Advanced medical micro devices


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Advanced medical micro devices

  1. 1. Advanced Medical Micro-DevicesPlatform Technology Future Research FocusProfessor Arnan MitchellAssociate Professor Kourosh Kalantar-zadeh
  2. 2. Overview• Introduction to lab-on-a-chip biomedical micro-devices (Assoc. Prof Kourosh Kalantar-zadeh)• Biomedical Devices Research „Market‟ and Competition (Prof Arnan Mitchell)• Lead questions, Objectives and ProposalRMIT University©2010 2
  3. 3. Introduction to Lab-on-a-chip microdevices• Scales one or more laboratory processes to fit within a micro-chip• Microfluidics is a major technology component of lab-on-a-chip• Can also integrate – Microelectromechanical (MEMS) – Integrated optics – Electronics – Thermal control• Enables – Efficient reagent use (pico-litre) – Precise control of local environment – In-situ monitoring at micro-scale – Parallel operationRMIT University©2010 3
  4. 4. Bio Fluidics (tumour cells) • There are well cited initial reports on unique microfluidic platforms capable of efficient and selective separation of viable tumour cells (TCs) from peripheral whole blood samples, mediated by the interaction of target TCs with antibody under precisely controlled laminar flow conditions, and without requisite pre- labelling or processing of samples. Ref: Isolation of rare circulating tumour cells in cancer patients by microchip technology, Nagrath S, Nature, 2007The workstation setup for TC separation. The sample is continually mixed on a rocker, and pumped through the chip using a pneumatic-pressure-regulated pump.b, The CTC-chip with microposts etched in silicon. c, Whole blood flowing through the microfluidic device. d, Scanning electron microscope image of a captured NCI-H1650 lung cancer cell spiked into b(pseudo coloured red). The inset shows a high magnification view of the cell. RMIT University©2010 4
  5. 5. Bio Fluidics • Recently: RMIT researcher Arnan Mitchell in collaboration with the Australian Centre for Blood Diseases developed a microfluidic system for the investigation of platelet aggregation and thrombus growth (two NHMRC development grants).Ref: A shear gradient-dependent platelet aggregationmechanism drives thrombus formation, Nature Medicine,2010.(a) images demonstrating the effect of localized vascularstenosis on platelet aggregation after localized crush injuryof a mouse mesenteric arteriole (b) CFD simulation ofblood flow dynamics after localized vessel wallcompression (c) image sequence of blood perfusionthrough a microchannel comprising a side-wall geometrydesigned to induce a sharp phase of accelerating shearfrom 1,800 s-1 coupled to an immediate shear decelerationapproaching 200 s-1. (d) Representative aggregationtraces showing the response of whole-blood perfusionthrough the microchannel in c. (e) Relative thrombus size(% of maximum size) in wild-type mouse arterioles as afunction of applied downstream vessel compression RMIT University©2010 5
  6. 6. Bio FluidicsRef: A fast, robust and tunable synthetic gene oscillator, Stricker, J, Nature, 2008 • It is possible to use microfluidics in revealing genetic circuits. Investigation of gene circuits biological clocks as emerging fields. Stricker et al. developed devices tailored for cellular populations at differing length scales, to investigate the collective synchronization properties along with engineered gene network with intercellular coupling that is capable of generating synchronized oscillations in a population of cells. Single-cell fluorescence trajectories for A, MG1655Z1/pZE12-yemGFP-ssrA cells expressing LacI constitutively and containing neither positive or negative feedback loops (induced with 2 mM IPTG), or B, JS013 cells containing the negative feedback oscillatorMovie shows a timelapse microscopy of JS011 cells continuouslyinduced with 0.7% arabinose and 2 mM IPTG at 37 C. The brightfieldimage is shown in grey, and fluorescence is shown in green. Total timeof movie is 228 min with a sampling rate of one image every 3 min. RMIT University©2010 6
