BIOANALYTICAL AND BIOMEDICAL MICROSENSORS. Gerald A. URBAN Laboratory for Sensors IMTEK Freiburg/Germany. G. A. Urban Slide 1 3

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1 BIOANALYTICAL AND BIOMEDICAL MICROSENSORS Gerald A. URBAN Laboratory for Sensors IMTEK Freiburg/Germany G. A. Urban Slide 1 3

2 DISTINGUISHING FEATURES Unique combination of Computer Science and Microsystems Engineering One of the largest university based MEMS institution worldwide First curriculum in MEMS Extensive state-of-the-art cleanroom facilities 1400 students 22 Million extrenal research funding 3. Place ranking of german Wissenschaftsrat ~ 40 patent applications /a (2005 now) G. A. Urban Slide 2

3 OUTLINE History: Where we are going? Megatrends - Personalized Medicine Biomarker Analytics Microbiosensors/Lab-on-Chip G. A. Urban Slide 3

4 HISTORY ADVANCEMENTS IN MEDICAL TREATMENT Industrialization: food production, goods, Hygienic concepts Anesthesiology - surgery ECG / X-ray BioMedical Engineering / Antibiotics Computerization - Molecularization - Miniaturization Imaging Anesthesiology, ICU Dialysis Biomaterials Molecular imaging Implants Minimal invasiv surgery G. A. Urban Slide 4

5 MEGATRENDS Lifestyle diseases cardiovascular, diabetes,.. Aging population cancer, neurodegenerative diseases EMERGING DISEASES: New infectional diseases Multiple antibiotic resistance of bacterias (MRSA) NEW MEGATRENDS: Personalized Computerization Medicine - Molecularization - Biologization - Miniaturization - Nanomedicine Biomarker Systems biology from micro to nano G. A. Urban Slide 5

6 Costs of disease AGING POPULATION Hypertonia Neurodegener./psychotic diseases Cancer Diabetes Cardiac insufficiency Age (y) G. Urban, VDE Positionspapier Theranostische Implantate 2011 G. A. Urban Slide 6

7 PERSONALIZED MEDICINE Diagnostics Tailor therapy and manage a patient s disease better through use of molecular insights (Systems Biology) and diagnostic tests biomarkers Adapted from T. Gutjahr, Roche G. A. Urban Slide 7

8 PERSONALIZED MEDICINE or therapy G. A. Urban Slide 8 G.Urban, VDE Innovationsreport 2012

9 PERSONALIZED MEDICINE PHARMA COMPANY MARKET CONCEPT / NEED BUT Sell Pharmaka with Companion diagnostics tools as a complete system It s not only big VALUE CHAIN: Production / System house / Marketing-Sales pharma! ECONOMIC/ADDED VALUE Very high G. A. Urban Slide 9

10 PERSONALIZED MEDICINE one time - often - frequently continuous - implanted MONITORING Centralized lab Near patient ICU IVD POC HomeCare Gen tests Mutation Protein assays Glucose Blood pressure G. A. Urban Slide 10 G.Urban, VDE Innovationsreport 2012 Genotyping Mutation analysis Protein marker Pathogen analysis or therapy Blood pressure Glucose Tumor Marker

11 BIOLOGIZATION: BIOMARKER Systems Biology Investigation of the origin of diseases by basic biological research: Scientific description of complex, dynamic biological pathways ANALYTICS OF BIOMARKER Description/Expression of Genes (~10 4 ) Monitoring of Proteins (~10 5 ) Monitoring chemical and physical metabolic parameters (~10 3 ) G. A. Urban Slide 11

12 PATHWAY ANALYSIS: Bioanalytics of Biomarker using LAB on CHIP and SENSORS Analysis of Human Genom Mutation analysis Gen expressions/rna Lab-on-Chip Oligonucleotide Arrays Gensequencing Protein analytics Biochip-Array e.g. SEPSIS marker in-vivo monitoring of blood pressure and small molecules with microbiosensors G. A. Urban Slide 12

13 BIOMARKER OLIGOCHIPS - Sequencing of 4th generation Primer with replication-stopping or facilitating Oligonucleotides Complementary bases (A,C,G,T) Analysis of the whole human genome < 10 4 US$ Company: IonTorrent G. A. Urban Slide 13

14 Sequencing with ph Sensors ph-sensor array ISFET Analysis of the whole human genome < 10 4 US$ Company: IonTorrent G. A. Urban Slide 14

15 NANOMEDICINE Next generation: Nanopore sequencing / Nanotechnology ~nm The harvard nanopore group Courtesy of Paul Montie Design G. A. Urban Slide 15

16 SEQUENCING MARKET GLOBAL VALUE OF SEQUENCING PRODUCTS AND SERVICES BY TYPE, Oligonucleotide µarray Market: ~1,5 Billion/a (2012) G. A. Urban Slide 16 BCC research

17 METABOLIC BIOMARKER EMERGENCY ROOM / OP-THEATER / INTENSIVE CARE ACUTE MEDICINE / INFECTION MONITORING AGING POPULATION / CHRONIC DISEASES Monitoring of Biomarkers: OP/ ICU Ambient Assisted living In elderly, chronic ill people Acute markers, Cardiac markers, Biochemical biomarkers, Blood pressure.lab on MICROCHIP G. A. Urban Slide 17

