing the quantitative structure-activity relationships (QSAR) between the compounds, which allows the structure of compounds to be modified or affected in a new iterative cycle.
  • the advantages afforded by these systems include the low amounts of reagents needed, the low cost involved, and the ability to apply reliable, parallel, process automation and unique detection techniques (Sundberg, S.A., Curr. Opin. Biotechnol, 2000, 1 1 , pp. 47-53).
  • the CellChip system was developed by Cellomics (Pittsburgh, PA, USA) and ACLARA (Mountain View, CA, USA) for assay using live cell cultures.
  • a mono or multi-layer hybrid sheet is particularly suitable for producing compounds, and especially biologically active materials (i.e. drugs or pesticides), for optimizing the chemical structure of materials, and for miniaturizing biological processes.
  • This chip should include units that are directly connected to one another, preferably via a micron-sized channel network, and should perform the following functions: (1 ) the synthesis and work-up of compounds, (2) analysis of the compounds, (3) interaction studies on the compounds, preferably biological, biological utilization, metabolism or toxicity assays with biomolecules, cells, and tissue samples obtained from or related to live organisms, and (4) the establishment of quantitative structure-activity relationships (QSAR) for the compounds. which allows the structure of compounds to be modified or affected in a new iterative cycle.
  • QSAR quantitative structure-activity relationships
  • this invention involves a small hybrid sheet (chip), used to miniaturize chemical, biochemical, and biological processes, characterized by that it consists of mono or multilayer sheet (chip) comprising the following directly connected units:
  • a unit used for the execution of biological assays of compounds and the transport of raw materials, reagents, and final products and preferably, an electronic unit, more preferably a semi conductor chip into which the following have been burnt:
  • This invention also includes the manner of application of the small hybrid sheet (chip) described above; namely, the production, analysis and assay of biologically active compounds, and the measurement of their metabolism, toxicity, and any other adaptable biological interaction.
  • reaction chain is formed with a wide selection of substituents (from the reagent set) for structural diversity, so that structural optimization may also be executed primarily at these diversity points when the system is running.
  • a reaction chip which has a micro channel system consisting of an eight- point hole converging at a star point
  • the change in color of bromo-phenol blue indicator will indicate how the reaction is progressing.
  • 0.1 DL of acid and base enter the reactor channel, equally divided between the two feeding channels, establishing an electrokinetic difference in the electric field intensity (0.25-0.5 kV/cm) between the reactor channel and the two feeding channels.
  • the change of color of the bromo-phenol blue indicator to yellow, corresponding to a neutral pH indicates that the reaction has run to a full and immediate completion.

Abstract

This invention involves a small hybrid sheet (chip), used to miniaturize chemical, biochemical, and biological processes, characterized by that it consists of mono or multilayer sheet (chip) comprising the following directly connected units: a) a unit used for synthesis and work-up of compounds and the transport of raw materials, reagents, and final products; b) a unit used for the analysis of compounds and transport of raw materials, reagents, and final products; c) a unit used for execution of biological assays of compounds and the transport of raw materials, reagents, and final products; and d) preferably an electronic unit, into which software source codes for analysis and control have been burn. The small hybrid sheet (chip) may be applied to the production, analysis, and assay of biologically active compounds, and to the measurement of their metabolism, toxicity, and other adaptable interactions.

