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Biosensors ביו-חיישנים – עקרונות ויישומים מרפואה ביתית ועד לניטור סביבתי Dr. Ronen Almog מכון טכנולוגי חולון R. Almog.

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Presentation on theme: "Biosensors ביו-חיישנים – עקרונות ויישומים מרפואה ביתית ועד לניטור סביבתי Dr. Ronen Almog מכון טכנולוגי חולון R. Almog."— Presentation transcript:

1 Biosensors ביו-חיישנים – עקרונות ויישומים מרפואה ביתית ועד לניטור סביבתי
Dr. Ronen Almog מכון טכנולוגי חולון R. Almog

2 Outline Biosensors Detection principles: Electrochemical Optical
Mechanical Lab on a chip/BioMEMS Examples: Diabetes - glucose monitoring Water toxicity detection R. Almog

3 Elements of a biosensor
R. Almog

4 Biosensor definition An integrated device consisting of
a biological recognition element and a transducer capable of detecting specific biological/chemical compound and converting it into an electronic signal. R. Almog

5 Biosensors applications and importance
Medical/health monitors Homeland security Pharmaceutical industry Food industry Simplicity Miniaturization Biosensors Features Selectivity Rapid Sensitivity R. Almog

6 Biological recognition elements
Enzymes and their substrates Antibodies and their antigens Nucleic acids and their complementary sequences Whole cell A - T G - C R. Almog

7 On Size and Scale R. Almog

8 Enzymes Large protein molecules. Catalyze chemical reactions.
Used as tools to perform various biochemical reactions in the cell. Participates actively in the transformation of chemical A (the substrate) to chemical B (the product) but remains unchanged at the end of the reaction. R. Almog

9 Immunosensors: Antibody – Antigen recognition
Antibody - proteins, produced by the immune system of higher animals in response to the entry of “foreign” materials into the body, eg. viruses, bacteria Bind tightly to the foreign material (the antigen) that provoked the response and mark it for attack by other elements of the immune system. Antibodies are also very specific- they need to be, in recognizing and binding to the foreign substance only and not to materials native to the organism. If an antigen is present in that medium, it will be bound by the antibody to form a larger, antigen-antibody complex. This will change some physicochemical parameter (usually mass or an optical parameter) of the environment at the transducer surface of the sensor and that change is subsequently detected. R. Almog

10 Antibody structure R. Almog

11 The transducer Chemical change Physical change
The key part of a biosensor is the transducer which makes use of a physical change accompanying the reaction. The most common are: 1. Electrochemical-Amperometric : Measures currents generated when electrons are exchanged between a biological system (in solution) and an electrode in a constant potential. 2. Optical detection - refractive index change or fluorescence 3. Mechanical detection 4. Conductometric/Impedimetric : detect changes in conductivity/impedance between two electrodes. R. Almog

12 Transducers - sensing methods in biosensors
R. Almog

13 Use: Bioassay of prostate-specific antigen (PSA)
MEMS - MicroElectroMechanichal sensors Use: Bioassay of prostate-specific antigen (PSA) R. Almog

14 Optical sensors - Biacore example
R. Almog

15 Reasons for Miniaturization
R. Almog

16 Biochips Microelectronic-inspired devices that are used for delivery, processing, analysis, or detection of biological molecules and species. These devices are used to detect cells, microorganisms, viruses, proteins, DNA and related nucleic acids, and small molecules of biochemical importance and interest. BioMEMS Biomedical or biological applications of MEMS (micro electro mechanical systems) R. Almog

17 R. Almog

18 Lab-on-a-chip R. Almog Burns et al. Science 282, 484, 1998

19 BioChip/BioMEMS Materials
Silicon • Glass, Quartz • Polymers – Poly (dimethylsiloxane) (PDMS) – Poly (methyl methacrylate) (PMMA) – Teflon, etc. Considerations • Biocompatibility, ideal for biomedical devices • Transparent within the visible spectrum • Rapid fabrication • Photo-definable • Chemically modifiable R. Almog

20 Biochip - microfluidics
Key Attributes of Biochips 1. Small length scale 2. Small thermal mass 3. Laminar flow 4. High surface-to-volume ratio R. Almog

21 Clark’s Glucose electrode
The Oxygen electrode Clark’s Glucose electrode R. Almog

22 Biosensors History R. Almog

23 Technology evolution 6 analyses from a drop of blood in about one minute. R. Almog

24 Diabetes - Glucose Biosensor
The user carries a wallet sized case that contains the testing equipment A lancet pierces the skin on the finger The user places this blood sample on a test strip and inserts it into the reader Electrochemical detection R. Almog

