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The Peter Brojde Conference 2011
Biological Sensing and Micro Systems
The 21st of June 2011, Yad Hashmona Israel
Abstracts
Prof. Stephen Quake: Stanford University.
Biological Large Scale Integration
Abstract: The integrated circuit revolution changed our lives by automating computational tasks on a
grand scale. My group has been asking whether a similar revolution could be enabled by automating
biological tasks. To that end, we have developed a method of fabricating very small plumbing devices
- chips with small channels and valves that manipulate fluids containing biological molecules and
cells, instead of the more familiar chips with wires and transistors that manipulate electrons. Using
this technology, we have fabricated chips that have thousands of valves in an area of one square inch.
We are using these chips in applications ranging from screening to structural genomics to
ultrasensitive genetic analysis. However, there is also a substantial amount of basic physics to explore
with these systems - the properties of fluids change dramatically as the working volume is scaled from
milliliters to nanoliters!
Dr. Yaacov Nahmias: The Hebrew University
Development of a Microfluidic Transcriptional Activity Array
Abstract: Gene expression is a fundamental cellular process allowing cells to dynamically respond to
environmental changes. This process is controlled by the interactions of nanoscale protein complexes,
called transcription factors, and DNA. As transcription factors regulate each other, such interactions
take the form of a gene network, analogous to an electronic circuit. Gene networks control cellular
response to environmental changes on a fundamental level. Therefore the ability to continuously
monitor this network would permit to directly observe and eventually control cellular information
processing. Regretfully, the massive amount of data required to elucidate changes in the network
critically limits this approach. Using state-of-the-art techniques, such as ChiP-on-chip or gene arrays
such analysis requires Herculean efforts and prohibitive costs. The technology that renders this project
feasible is the Transcriptional Activity Array (TAA), a microdevice allowing the high-throughput
screening of transcriptional dynamics using destabilized copGFP reporter cell lines in an addressable
microfluidic cell array. The TAA is constructed using two-layer soft lithography allowing the seeding
of distinct GFP-reporter cells in each row while exposing them in the perpendicular direction to
multiple soluble factors. This creates a matrix of experiments where each column defines the dynamic
response of multiple transcription factors to a single stimulus, and each row defines the dynamic
response of a single transcription factor to multiple stimuli. By creating a window to the temporal
patterns of transcriptional regulation, the TAA is poised to make important contributions to our
understanding of transcription factor networks and dynamic processes such as development, wound
healing, or disease.
Dr. Roy Bar-Ziv: The Weizmann Institute.
Synthetic gene expression systems on a chip.
Abstract:
Dr. Ido Braslavsky: The Hebrew University.
Microfluidic-based investigation of ice binding proteins
Abstract: Ice binding proteins (IBPs) have evolved in cold-adapted organisms, protecting them
against freezing conditions by arresting ice crystal growth and inhibiting ice recrystallization. IBPs
reduce the freezing temperature of ice below the melting point, a phenomenon defined as thermal
hysteresis and used to quantify the activity of these proteins. The control over ice growth has a
tremendous potential in preventing frost damage to plants, in cryo-preservation of cells, tissues and
organs, and in the food industry. The mechanism of action of IBPs is not well understood. In
particular, it is not clear why the thermal hysteresis activity depends on IBPs concentration, and
whether the binding of IBPs to ice is permanent or fast exchange between bound proteins and those in
solution occurs. In order to investigate the kinetics of the interactions between IBPs and ice we
conjugated IBPs to GFP, which allows their visualization and quantification. We developed
microfluidic devices that enable the exchange of the fluid around the ice crystals in a tight
temperature-controlled environment with a resolution of less than 0.01 oC while observing the crystals
and the GFP-IBPs by an inverted microscope. Using these temperature-controlled microfluidic
devices, we demonstrated that growth of small ice crystals (30-50 µm) covered with IBPs is stopped
for hours, and the thermal hysteresis activity is remained high even after the IBP solution surrounding
the crystal is replaced by a protein-free buffer. These experimental results provide strong evidence
that the surface-bound IBPs are sufficient to inhibit ice growth without the need for more IBP
molecules in the solution. The ability to tightly control the temperature in the microfluidic devices
enable advancement of IBP research as well as related fields including cryobiology,
biomineralization, and crystal growth.
