Postdoctoral research: Microfluidics, Systems Biology and Cancer Stem Cells
Currently I am a postdoctoral associate at Steve Quake's group at Stanford University, Bioengineering Department. My work is aimed at fusing together biology, physics and engineering to solve both fundamental and applied problems in biomedical sciences. I develop microfluidic technologies and use them for systems level investigations of cell signaling and gene regulatory networks. In particular, I use an extremely powerful cell culture system for high-throughput single cell analysis. I am also developing a microfluidic cell sorter for use in single cell analysis and genetic diagnosis of cancer.
On the systems biology front, the problems I am interested are:
a) How does the cell mount specific responses to different stimuli using a single signal mediator? A good example to such a signal mediator is the transcription factor NF-KB, which is involved in a multitude of basic cellular functions such as inflammation, and its misregulation is involved in a variety of diseases including cancer. NF-KB pathway can be triggered by hundreds of external stimuli, which in turn regulates the expression of more than 100 genes. Each response requires a different subset of genes. How does a single transcription factor manages to regulate such responses specifically? To answer such questions, I am using mouse fibroblast cells as model organism and utilize microfluidic high-throughput single cell analysis and fluorescent protein technology. In collaboration with Covert Lab, we make time lapse videos and extract high quality, quantitative data, and use it to mathematically model NF-KB signaling to improve our understanding of the emergent network properties.
b) How does the cell determine its size? Cells don't divide unless they reach a certain size. Cell cycle is one of the most studied fields in biology, yet the underlying mechanisms are far from fully understood. With Jan Skotheim, I try to identify the new feedback mechanisms in pathways involved in mammalian cell cycle using a combination of our microfluidic cell culture technology, gene cloning and RNAi.
Most of the work in systems biology emphasize the role of genetic noise that lead to randomness in the way a biological system operates. For example, genetically identical cells can take on very different phenotypes as a result of the fluctuations in key protein expression levels. Development, on the other hand, is extremely robust and strictly controlled. There is no room for variations in the developmental processes, as most often they are either fatal or severely impaire the organism. A fundamental question in Biology is how robustness arise from the chaotic bio-chemical interactions. I have recently started an exciting new project, in collaboration with Mark Krasnow, which we investigate mammalian lung development in order to identify the genetic pathways that govern the local and global modes of control in airway development. As usual, the experimental prowess of microfluidics will be key in figuring out these pathways in a quantitative fashion with single cell resolution.
Doctoral research: Nonlinear optics, Photonic materials and devices, Holography
My research during graduate school involved several topics in nonlinear optics, photonic materials, photonic devices and holography. The first project I took during my PhD work with Prof. Nasser Peyghambarian was on photorefractive polymers . Photorefractive Polymers are organic holographic storage materials that allow recording of highly efficient, dynamic holograms and have applications in optical data storage, medical imaging, adaptive optics and most importantly holographic 3D displays. We have successfully completed the project on "infra-red sensitization of photorefractive polymers using two-photon absorption", which resulted in the development of PR polymers operating at 1550nm for the first time. Since then, I have been working on Photonic Crystals and Plasmonics, and an exciting new project on developing the first updateable holographic 3D displays based on photorefractive polymers. You can find more information about these project below.
Updateable holographic 3D displays
There is considerable interest for a dynamically updateable 3D display that does not require special eyewear (autostereoscopic) for applications such as medical, military and industrial imaging. Among various techniques, holographic stereography gives the best spatial resolution and the most realistic images. Photopolymers have been traditionally used to record the complex, high resolution holograms needed for 3D displays. Holograms in photopolymers are based on an irreversible photo-chemical process called photo-polymerization. This irreversibility results in fixed holograms that can not be erased and updated. The need for an updateable holographic medium is obvious, because, first: it would reduce the cost per image considerably, second: updating capability would significantly extend the applications of 3D displays where real-time or near real-time (update time of a few minutes) imaging is necessary. Photorefractive polymers we develop offer reversible recording, high efficiency and very large size (several feet across) making them very good candidate materials for 3D displays. Recently we have started a new project that aims to bring together the already matured stereoscopic holographic techniques (see, for example, Zebra Imaging) and photorefractive polymers to develop the first updateable holographic 3D display with memory and large size, suitable for immediate practical use. The project is supported by AFOSR. I work as the lead graduate student on this project that requires designing and building a holographic printer for pixel-by-pixel recording of a display, developing necessary codes to generate 3D images to be uploaded to the printer and finally developing the holographic material system.
