Advanced medical micro devices

Advanced Medical Micro-DevicesPlatform Technology Future Research Focus

Professor Arnan Mitchell

Associate Professor Kourosh Kalantar-zadeh

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 Proposal

RMIT University©2010 [email protected] 2

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 operation

[email protected] University©2010

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.

The 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 blood

(pseudo coloured red). The inset shows a high magnification view of the cell.

Ref: Isolation of rare circulating tumour cells in cancer patients by microchip technology,

Nagrath S, Nature, 2007


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).

(a) images demonstrating the effect of localized vascular

stenosis on platelet aggregation after localized crush injury

of a mouse mesenteric arteriole (b) CFD simulation of

blood flow dynamics after localized vessel wall

compression (c) image sequence of blood perfusion

through a microchannel comprising a side-wall geometry

designed to induce a sharp phase of accelerating shear

from 1,800 s-1 coupled to an immediate shear deceleration

approaching 200 s-1. (d) Representative aggregation

traces showing the response of whole-blood perfusion

through the microchannel in c. (e) Relative thrombus size

(% of maximum size) in wild-type mouse arterioles as a

function of applied downstream vessel compression

Ref: A shear gradient-dependent platelet aggregation

mechanism drives thrombus formation, Nature Medicine,

2010.


6

Bio Fluidics

• 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.

Movie shows a timelapse microscopy of JS011 cells continuously

induced with 0.7% arabinose and 2 mM IPTG at 37 C. The brightfield

image is shown in grey, and fluorescence is shown in green. Total time

of movie is 228 min with a sampling rate of one image every 3 min.

Ref: A fast, robust and tunable synthetic gene oscillator, Stricker, J, Nature, 2008

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 oscillator


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)


8

• 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.

Bio Microfluidics Dielectrophoresis


9

Optical fluidics - dielectrophoresis

• Development of tuneable optical

waveguides based on nanofluidics

450 nm particles 230 nm particles

Dielectrophoretically Assembled Particles: Applications for

Optofluidics Systems, K. Khoshmanesh, C. Zhang, J. L.

Campbell, A. Kayani, S. Nahavandi, A. Mitchell, K. Kalantar-

zadeh, Electrophoresis and Applied physics Letters.

Investigation of different designs for

microelectrodes (curved electrodes)


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)


11

Switchable Surfaces - Superhydrophobicity

ZnO nanorods grown

from an HMT solution on

ITO glass

ZnO nanorods grown

from a NaOH solution

on ITO glass

Drug delivery

Sensors

Microfluidics Electrowetting of superhydrophobic

ZnO nanorods

Author(s): Campbell JL, Breedon M,

Latham K, kalantar-zadeh K., et al.

Source: LANGMUIR Volume:

24 Issue: 9 Pages: 5091-5098 ,

2008


12

Localized effects

• Integrated Micro-thermoelectric heaters/coolers

Micrograph of Sb2Te3 films

Room temperature deposition

Micro thermoelectric cooler

Heat sink flow

Flow to be cooled

Circuit board electrical connections

700m

PDMS


Heat sink flow

Flow to be cooled


700m

PDMS


Heat sink flow

Flow to be cooled


700m

PDMS

G. Rosengarten, S. Mutzenich, K.

Kalantar-zadeh, “Integrated

Microthermoelectric Cooler for Microfluidic

Channels,” Experimental Thermal Fluid

Science, Volume 30, Issue 8, August

2006, pp. 821-828.

PDMS

Glass

Water

Thermal InsulatorThermal Insulator

5 5 uum SU8m SU8

Inlet Outlet

400 um

40 um

PDMS

Glass

Water

Thermal InsulatorThermal Insulator

5 5 uum SU8m SU8

Inlet Outlet

400 um

40 um

Super cooling, Whitesides et al., Lab on a

chip, 2007


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

science and energy conversion.The nanoparticle (grey circle) is attracted to the surface by van der Waals forces (blue line),

but repelled by electrostatic forces (red line), and is shown here at the minimum of the

combined potential (green line)

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

Ref: Principles and applications of nanofluidic transport, Sparreboom, Nature nanotechnology 2009].


Research Opportunities for

Lab-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)


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)


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)[email protected] University©2010

Centre for Biomedical micro-Devices: Value Proposition

• This proposal is not for a

biomedical research centre

• An engineering centre - working with

scientists and biomedical researchers

17

Centre for

Biomedical

Microdevices

PhysicsChemistry

Mech-

Eng

Elec-

Eng

Health

Institute

Biomedical Industry

State/Federal

Government

Initiatives

Clinical Researchers

NHMRC

Project/Centre

Grants NHMRC

Development

Grants

Philanthropic

grants

External

Biomedical

Researchers


Centre for Biomedical micro-Devices:

Where are we now?

• Microfabrication largely in MMTC

• MMTC is doing well, but sub-critical

(not candidate to lead CoE)

• Strongly linked to SECE

(not cross-university)

• Do not yet exploit expertise in control

• Sub-critical links to

Physics and Chemistry

• Poor links to opportunities in

mechanical engineering

• Links to biomedical through

external partners ...

18

?

?

MMTC

External

Biomedical

Researchers

PhysicsChemistry

Mech-

Eng

Elec-

Eng

Health

Institute


Vision for Centre for Biomedical micro-Devices

• Develop the MMTC into a large,

cross-university research centre

(grow to critical mass)

• Strengthen ties to physics and chemistry

• Create new ties to mechanical engineering

(particularly focused on micro-fluidics)

• Create strong, multi-faceted

ties to the Health Institute

(help grow to critical mass)

• Lever differences

(new funding

opportunities)

19

Health

Innovations

Institute

Centre for

Biomedical

Microdevices

PhysicsChemistry

Mech-

Eng

Elec-

Eng


External

Biomedical

Researchers

Lead Research Questions

1. 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?”


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!)


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!)


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 [email protected]

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 [email protected] 24

Advanced medical micro devices

Technology

Transcript of Advanced medical micro devices