Prof. Yuri Feldman: The Hebrew University
Dielectric Spectroscopy and Biological Sensing
Abstract: Whenever water interacts with another dipolar or charged entity, there exists a broadening
of its dielectric relaxation peak This broadening can be described by the phenomenological ColeCole law (CC), which can be represented by a frequency dependent complex dielectric permittivity
ε*(ω):
(1)
where ω is the cyclic frequency, i is the imaginary unit, ∞ is the high frequency limit of the complex
dielectric permittivity, Δε is the dielectric strength of the relaxation process, τ is a characteristic time
scale and the exponent α is referred to as a measure of symmetrical broadening in the dielectric losses
relaxation peak (0<α≤1). A new phenomenological approach has been recently presented (A.
Puzenko, P. Ben Ishai and Yu. Feldman, Physical Review Letters (2010) 105, pp. 037601-4) that
clarifies a physical mechanism of the dipole-matrix interaction in complex systems (CS) underlying
the CC behaviour.
The talk will demonstrate how the model described above can define the state of water in complex
systems, including the biological ones. The model sheds light on the exchange between the bound and
bulk water around a biological system by concurrently studying the dynamics and structural aspects of
the relaxation peak. A practical implementation of expected results is associated with feasibility of
dielectric spectroscopy data in medicine, biochemistry, food processing, non-invasive monitoring,
general diagnostic, drug intervention, etc.
Prof. Jan Gisma:The University of Rostov
AC-electrokinetics: An overview of general principles, effects, methods and medical
applications
Abstract: Whereas impedance methods detect the frequency dependence of the direct electric
response of a suspension, electrokinetic methods investigate the frequency dependence of oriention,
deformation, movement, aggregation or rotation of single objects, like cells. The effects can be
observed microscopically. They arise from the interaction of the induced polarization of the objects
with the inducing external field and can be exploited for dielectric particle characterization and for
handling or manipulating microscopic and submicroscopic particles like cells, organelles,
supramolecular structures, viruses or artificial colloids. Traditional AC-electrokinetic characterization
methods had a limited frequency and conductivity range or required the microscopic observability of
field-induced particle movements. New designs of measuring chambers, light scattering and
dielectrophoretic field trapping methods solve these problems and access the GHz frequency as well
as the submicroscopic particle ranges. First lab-on-chip systems exploiting the principles are available
on the market. The higher resolution of the electrokinetic methods for the electric parameters of single
objects allows for the detection of new polarization effects and time-dependent parameter changes at
the single particle or cell levels.
An introduction is given on the interrelations of the various AC-electrokinetic methods, new
developments, cell-tech and medical applications.
Prof. Micha Spira: The Hebrew University
Bio-inspired breakthrough: Functional interface between nerve cells and micro/nano-electronic
devices.
Abstract: The development of Brain Machine Interface (BMI) technologies is driven by the belief that
when successful such interfaces could be applied to replace damaged sensory organs (as the retina),
replace motor part (limbs), link disrupted neuronal networks (injured spinal cord), generate hybrid
neuro-electronic computers and others. Nevertheless, despite decades of research and development,
contemporary approaches fail to provide satisfying scientific concepts and technological solutions to
generate efficient and durable interfaces between neurons and electronic devices.
In the presentation I will describe a novel biologically inspired breakthrough approach to enable the
generation of efficient bidirectional electrical coupling between cultured neurons and extracellular
multi-microelectrode array. The cell biological, molecular and physical principals underlying the
novel neuroelectronic configuration will be explained.
The prospective of using our approach for long-term, non-invasive, multisite intracellular recording
and stimulation for brain research and clinical BMI applications will be discussed.
Prof. Uriel Levy: The Hebrew University.
Integrated nanophotonic platform for label free biosensing
Abstract: In recent years the concept of label free biosensing is rapidly developing. In contrast to a
conventional sensing scenario, in which a binding process is typically monitored by transduction
labeling elements, e.g. fluorescent dyes the approach of optical label free biosensing is based on
measuring a shift in resonance frequency resulted by a change in the effective refractive index of an
optical resonator, grating, or interferometer. Specifically, the SPR approach is now used in a variety
of commercial sensing products.
While the SPR approach offers large sensitivity (defines as the shift in resonance wavelength per
refractive index unit - RIU), it cannot provide narrow resonance linewidth, primarily as a result of the
ohmic loss in the metal. Dielectric structure allows circumventing this obstacle by providing very high
quality factors. Significant effort is devoted to configurations based on silicon resonators or silica
micro toroid resonators.
Here, we take a different approach by constructing resonators based on silicon nitride platform. This
platform supports tight confinement of light (owing to the relatively high refractive index, ~2), offers
thermal stability owing to the relatively low thermo optic coefficient, and can allow high optical
power to go through the device due to the negligible two photon absorption. Most importantly, it
allows operating at the wavelength regime around 750-1200 nm. This regime is bounded by
absorption of proteins toward the visible (<750nm) and the increasing absorption of the water toward
the infrared (>1200nm).