25 הינשוף Alcohol Test – Drager Alcotest 7110
The Alcotest 7110 Standard is a highly developed measuring instrument for precise determination of breath alcohol concentration. Two different and independent measuring systems: Infrared spectroscopy – λ=9.5µm Electrochemical measurement / R. Almog

26 Example - insect MEMS hybrid
A radio-controlled beetle 6 electrodes affixed to the brain and muscles 1.3g electronic module Max weight: 3g The University of California, Berkeley R. Almog IEEE MEMS, January 2009

27 Example: Toxichip R. Almog

28 Water toxicity detection - motivation
1. Homeland security THE THREAT: Intentional poisoning of a drinking water source 2. Enviromental pollution THE NEED: A rapid early toxicity warning device 3. Pharmaceutical screening applications R. Almog

29 Toxicity detection systems
Toxicity bioassays The only question need to be asked is “Is the sample toxic?” Standard toxicity bioassays, mostly designed for environmental purposes, are unsuitable for our needs: size, response time. R. Almog

30 The goal To develop a portable system that can detect the presence of unknown acute toxicity chemicals in drinking water within 20 minutes. R. Almog

31 Whole-cell biosensor:
The biological material is an intact, living, functioning cell. E. Coli bacteria Toxichip whole cell biosensors: Bacterial cells Genetically modified Bioluminescent Tailored to respond to different cell stress factors Three elements in the solution 1. Reporter cells: live cells “tailored” to detect toxicity. We use Escherichia coli (E. coli) bacteria as a whole cell sensor. 2. Biochips: disposable, credit card size, containing the cells. 3. Analyzer: a small mobile instrument into which the chip will be inserted, and which will provide the reading. R. Almog

32 E. Coli bacteria Biochip array R. Almog

33 Chemical energy is converted to light energy.
Bioluminescence The emission of light by a living organism as the result of a chemical reaction. Chemical energy is converted to light energy. Insects Marine organisms Fungee Emission spectrum: Visible - blue-green ( nm) Bacteria R. Almog

34 At least two chemicals are required:
Bioluminescence At least two chemicals are required: The one which produces the light is generically called a "luciferin“. The one that drives or catalyzes the reaction is called a "luciferase." Each organism has its own luciferin and luciferase compounds. Luciferin (substrate) Luciferase (enzyme) + Product: Oxyluciferin + light O2 R. Almog

35 Bacteria engineering for toxins detection
Two types of biochemical response to toxins : Type I Normally doesn’t emit light. Toxin exposure induces light emission. Sensitive to low concentration of toxins with a dose-dependent signal. Type II Constitutive test Normally emits light. In the presence of a toxin, the signal intensity decreases. Respond to high concentration of toxins R. Almog

36 Type I - bacteria engineering for toxins detection
The fusion of two genetic elements inside a host E. coli bacteria: Sensing element: A promoter of a gene involved in the response to the desired target. Reporting element: A Bioluminescent gene. – generates the Luciferin and Luciferase when experssed R. Almog

37 Toxins list R. Almog

38 Example - cell bioluminescence response
Bacteria response to mitomycin C - chemotherapeutic agent R. Almog

39 Effect of toxin concentration:
R. Almog

40 We use Nalidixic Acid (NA) as the model toxin
Measurement of the bacterial bioluminescence response to different NA concentrations under static condition (no flow). Here the bacteria were suspended in LB. R. Almog

41 Single Photon Avalanche photoDiode PDMS Biochip
Elastomer, Simple, fast, modular, cheap, reproducible, disposable Single Photon Avalanche photoDiode Microfluidics interface system for the PDMS biochip Inlet Outlet Glass cover PMMA base 10mm PDMS PMMA Glass SPADs Stainless steel Bacteria immobilized in Agar R. Almog

42 4 main channels: sample, positive, negative and constitutive.
The biochip layout: 4 strains 4 main channels: sample, positive, negative and constitutive. The sample, positive and negative channels consist of four different bacteria strains immobilized in agar. The constitutive channel consists of “Normally On” bacteria. R. Almog

43 Bacteria panel 2 toxins: Nitrogen mustard, Potassium cyanide
2 strains (promoters): nhoA, grpE R. Almog

44 R. Almog

45 HUJI - Shimshon Belkin’s group:
Acknoledgments Prof. Yosi Shacham Ramiz Daniel Klimentiy Levkov Matan Peer Yaniv Chen Ragini Raj Singh Sefi Vernick Amit Ron Mordechai Aharonson Tsvi Shmilovich Arthur Rabner HUJI - Shimshon Belkin’s group: Sharon Yagur-kroll Tal Elad Sahar Melamed R. Almog

46 The end Thank you! R. Almog

47 E. Coli bacteria Biochip array R. Almog

48 Optical sensors - Biacore example
R. Almog

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