  7. 7. Protein stamping: Precise Control of Microbiology• Micro-contact printing to stamp protein islands (fibrinogen)• Flow blood platelets over array• Can observe platelet adhesion (in unprecedented detail)RMIT University©2010 7
  8. 8. Bio Microfluidics Dielectrophoresis • Dielectrophoresis of micro and nano particles • The sorting of live and dead cells by a DEP system. Dielectrophoretic Manipulation and Separation of Microparticles Using Curved Microelectrodes,K. Khoshmanesha, , C. Zhangb, F. J. Tovar- Lopezb, S. Nahavandic, A. Z. Kouzania, J. R. Kanward, S. Baratchid, K. Kalantar-zadehb, A. Mitchellb, Electrophoresis and Microfluidics and Nano fluidics.RMIT University©2010 8
  9. 9. Optical fluidics - dielectrophoresis • Development of tuneable optical waveguides based on nanofluidicsInvestigation of different designs formicroelectrodes (curved electrodes)Dielectrophoretically Assembled Particles: Applications forOptofluidics Systems, K. Khoshmanesh, C. Zhang, J. L.Campbell, A. Kayani, S. Nahavandi, A. Mitchell, K. Kalantar-zadeh, Electrophoresis and Applied physics Letters. 450 nm particles 230 nm particles RMIT University©2010 9
  10. 10. Digital Micro-fluidics: Control• Use immiscible fluids (oil and water)• Micro-droplets are highly stable• Can be monitored and controlled as discrete entities (like binary elements)• Excellent platform for – High throughput drug discovery – New paradigms in control „Microfluidic Bubble Logic‟, Manu Prakash and Neil Gershenfeld, MIT (2007)RMIT University©2010 10
  11. 11. Switchable Surfaces - Superhydrophobicity ZnO nanorods grown from a NaOH solution on ITO glass ZnO nanorods grown from an HMT solution on ITO glassDrug deliverySensorsMicrofluidicsElectrowetting of superhydrophobicZnO nanorodsAuthor(s): Campbell JL, Breedon M,Latham K, kalantar-zadeh K., et al.Source: LANGMUIR Volume:24 Issue: 9 Pages: 5091-5098 ,2008 RMIT University©2010 11
  12. 12. Localized effects • Integrated Micro-thermoelectric heaters/coolers Micrograph of Sb2Te3 films Room temperature deposition Micro thermoelectric Flow to Heat cooler be sink cooled flow PDMS Circuit board electrical connections 700m 400 um Inlet Outlet PDMS G. Rosengarten, S. Mutzenich, K. Kalantar-zadeh, “Integrated 40 um Water Microthermoelectric Cooler for Microfluidic Channels,” Experimental Thermal Fluid Science, Volume 30, Issue 8, August Thermal Insulator Glass 2006, pp. 821-828. 5 um SU8Super cooling, Whitesides et al., Lab on achip, 2007 RMIT University©2010 12
  13. 13. Nano-fluidics A recent venue in microfluidics has been emerged in the fusion of nanofluidics and optical operations where novel methods of bioanalysis and directed assembly are investigated. It is possible to implements such fusions in the applications of nanofluidic devices in the separation The nanoparticle (grey circle) is attracted to the surface by van der Waals forces (blue line), science and energy conversion. but repelled by electrostatic forces (red line), and is shown here at the minimum of the combined potential (green line)Ref: Principles and applications of nanofluidic transport, Sparreboom, Nature nanotechnology 2009]. Schematic of a nanofluidic field-effect transistor. In a nanofluidic transistor the flow through a nanochannel can be driven by pressure, an applied electric field or a concentration difference. By applying a bias voltage between the gate electrode and the solution, the wall potential can be changed, modulating the counter-ionic charge in the solution. Schematic showing a modified porin (grey) between bilipid membranes (red). The walls of the pore through the molecule are modified so that there are regions of positive (blue) and negative (red) charge. Since the electrical double layers are comparable with the diameter of the pore, a p–n junction that is equivalent to an electronic diode is created, as shown in the current– voltage curve on the right. Reprinted with permission RMIT University©2010 13