Recently we have achieved encouraging results which may open up the possibility of the first commercially available updateable 3D displays in a next few years. The first generation photorefractive 3-D display we developed is based on horizontal parallax imaging, has a size of 4x4 inches (largest to date), shows single color (red) images, and can be updated within 3 minutes and be viewed for up to 3 hours without significant decay. Images can be erased any time by application of a uniform laser beam at 532nm. The paper reporting this achievement has been published in Feb 7 issue of Nature. (Vol 451, p 694).
The future directions in this research include 1) Development of full-parallax, single color, large size (10x10 inches) displays that can be updated within 10 minutes 2) Development of full-color large area displays 3) Integration of full-color and full-parallax in large sized displays.
Here are two videos showing the display operation:
Video 1 (Views from the 3D display)
Video 2 (Recording and erasing of the 3D display)
Figure: Image processing, recording of spatially multiplexed stereograms, their display and erasing.
A CNN hologram that wasn't
During the 2008 US presidential elections, CNN's News showed an interview by Wolf Blitzer with reporter Jessica Yellin, which they called a "hologram interview". Now, I don't know who came up with this bright idea, but it worked beautifully exploiting the hunger among Star Wars junkies and 3D hologram adorers for a real-time "Princess Leila" type holographic video display, making CNN coverage of the elections headline news all around the world. While being a publicity success story, and unfortunately for 3D hologram enthusiasts, this was nothing close to a true hologram. In fact, there is no big difference between CNN's stuff and the holographic video of the first Star Wars movie some 20 yeas ago: they only exist on the TV screen. A hologram faithfully reproduces the reflected light from an object, allowing us to see it as if the real object was there floating in the air, so much so that the observers will reach forward trying to grab it. It exhibits important visual cues such as depth and parallax, that can not be truly represented by two-dimensional displays such as TV screens. CNN's stuff was nothing but some computer graphics trick, and anybody who is literate in physics and optics figured it right away. What Wolf Blitzer looking at was not a hologram but possibly a red spot on a screen.
Holographic displays came a long way, and first generation 3D displays based on holograms are already commercially available. These are static holograms though, meaning that the images they show do not move, and they can not be erased and replaced with new images. We have demonstrated the first refreshable holographic displays a year ago (see above), but the refresh rate was too slow to satisfy real-time display (streaming video needs a refresh rate of at least 30 images per second). We are working hard on extending this technology to real-time video, but there are significant challenges that need to be overcome before we see anything like CNN's "hologram interview" in "real life". While we and and other groups around the world are working towards this goal of a true 3D holographic display, a little help in getting some publicity in our field is certainly appreciated. Therefore, thank you CNN for bringing the holograms into mainstream news again. (I say again, because CNN featured an interview with my colleague Prof. Nasser Peyghambarian about holographic displays in October, just a few weeks before the elections, where Nasser explained how novel this technology is and what we are doing to improve it. All CNN needed to do was to look at their own website to get the facts right about holographic displays)
Photonic crystals and plasmonic devices
Photonic crystals are the semiconductors of light. The number of publications in this field are growing exponentially since their discovery in the late 80's. Three years ago we took part in a new program (APEX) that aims to develop new materials and techniques to enable large scale fabrication of photonic crystals and novel devices based on photonic band-gap materials, and involves a number of institutions and universities. I joined the project as the lead graduate student at University of Arizona during its initial phase at a time where there was no photonic crystal related work in our group except for photonic crystal fibers, and helped shape our approach in this rather unfamiliar territory. In time, we have identified materials and techniques which resulted in very exciting directions which we are actively pursuing at the moment. This work allowed me to gain experience in the design, fabrication and characterization of organic and semiconductor photonic devices. Performing PBG calculations, designing and fabricating photonic devices in the cleanroom and characterizing them is a part of this work. We also work on infiltrating photonic crystals (actual devices and/or polymeric templates) with a variety of active and passive optical materials. Our efforts in this field have so far resulted in several conference papers, two patent applications (THZ emitter disclosure), and 3 manuscripts we are getting ready for publication:
1) Infiltration of photonic crystal devices and templates: Although 3D photonic crystals with full PBG in the optical regime has been shown previously, their large scale use is still difficult due to the challenging nature of the fabrication process. Photonic crystals are typically fabricated from semiconductors or metals using lithographic techniques, which makes 3D fabrication and extension to large scales extremely difficult. An alternative method we use is to fabricate a polymeric template using a relatively easy technique such as interference lithography, self organization or two-photon direct writing and infiltrate this structure with high-index materials to achieve the necessary index contrast. We have shown (OSA conference paper) very efficient infiltration of such templates with a variety of materials (photoconducting polymers, nanocrystals, non-linear dyes and nano-amorhous carbon) with a variety of techniques (melt processing, casting, CVD).