Description

HYBRID CHIP FOR THE MINIATURIZATION OF CHEMICAL , BIOMEDICAL , AND BIOLOGICAL PROCESSES AND METHOD OF APPLICATION
The invention consists of α small hybrid sheet (chip) used for miniaturizing chemical, biochemical, and biological processes, along with a method for its application.
As a result of the mapping of the human genome, thousands of new proteins remain to be identified. Identifying these proteins as potential drug targets will constitute one of the most important challenges for drug research in coming years. Numerous methods have been developed for associating the new proteins discovered by means of the genome with particular diseases, including comparative 2D electrophoresis (A. Gδrg, Proteomics, 2000, July 3) and isotope labeling combined with mass spectrometry (S.P. Gygi et al, Proteomics, 2000, July 31 ).
In many cases, these methods do not yield results when, for example, proteins are available only in low concentrations. Separating, detecting, and identifying large numbers of proteins is also difficult. The most significant demand on newly emerging technological solutions is that they identify not only the protein related to a particular disease, but also the small molecules, which are capable of influencing these proteins. The new study of chemical genomics allows the single-step identification and validation of target proteins and binding small molecules. (G. Dormάn, et al. Current Drug Discovery, 2001 , 1 , 21-24). With the development of combinatorial chemistry, in which every possible combination of building blocks are attached to a central core, it is now possible to produce a large number of new small molecules, as well as new analogues of previously known effective drug molecules.
The drug analogues produced by combinatorial chemistry using the results of chemical genomics and proteomics are subjected to multi-stage tests (assays) in order to select the compounds with an acceptable level of biological activity (number of hits). Then, using combinatorial chemistry, new, small molecule compound libraries are generated, based on structure similarity of such hits and the new molecules are assayed. After several iterative steps, compounds and compound libraries with favorable biological activity, called leads, are obtained. In the literature, the first step in the above process is called lead selection, while the sum of all further steps, through which the properties of the drug candidate are enhanced according to the criteria of drug development, are called lead optimization.
The four main elements of lead optimization are: (1 ) synthesis and work-up of compounds, (2) chemical analysis of the compounds, (3) biological assay of the compounds and (4) establishing the quantitative structure-activity relationships (QSAR) between the compounds, which allows the structure of compounds to be modified or affected in a new iterative cycle.
Several companies in the world market offer lead optimization services using different techniques and technologies. The most significant systems apply high-throughput synthesis, work-up, analysis, and assay methodologies, robotic techniques, and various other computer aided systems, such as the platform used by ComGenex, Inc. (Budapest, Hungary), (P. Krajcsi et.al.. poster, CHI Drug Discovery Japan, Tokyo, Japan, Jan 26-Feb 2, 2002) or that described in a patent specification by 3-Dimensional Pharmaceuticals, USA (US patents 5463564, 5574 656, 5684 711 and 5901 069). In each of these systems, the particular compound libraries are tested specifically for one or more target proteins.
Numerous experiments have been carried out with the aim of producing a high-throughput, compact method; however, these attempts have yielded only minor advancements. The quantity of each small molecule needed for the assay is still considerable, although high-throughput systems are an improvement over earlier, more conventional methods, and it is difficult to incorporate and compact all developmental stages of the lead optimization process into a single device.
One way to resolve the aforementioned disadvantages is to use miniaturization, a process that has become feasible in the last few years with the development of methods to fabricate micron-sized machinery and devices. Using miniaturization, it is possible to reduce both the quantity of compounds and time needed for the processes (Shi, Y. et.al.. Anal. Chem., 1999, 71 , pp. 5354-5361 ), decrease the amount of target protein solution, and mitigate problems associated with distillation of the solvent (Litborn, E. and coworkers, J. Chromatogr. 2000, 745, pp. 137-147). The mass transfer and movement of fluids can also be enhanced using interconnected channels. With the miniaturization of all developmental stages in lead optimization, and especially of each optimizing step, a single, compact, and multifunctional device may be constructed. Our invention is based on the recognition that by employing miniaturization, the synthesis, work-up, analysis, and biological assay steps of a compound library, as well as the steps involved in lead optimization, can be integrated into a single or multi-layered hybrid chip.
The high-density immobilization of small molecules on small chips represented a revolutionary change in the synthesis and analysis of small molecules. After synthesis, molecules are immobilized on the chip in a plane matrix configuration that is conducive to the subsequent step of biological screening.
Possible methods for producing the microarray and methods for immobilizing small molecules are addressed in a Hungarian patent (application number P- 02-01091 ). The advantage of using these methods is primarily that a vast number of different sample molecules can be placed next to each other (1000 molecules/square centimeter) in what amounts to a two-dimensional format, and that by applying several layers, an assay can be performed not only on one or more protein targets, but on the entire proteome (MacBeath G, Genome Biol., 2001, 2, p.2005).
In the case of microarrays, however, the synthesis and biological screening steps are separated. Since there is no direct feedback, the system is not applicable to iterative or cyclic optimization.
The latest research in lead optimization favors the use of microfluidic systems based on a network of microchannels. Schreiber et.al., for example, have published results on miniaturized cell culture assays and the advantages they provide (Chem. Biol., 1997, 4, pp. 961-975). In another research project, Litbom et.al. carried out tests in nanovials (Electrophoresis, 2000, 21 , pp. 91-99), in which the test reaction occurred with higher efficiency than in conventional microfuge vials. The Luminex, Inc. (Austin, TX, USA) extended its bead-based assay (carried out using compounds immobilized on spherical micro-beads) with the addition of microfluidic methods, allowing various kinds of assays to be run in a single experiment. Numerous companies, such as +Orchid Biocomputer (Princeton, NJ, USA) or Caliper Technologies (Mountain View, CA, USA), have developed „Lab-on-a-chip" systems (Guttman et.al., J. Chromatogr. A., 2002, 943, pp. 159-183) capable of performing microfluidics-directed cell-based assays. The advantages afforded by these systems include the low amounts of reagents needed, the low cost involved, and the ability to apply reliable, parallel, process automation and unique detection techniques (Sundberg, S.A., Curr. Opin. Biotechnol, 2000, 1 1 , pp. 47-53). The CellChip system was developed by Cellomics (Pittsburgh, PA, USA) and ACLARA (Mountain View, CA, USA) for assay using live cell cultures.
