Advanced medical micro devices

Advanced Medical Micro-Devices
Platform 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 Arnan.mitchell@rmit.edu.au 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

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, 2007

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


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 aggregation
mechanism drives thrombus formation, Nature Medicine,
2010.

(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


Bio Fluidics
Ref: 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 oscillator

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.


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)


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.


Optical fluidics - dielectrophoresis
• Development of tuneable optical
waveguides based on nanofluidics

Investigation of different designs for
microelectrodes (curved electrodes)

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.
450 nm particles 230 nm particles


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)


Switchable Surfaces - Superhydrophobicity

ZnO nanorods grown
from a NaOH solution
on ITO glass

ZnO nanorods grown
from an HMT 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


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 SU8

Super cooling, Whitesides et al., Lab on a
chip, 2007


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


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)

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
Microdevices
Clinical Researchers
State/Federal
Health Government
Initiatives
Institute
NHMRC
Project/Centre External
Grants NHMRC
Development Biomedical
Grants Researchers


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
Researchers


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
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?”


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!)

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?)

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!


Advanced medical micro devices

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