  14. 14. Research Opportunities forLab-on-a-chip Biomedical Micro-Devices• Healthcare: rapid bioassays, assays for home testings, drug-delivery (home healthcare, eventually point-of-care approach)• Safety and surveillance: first responders (paramedics, police and homeland security)• Pharmaceutical industry: drug discovery (testing of bio-pharmaceuticals, in situ monitoring and control of reactions)• Biomedical research: genomics, proteomics, metabolomics, hemotology ... – Micro-equipment for micro-biology – Pristine environment (interior microfabricated in clean room– perfectly clean/sterile) – Rapid, precise, parallel control (think of creating experiments like writing software)• Accessible Platform for multidisciplinary biomedical research: Fundamental physics, chemistry, and mechanical engineering (and impact on micro-biology)RMIT University©2010 14
  15. 15. Research „Market‟ for Biomedical Micro-devices:Available Funding• Compete for funds in basic science (help others in other fields)• Each CI may have 6 projects (ARC Discovery only 2)• No industry partner needed for NHMRC Development (simpler than ARC Linkage)• Extra avenues - more growth• Multi-faceted grant success will help eventual centre bid (biomedical and engineering)RMIT University©2010 15
  16. 16. Research „Market‟ for Biomedical Micro-devices:Collaborators and competitors• Collaborators already identified – The RMIT Health Institute – The Australian Centre for Blood Diseases (Monash at the Alfred) – The Walter and Elisa Hall Institute (Malaria) – Bio21 (The University of Melbourne) – The University of Sydney (CUDOS, Opto-fluidics) – UNSW Thermofluids group (cooling and energy)• Potential new collaborators (some) – CSIRO (Agriculture Flagship) – Monash University (microfluidics group) – Small to Medium Biomedical industry (Planet Innovation, Grey)• Competitors (similar capabilities – different approach) – The Minifab (Swinburne) – Melbourne Centre for Nanofabrication (Monash node?) – Ian Wark Insitute, Uni SA (NCRIS funded Lab-on-a-chip)RMIT University©2010 16
  17. 17. Centre for Biomedical micro-Devices: Value Proposition• This proposal is not for a Chemistry biomedical research centre Physics Mech-• An engineering centre - working with Eng scientists and biomedical researchers Philanthropic Elec- grants Eng Centre for Biomedical Industry Biomedical MicrodevicesClinical Researchers State/Federal Health Government Initiatives Institute NHMRC Project/Centre External Grants NHMRC Development Biomedical Grants Researchers RMIT University©2010 17
  18. 18. Centre for Biomedical micro-Devices:Where are we now? Mech- Eng• Microfabrication largely in MMTC Chemistry Physics• MMTC is doing well, but sub-critical (not candidate to lead CoE) ?• Strongly linked to SECE (not cross-university) Elec-• Do not yet exploit expertise in control Eng MMTC• Sub-critical links to Physics and Chemistry• Poor links to opportunities in ? mechanical engineering• Links to biomedical through external partners ... Health External Institute Biomedical ResearchersRMIT University©2010 18
  19. 19. Vision for Centre for Biomedical micro-Devices• Develop the MMTC into a large, cross-university research centre Chemistry (grow to critical mass) Physics Mech-• Strengthen ties to physics and chemistry Eng• Create new ties to mechanical engineering Elec- (particularly focused on micro-fluidics) Eng• Create strong, multi-faceted Centre for ties to the Health Institute Biomedical (help grow to critical mass) Microdevices• Lever differences (new funding opportunities) Health Innovations External Institute Biomedical ResearchersRMIT University©2010 19