In our experiments, we found that a mono or multi-layer hybrid sheet (chip) is particularly suitable for producing compounds, and especially biologically active materials (i.e. drugs or pesticides), for optimizing the chemical structure of materials, and for miniaturizing biological processes. This chip should include units that are directly connected to one another, preferably via a micron-sized channel network, and should perform the following functions: (1 ) the synthesis and work-up of compounds, (2) analysis of the compounds, (3) interaction studies on the compounds, preferably biological, biological utilization, metabolism or toxicity assays with biomolecules, cells, and tissue samples obtained from or related to live organisms, and (4) the establishment of quantitative structure-activity relationships (QSAR) for the compounds. which allows the structure of compounds to be modified or affected in a new iterative cycle.
/ Chemical reaction module
Work-up and analitics module
Jiological screening
Figure imgf000007_0001
module
QSAR model building module
In accordance with the above, this invention involves a small hybrid sheet (chip), used to miniaturize chemical, biochemical, and biological processes, characterized by that it consists of mono or multilayer sheet (chip) comprising the following directly connected units:
a) a unit used for the synthesis and work-up of compounds and the transport of raw materials, reagents, and final products;
b) a unit used for the analysis of compounds and the transport of raw materials, reagents, and final products;
c) a unit used for the execution of biological assays of compounds and the transport of raw materials, reagents, and final products; and preferably, an electronic unit, more preferably a semi conductor chip into which the following have been burnt:
(i) a software source code of at least one computer program for the realization of a function algorithm between biological activity and the chemical structure of compounds; whose input is the chemical structure and biological activity of one or more compounds, and whose output is the chemical structure (s) of further compound (s) (one or more) likely to display the desired degree of biological activity,
(ii) a software source code of a synthesis program whose input is the chemical formula(e) of one or more compounds obtained as the output of part (i), and whose output is the laboratory synthesis protocol of these compounds
(iii) the software source code of a control program whose input is the one or more laboratory synthesis protocols obtained as the output of the previous step (ii), and whose output is the control program for the unit described in subsection a).
(iv) and finally, preferably the software source code of a control program that controls the operation of the units described under subsections (a) through (d), including launch, shut down, and optimization of these units, preferably the software source code of a control program that controls the biological assay by means of a threshold to be attained during the assay. The small hybrid sheet (chip) described as part of this invention may be constructed from any suitable material, preferably metal, glass, plastic, rubber, or inorganic materials (substances).
This invention also includes the manner of application of the small hybrid sheet (chip) described above; namely, the production, analysis and assay of biologically active compounds, and the measurement of their metabolism, toxicity, and any other adaptable biological interaction.
In the application described as part of this invention, the transport of compounds and biological media may be effected by means of pressure differences, differences in the electric field strength, or other forces describable through physical properties.
The hybrid chip described as part of this invention, which can be made from any suitable material, preferably metal, glass, plastic, rubber, or inorganic materials (substances) and containing a micro-network, is capable of performing particular functions, such as the synthesis of compounds, or the optimization of given physical, chemical, or biological parameters required for such synthesis, or the lead optimization preferably of drugs or agrochemicals, or chemical process optimization or other similar functions.
A substantially new aspect of the hybrid chip is that, when operated by means of modular and micro-networks, the possibility of direct, structure- based feedback with computerized data acquisition and analysis arises, allowing the optimizing cycles to be run in an iterative manner. To use our invention, the procedure for optimizing biochemical processes described below may be followed. First, the main steps of the chemical reaction are determined using retrosynthetic analysis, resulting in the core of the desired chemical structure. Then, based on this information, the chip- elements best suited for executing the reaction are selected and connected to one another.
Following each reaction step, it is preferable to introduce a work-up unit. The reaction chain is formed with a wide selection of substituents (from the reagent set) for structural diversity, so that structural optimization may also be executed primarily at these diversity points when the system is running.
In the micro-networks, the work-up, identification, and quality control of the compounds produced in either parallel or consecutive fashion occurs in the analysis unit, in the next unit, the assay measuring the interaction of the compounds (preferably biological activity, metabolism, toxicity, etc) against a biological medium is determined. The data obtained are sent to a central computer where the structure-activity relationship is determined using modeling software. The software automatically generates a new set of molecules expectedly have better biological activity characteristics. The molecules of the new set are produced in the reaction unit(s) during the next cycle, after which they are assayed again. This cyclic operation continues until the desired property value is reached. Examples:
1. Execution of an acid-based reaction in the reaction unit
In a reaction chip, which has a micro channel system consisting of an eight- point hole converging at a star point, we measure 10 DL 1 M aqueous HCI solution and 10 DL 1 M aqueous sodium hydroxide solution into each hole. The change in color of bromo-phenol blue indicator will indicate how the reaction is progressing. 0.1 DL of acid and base enter the reactor channel, equally divided between the two feeding channels, establishing an electrokinetic difference in the electric field intensity (0.25-0.5 kV/cm) between the reactor channel and the two feeding channels. The change of color of the bromo-phenol blue indicator to yellow, corresponding to a neutral pH, indicates that the reaction has run to a full and immediate completion.
2. Measuring of model interactions showing chemical luminescence in the biological screening unit.
Test solutions A and B (10 DL - 10 DL 0.2 mM dibutyl-phthalien solution) are added to each feeding hole of a chip with 4 feeding holes designed for biological screening.
Solutions A and B equally sucked into the interaction unit (0.1 DL), using a 10 mBar vacuum emitted sharp chemoluminescent signals, whose intensity can be measured and numerically interpreted.
Different intensities may be obtained by conducting the interaction tests at various temperatures (20- 60°C).