In this talk we demonstrate a silicon nitride microring resonator tailored for sensing in aqueous
environment and optimized to operate around the wavelength of 970nm we obtained a maximal
quality factor of 75000 and extinction ratio up to 15dB, together with significant mode overlap with
the surrounding cladding (~20%). Our system offers figure of merit of about
FOM   /   7500 [1/ RIU ] . This FOM defines the shift in resonance wavelength RIU
normalized the resonance linewidth. A FOM of 7550 is considered as very high taking into account
the small dimensions of the resonator and its on chip integration capability using CMOS compatible
process. It can be further improved by considering modifications such as slot waveguide resonator or
an annular Bragg resonator.
In addition, we demonstrate the approach of analyte transport using digital microfluidic (DMF).
Specifically, we integrate the DMF platform with the silicon nitride microring platform. This way,
small droplets containing the analyte can travel on chip towards the resonator, while the transmission
of the resonator is closely monitored. This approach offers electrical control over the droplet position,
in contrast with the conventional microfluidic approach which is based on pressure driven flow. We
envision using this approach for the analysis of multi droplet in multi-resonator system, where each
resonator is performing measurements at a different wavelength. Therefore, the approach can offer
spectroscopic measurement of miniaturized droplet using electrical control. Such an approach may
pave the way for high throughput label free biosensing on a chip that is also integrated with electronic
functionalities.
Dr. Eran Socher: Tel Aviv University
Challenges and Opportunities for mm wave CMOS integrated circuits in Bio-sensing.
Abstract:
Dr. Gilad Yossifon: The Technion
Non-Linear Electrokinetics of Nanochannels.
Abstract: Electrokinetics promises to be the technique of choice for many portable and miniaturized
micro- and nano-fluidic based devices (e.g. diagnostic chips, fuel cells etc.) and will become
increasingly important for many future nanoscale materials with large surface to volume ratio.
Nanofluidics is not just a scaled-down version of microfluidics, but has fundamental differences with
new forces at play. In particular, when the cross section dimensions of the nanochannel approach
those of the electric Debye layer (EDL) (~10-100 nm), overlapping of opposite wall EDLs result in its
ion-permselective properties. Combining electrokinetics and nanofluidics forms a basis for novel
energy-related, healthcare/environmental applications and other ion/proton permselective devices.
However, despite two centuries of research, our understanding of ion transport and electro-osmotic
flow in and near nanochannels/nanoporous membranes remains woefully inadequate. With the advent
of nanofabrication technology, we can now fabricate well controlled nanochannel structures that
exhibit such ion perm-selective characteristics. The talk reviews various ion-flux and hydrodynamic
anomalies unraveled by us [1-4] in such devices and speculates on their potential applications. In
particular, we demonstrate how the concentration-polarization phenomenon, occurring at relatively
high voltage, can be utilized to preconcentrate nanocolloids/biomolecules and amplify their effects on
nanochannel conductance. Furthermore, we are using the instability induced electro convection
vortices to trap and concentrate nanocolloids. Such a novel nano-slot sensor that employs an
electrochemical impedance meter was recently demonstrated by us to be able to quantify DNA
concentration with pico-molar sensitivity. Other phenomena such as ionic current rectification,
nanochannel array communication and field focusing effect are shown to enable the control of the
nanochannel overlimiting current so as to perform various nanofluidic-based nano-analytics
functionalities.
[1] G. Yossifon and H.-C. Chang, "Selection of non-equilibrium over-limiting currents:
universal depletion layer formation dynamics and vortex instability", Phys. Rev. Lett.
101, 254501 (2008).
[2] G. Yossifon, Y.-C. Chang and H.-C. Chang, "Asymmetric rectification, gating voltage
and interchannel communication of nanoslot arrays due to entrance space charge
polarization", Phys. Rev. Lett. 103, 154502 (2009).
[3] H.-C. Chang and G. Yossifon, "Understanding electrokinetics at the nanoscale: a
perspective", Biomicrofluidics 3, 012001 (2009).
[4] G. Yossifon and H.-C. Chang, "Changing Nanoslot Ion Flux with a Dynamic Nanocolloid
Ion-Selective Filter: Secondary Overlimiting Currents due to Nanocolloid-Nanoslot
Interaction", Phys. Rev. E, 81, 066317 (2010).