  20. 20. Lead Research Questions1. Optofluidics: “Can we lever momentum in integrated from CUDOS to achieve fundamentally new opto-fluidic sensors for lab-on-a-chip?”2. Microfluidic devices for the study of blood: “Can we use our expertise in microfabrication, mechanical engineering and control to pioneer change the way that the Australian Centre for Blood Diseases conducts its research? “3. Automated Microplatforms for Drug Discovery: “Can we use our expertise in microfabrication, mechanical engineering, chemical sensing, surface and nano-science and control to create unique platforms enabling RMIT Health Institute to become Australia‟s leader in pharmaceutical research?”4. Surface Acoustic Waves for Biomedical Devices: “Can we team with complimentary expertise at Monash University to become undisputed national leaders in the biomedical application surface acoustic waves and attract an international Laureate Fellow?”5. Surface Science for Lab-on-a-chip: “Can we use our expertise in fundamental simulation, synthesis, modfication and characterisation of surfaces to create new technologies for manipulating biological fluids?”RMIT University©2010 20
  21. 21. Proposed Input from R&I• Buy a group (Bring their own research $$) – 1 New Innovation Professor in Microfabrication (will become Centre leader) – 1 New Academic Professor in Microfluidics (affiliated with SECE and SAMME) – Support for recruitment of Laureate and Future Fellows – 1-2 Postdoctoral Researchers (work with professors) – 1 R&D Engineer in Micro/Nano Fabrication (Academic B) – 1 Microfabrication Technician (HEW 6),1 Admin Support (HEW 4)• Linking Personnel: – 10 Postdoctoral fellowships (light-weight seed funding) – Funded at 50% for 12 month terms – competitive proposals in platforms for biomedicine• Estimated cost: $2M per year for 3 years ($6M total)• Need Space! (integrated laboratory and dedicated team office space!)RMIT University©2010 21
  22. 22. Projected Outcomes over 3 years (Research Income) Projected Research Income SCHEME QTY. AVG. FUNDING INCOME People Support Laureate Fellowship 1 $2,400,000 $2,400,000 Future Fellowships 2 $800,000 $1,600,000 Australian Post-Doctoral Fellowships 4 $300,000 $1,200,000 Research Support ARC Centres of Excellence 1 ARC Discovery Projects 2 $350,000 $700,000 NHMRC Project Grants (Participant) 3 $635,000 $1,905,000 Philanthropic Grants (Category 1) 6 $35,000 $210,000 Development Support NHMRC Development Grants 3 $300,000 $900,000 ARC Linkage Projects 4 $290,000 $1,160,000 Infrastructure Support ARC LIEF Grants 3 $150,000 $450,000 Philanthropic Grants (Category 1) 2 $35,000 $70,000 TOTAL $10,595,000• On top of what we would be doing without investment• Assumes 30% success rate (so will apply for 3 times this!)RMIT University©2010 22
  23. 23. Other Aims (not research income)• Major thrust for proposed joint engineering centre (re-invent the MMTC)• Lever funds >$1M Victorian Government (Learn how to lobby!)• Create environment that could attract: – Laureate Fellowship applicant – Future Fellows (in micro-technologies) – ARC APD applicants from outside RMIT (young leaders competing to get in)• Fruitful interaction with Health Institute, Mech. Eng., Physics and Chemistry (leading to longer term funded collaborations)• Successfully link to expertise in Excellent publications and promotion – 45 extra A and A* journal publications (beyond organic growth of 10%) – 3 Nature scale publications (with appropriate media coverage)• Link to world leading international researchers (eg Chi Ming Ho – UCLA)• Build platform for credible Centre of Excellence bid (in 5 years?)RMIT University©2010 23
  24. 24. Invitation to participate• This presentation is intended to stimulate discussion• Please do contact us if you feel that – Your research can contribute to lab-on-a-chip platforms – Lab-on-a-chip platforms can contribute to your research• This is all about creating critical mass in a focus area!RMIT University©2010 24