Claims

1. A small hybrid sheet (chip), used to miniaturize chemical, biochemical, and biological processes, characterized by that it consists of mono or multilayer sheet (chip) comprising the following directly connected units:
a) a unit used for the synthesis and work-up of compounds and the transport of raw materials, reagents, and final products;
b) a unit used for the analysis of compounds and transport of raw materials, reagents, and final products;
c) a unit used for the execution of biological assays of compounds and the transport of raw materials, reagents, and final products; and
d) preferably an electronic unit, more preferably a semi conductor chip into which the following have been burnt:
(i) the software source code of at least one computer program for the realization of a function algorithm between biological activity and the chemical structure of compounds; whose input is the chemical structure and biological activity of one or more compounds, and whose output is the chemical structure(s) of one or more further compounds likely to display the desired degree of biological activity. (ii)the software source code of a synthesis program whose input is the chemical formula (e) of one or more compounds obtained as the output of part (i), and whose output provides the laboratory synthesis protocol for these compounds
(iii) the software source code of a control program whose input is the one or more laboratory synthesis protocols obtained as the output of the previous step (ii), and whose output provides the control program for the unit described in subsection a).
(iv) furthermore, preferably the software source code of a control program that controls the operation of the units as per subsections (a) through (d), including launch, shut down, and optimization of these units, preferably the software source code of a control program that controls the biological assay by means of a threshold to be attained during the assay.
2. The small hybrid sheet (chip) described under Claim 1 , characterized by that it consists of any suitable material, preferably metal, glass, plastic, rubber, or inorganic materials (substances).
3. The application of the small hybrid sheet (chip) described under Claim 1 , meaning the production, analysis, and assay of biologically active compounds, and the measurement of their metabolism, toxicity, and other adaptable biological interactions. The application described under Claim 3, characterized by that the transport of the compounds and biological media may be affected by means of pressure differences, differences in the electric field strength, or other forces describable through physical properties.
PCT/HU2003/000063 2002-08-01 2003-07-30 Hybrid chip for the miniaturization of chemical, biomedical, and biological processes and method of application WO2004012856A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996008781A1 (en) * 1994-09-16 1996-03-21 3-Dimensional Pharmaceuticals, Inc. System and method of automatically generating chemical compounds with desired properties
US5580523A (en) * 1994-04-01 1996-12-03 Bard; Allen J. Integrated chemical synthesizers
WO2000062919A1 (en) * 1999-04-16 2000-10-26 Norbert Schwesinger Modular chemical microsystem
WO2001097152A2 (en) * 2000-06-10 2001-12-20 Hte Aktiengesellschaft The High Throughput Experimentation Company Computer-aided optimization of substance libraries

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580523A (en) * 1994-04-01 1996-12-03 Bard; Allen J. Integrated chemical synthesizers
WO1996008781A1 (en) * 1994-09-16 1996-03-21 3-Dimensional Pharmaceuticals, Inc. System and method of automatically generating chemical compounds with desired properties
WO2000062919A1 (en) * 1999-04-16 2000-10-26 Norbert Schwesinger Modular chemical microsystem
WO2001097152A2 (en) * 2000-06-10 2001-12-20 Hte Aktiengesellschaft The High Throughput Experimentation Company Computer-aided optimization of substance libraries

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