18 PRESSURE SENSORS Pressure sensors are poised to become the leading type of MEMS device, generating $1.5B in revenue Monitoring of Blood pressure (High value) ICP Disposable (and low-cost) MEMS pressure sensor is the infusion pump, used to introduce fluids, medication, or nutrients into a patient's circulatory system 60M units of these devices were shipped in Worldwide high-value MEMS pressure sensor revenue forecast, in US $M. (Source: IHS isuppli) G. A. Urban Slide 18

19 PRESSURE SENSORS FloTrac sensor attaches to an existing arterial catheter and automatically calculates key flow parameters such as continuous cardiac output stroke volume stroke volume variation systemic vascular resistance G. A. Urban Slide 19

20 MINIATURIZATION Codman Johnson&Johnson NICHE MARKET Additional parameters? 1 mm G. A. Urban Slide 20

21 MINIATURIZATION MONITORING BIOCHEMICAL BIOMARKERS LAB on CHIP G. A. Urban Slide 21

22 IN VITRO DIAGNOSTICS MARKET In vitro Diagnostic (IVD) Billion $ / 2011 (Technology Park, Lacuna AG) Glucose 9 Billion $ Molecular diagnostics 5 Billion $ POC 4 Billion $ Tumor marker 2 Billion $ G. A. Urban Slide 22

23 IVD HOME CARE Electrochemical Enzym: GOx Adsorbed read out Next steps: 1 cm Multianalyte measurements Monitoring Roche 23 G. A. Urban Slide 23

24 IVD PERSONALIZED MEDICINE IVD DIAGNOSTIC COMPANY MARKET CONCEPT Sell Devices with multiple diagnostic functions for POC / NP AAL ICU/OP VALUE CHAIN: Production sensors, electronics, housing / ECONOMIC/ADDED VALUE High, but high price pressure G. A. Urban Slide 24

25 POC MONITORING Diagnostics Markte Near Patient Testing 2005: 2.9 Mia Euro Roche OMNI S for blood gases, electrolytes and metabolites G. A. Urban Slide 25

26 POC MARKET POC diagnostics market reached 4$ - $13.4 billion (2010) gowth rate (CAGR) 3.7% Glucose monitoring market $7.6 billion Blood chemistry and electrolyte segment $2.2 billion (2010) G. A. Urban Slide 26 BCC research

27 POC MONITORING Lab on Chip: Low cost, fast, cheap, reliable Glutamate Temperature Pyruvate Lactate Glucose Flow Glutamine Glucose O 2 ½ O 2 Catalas e 1 mm Spin off Company: Jobst Technologies GOx H 2 O 2 O 2 Pt-Anode 2e - G. A. Urban Slide 27

28 Chip-based multianalyte analyzer POC ex-vivo discrete For use in the intensive care unit (ICU) and operating room (OR). A disposable multi-parameter microanalyser is integrated into an existing arterial or venous line on the patient. When a reading is required, blood is withdrawn from the patient into the device. All blood is returned into the patient after the measurement Si-chip: glucose, ph, carbon dioxide, oxygen and potassium ions 510(k) clearance Duration: 72h G. A. Urban Slide 28

29 AGING POPULATION: ELDERLY AND HANDICAPPED PERSONS HOW WE CAN HELP? USE SMART TEXTILES? Probably not!! Solution: Use currently available implants and integrate microsensors Hypertension monitoring: Miniaturized implanted pressure sensors HYPER-IMS G. A. Urban Slide 29

30 PERSONALIZED MEDICINE LONG TERM MONITORING IMPLANT COMPANY MARKET CONCEPT Sell Devices with diagnostic and rehabilitative (Theranostic) functions for AAL and ICU/OP PaceMaker market ~4 Billion $ VALUE CHAIN: System: production sensors, electronics, housing / ECONOMIC/ADDED VALUE High G. A. Urban Slide 30

31 IMPLANTED LAB CHIP PaceMaker: Monitoring of biomarkers with Implanted BIOSENSORS Power management Controller Sensorinterface Battery Blood Interface Packaging Microsensor Blood pressure Electrolytes Glucose,lactate Kidney biomarkers External receiver VDE Positionspapier Theranostische Implantate 2011 G. A. Urban Slide 31

32 IMPLANTED LAB CHIP Current in na IMTEK/Sensors: In vivo array po 2, ph, glucose, lactate, glutamate, K, Cystatin Glutamate 0,5 epileptic seizure 0,4 0,3 0, Time in min G. A. Urban Slide 32

33 EMERGING DISEASES : PATHOGENS POC / Lab-on-Chip: 1 Billion$/a Biomarker: RNA Detection Cell sample 10µl Sample Enrichment & cleaning target species Cell lysis Nucleic acid purification Nucleic acid diagnosis G. A. Urban Slide 33

34 RNA extraction chip Lab on Chip Thermo-electric lysis through Joule heating 2. Electrophoretic purification 3. Detection through realtime PCR P. Vulto, G.A. Urban, WO2008/ DE G. A. Urban Slide 34

35 RNA extraction chip Lysis electrode RNA Gel Cell sample Electrophoresis electrodes G. A. Urban Slide 35

36 G. A. Urban Loic Ledernez, Gregory Dame Slide 36

37 RNA concentration [Copies/µL] RNA concentration [CFU/µL] RNA extraction chip Extraction in 10 minutes: Volume 10µl E.coli tmrna Chip series Chip series 2 Chip series Linear fit chip series Ambion series Ambion series 2 Ambion series Linear fit chip series Slope: Slope: Detection Limit: 1 Cell/µl! Cell Cell concentration [CFU/µL] G. A. Urban Slide 37

38 THANK YOU FOR YOUR ATTENTION! G. A. Urban Slide 38