Point of Care Medicine

1. Point of Care Medicine Revolutionizing the State of the Art by Integration with Flexible Electronics? Wunmi Sadik and Antje Baeumner February 2007

2. target analyte (protein, cell, ions, small molecules, macromolecules) Y Recognition element (antibody, DNA, receptor, enzyme) Signal(optical, electrochemical, acoustic, thermal) State of the Art of Point of Care Medicine Principles of Diagnostic Tests

3. 1. Labeled recognition element Y Y Y Y Y Assay designed around separation of bound from non-bound recognition element State of the Art of Point of Care Medicine Principles of Diagnostic Tests How is the signal generated?

4. Y Typically with enzymes are recognition elements (enzyme binds to substrate and produces a product, the product or a side-product can be detected) State of the Art of Point of Care Medicine Principles of Diagnostic Tests How is the signal generated? 2. Signal is generated upon binding to analyte

5. Y Y State of the Art of Point of Care Medicine Principles of Diagnostic Tests How is the signal generated? 3. Signal is generated using a lab-made competitor analyte Formats either require separation of bound and non-bound competitor analytes or use a cross-reaction (quenching/excitation) (format is typically used, if direct formats discussed earlier are not feasible)

6. 1. On-site lateral flow assays e.g. pregnancy test (at home), Strep throat test (doctor’s office) Assay time: 2 – 10 minutes State of the Art of Point of Care Medicine Detection Platforms of Diagnostic Tests

7. 2. On-site biosensor e.g. glucose (at home) used by diabetics Medisense State of the Art of Point of Care Medicine Detection Platforms of Diagnostic Tests Assay time: 5 s – 5 minutes

8. 3. Off-site ELISA (Enzyme Linked ImmunoSorbent Assay) Since the 1980s used in clinical laboratories State of the Art of Point of Care Medicine Detection Platforms of Diagnostic Tests Assay time: 60 – 240 minutes

9. 4. Off-site PCR (Polymerase Chain Reaction) for DNA analysis Since the 1990s used in clinical laboratories 5. Off-site cell culture (for pathogen detection) Technology used since the early 1900s State of the Art of Point of Care Medicine Detection Platforms of Diagnostic Tests

10. Limitations of Current Point of Care Medicine Time from sample to result currently: hours, days desired: seconds to minutes Specificity (false positive or false negative results) Costs (not 10s – 100s of $ per test, but cents per test) Needed: On-site, in situ, in vivo

11. Research Directions - Multianalyte and multi-sample analysis with small volumes: Microarrays - Implantable sensors - real-time PCR (faster and dynamic results) - Investigation of nanoparticles - Nanostructures to better interface with biological molecules

12. Potential Applications with Flexible Electronics - Extreme miniaturization, bringing electronics to level of biomolecules/analytes (integration of transducer and biorecognition) - Direct interaction with cell surface receptors possible - Electronic signals in swabs, wipes, fibers, tubes (no color change needed, more sensitive)

13. But, imagine a world of flexibility….. Biotelemetry Bedside electrocardiography Virtual bronchoscopy Telemedicine Large area distributed flex sensor arrays

14. Intelligent Properties • Templated-based Self-assembly • Self-multiplication • Self-repair • Self degradation (selective) • Redundancy • Self-diagnosis • Learning • Prediction/notification 10 m

15. Synergy is the key to creating intelligent devices • Integrating multiple functions • Recognition/discrimination • Feedback • Standby • Appropriate response • Machine learning • Synthetic chemists • Material scientists use biomimetic • approaches

16. Probing Ab-Ag Reaction Dynamics Monitoring Ab-Ag Reaction Dynamics Sensor Tens of seconds for a typical assay conc. of nM Typical diffusion constant Time-scale for Ag diffusion Typical Association Rate • Testbed ideas: • Use the resulting signal to study biomolecular reaction and diffusion at small • length and time scales • (2) Adjust analyte concentration, choose reaction with different rates and separate • diffusion from reaction • (3) Study the dynamics of biomolecular reaction using the sensor.

17. Autonomous Oral Biosensor Device Microfluidic saliva collection and detection System

18. Telemedicine Detection module Electrodes are connected to a detection module with filtering and digitization Flex goggle Stimulation module Provides a synchronized pulse That controls flashes Of light In the goggle Surface detection electrodes Gold/silver electrode arrays Wearable pancreas (glucose sensor) Communication (mono directional Communization for Simulation Bidirectional synchronization of signal Collection and data transmission Flexible implant module Sensor arrays & actuators provide information Remotely monitoring vital signs (heart rate, muscle action, etc) Central Unit (PC)

19. Retina Prosthesis RPro Acuity 20/80(10°) Daniel Palanker et al…

20. Concept of Retinal Prosthesis • Schematic showing the concept of the retinal prosthesis. • Camera in the glass frame • Wireless transmitter • Extraocular electronic case (receiver) • Intraocular implant (electrodes array). Humayun.et.al, for chronical implatation in human:

21. Intracortical Neural Implant • Virtual bronchoscopy • Ultrasound array sensor • Retina stimulator • Multiplexermodule • To observe and record electrical signals in living cells. • Flexibility minimizes tissue damage

22. Bedside Echocardiography

23. Flex Security Installations Public places Battlefield Intelligent sensors Rapid results for formulating a response

24. Cell-based Biosensors Autonomous Multielectrode System for Monitoring the Interactions of Isoflavonoids with Lung Cancer Cells Analytical Chemistry, 76 (3) 552-560, 2004. Analytical Chemistry, 76, 2321-2330, 2004. Electrochemistry Communications, 5, 61-67, 2003. Chemical Research in Toxicology, 18 (3): 466-474 MAR 2005.

25. Current External control On-line recording Data treatment Graphical presentation Time Temperature control: 37°C 12 Channels x 8 electrodes PC Electric contact Bottom electrodes Top electrodes Multipotentiostat 96 well plate Cell culture Electrode system O2 + 4H+ + 4e- 2H2O AE RE WE Electrochemical Sensor Arrays • Designed as an O2 sensor for bacteria/cells monitoring • Use 96 well electrodes (gold plated) available in two configurations: top and bottom • Uses a conventional 96 well plate (sterile and disposable) in which the cells are cultured • S. Andreescu, O.A. Sadik, D.W. McGee, S. Suye, Anal. Chem. 76, 2004, 2321-2330.

26. V Potentiostat I To Outlet Reference Electrode Working Electrode Air in Counter Electrode Counter Electrode Working Electrode Reference Electrode Fluid Channel Air Channel Inlet Reservoir Electrochemical Single Well Microfluidic Equivalent-In the proposed design All the RE and CE are connected in series This smart design reduces the number of connectors and pads for individual connection

27. c Electrode Fabrication Lithography Cleaned flex substrate Chlorination in removal FeCl3 before photoresistremoval Coating with Gold Coating Insulator layer Fabricating gold collector layer (sputtering) Coating Platinum PDMS spunning with RE as insulating layer Coating Silver (sputtering) Fabricating Pt WE & CE connector and pads Micro-fabricated Silver Electrodes SF6+O2 etching treatment to expose the Ag/AgCl assembly (reactive ion etching) Photoresist Coating

28. Summary: Flex Medicine • Possibility of performing biochemical analyses at the POC • Continuous monitoring of biochemical variables • Supplement to conventional lab services (not replacement) • Decrease the therapeutic turn around time • Decrease the number of errors • Reduce blood-volume lost • Reduce the length of stay at ICU • Reduce morbidity/mortality rate • Recognize life-threatening situations early

29. Questions & Discussion…

30. Acknowledgements