In particular, we have shown 100% filling of 2D planar silicon photonic crystals with nanocrystal/polymer nanocomposites using the melt processing technique (Appl. Phys. Lett. 91, 221109). A provisional patent has been filed for the invention of this technique. These nanocomposites contain chemically functionalized TiO2 nanoparticles with an average size of 5nm that are dispersed to the polymer without aggregation, resulting in high optical quality. When a high loading (30wt%) is used the refractive index of the composite changes from 1.65 to 1.72 and a spectral red-shift in the photonic band-gap is observed due to the increased refractive index of the photonic crystal holes. The combination of photonic crystals and nanoparticle/polymer nanocomposites may have important applications such as hybrid OLED's, tunable photonic crystal devices and hybrid photovoltaics (solar cells).
Left: The planar photonic crystal filter device infiltrated with the nanocomposite. Middle/Right: Different sized holes of a silicon PC infiltrated with TiO2/polymer nanocomposite. Complete filling is achieved for all hole sizes. No aggregation of the nanoparticles is observed.
Left: The tranmission spectrum of the silicon photonic crystal infiltrated with a polymer composite (black line) and nanoparticle doped polymer composite (red line). A red-shift is achieved, which is controllable with the nanoparticle refractive index and loading level. Right: PBG calculations predict perfectly the red-shift observed in the structures infiltrated with the nanocomposite.
Also, we have achieved uniform coating of 3D polymeric templates with a metal doped nano-amorphous carbon compound (similar to, but better than diamond-like carbon) developed by Intex, inc. while keeping the periodicity intact, which may lead to fabricating large area, 3D metal-like photonic crystals in the near future, useful for thermal mid-IR emitters (patent pending). A detailed, but rather old conference paper describing this work could be found here: (SPIE paper)
2) Photonic crystal/surface plasmon based narrow-band thermally driven mid-IR emitters: Currently there are very few light sources for the mid-IR (2-20 microns) and Terahertz region (30 micron to 1 mm). However, important applications such as sensing (chemical and biological) and thermal imaging require cheap, relatively narrow band light sources in these regimes. Black-body sources can emit in the mid-IR, but they have very large bandwidths (tens of microns) and low efficiency. We have developed a photonic crystal/plasmonic narrow-band thermal emitter based on a novel material that has significant advantages compared to typical metal/semiconductor films used for this purpose. This device emits narrow band LED like radiation in the desired wavelengths with higher efficiency and will be able to switch (modulate) with a very high frequency compared to other thermally driven devices (to be submitted soon).
3) Photonic routers based on optically active polymer infiltrated photonic crystal waveguides and devices: Our success in infiltrating 2D nanostructures with polymers led to some exciting applications such as tunable photonic crystal waveguides and devices. For example, we have designed a photonic router that is based on azo-polymer infiltrated photonic crystal superprism device that would show all-optical switching between photonic channels. Superprism devices are very dispersive optical devices that can be used in WDM systems for optical multiplexing/demultiplexing. When its holes are infiltrated with materials that change their index of refraction under optical excitation, all-optical tunable DWDM routers and filters can be made. We are currently working on infiltrating some of the silicon superprisms with azo-polymers for applications at 1550nm (in progress).
Photorefractive polymers and their applications
Photorefractive polymers are organic
holographic materials which allow recording refreshable holograms with very high
speed and efficiency. They have applications in optical data storage, medical
imaging, free-space optical communication and holographic displays. My research
during the first 2 years of my PhD study mainly focused on
developing infra-red (IR) sensitive photorefractive polymers and their
applications. Previously, the longest operation wavelength for a photorefractive
polymer device was 820nm, and extending this to near IR (900nm to 1600nm), where
most of the applications become possible, was of critical importance for this
technology. We have developed new organic dyes and sensitization methods to
tackle this problem. In particular, we have used two-photon absorption
sensitization to reach the important wavelength of 1550nm.
Left: Two-photon sensitization energetics. Right: THG in organic thin-films. Pump is 1550nm and the green third harmonic is seen on a white card.
In this material, the optical excitation occurs in a non-linear dye (χ3) with the simultaneous absorption of two photons with half the excitation wavelength. Since most of the organic dyes absorb in the visible and do not extend beyond 800nm, it was necessary to use this rather difficult two-photon scheme to reach the 1550nm range. The recording beams from an amplified femtosecond laser with very high peak power (several GW/cm2) were used to record holograms through two-photon absorption sensitization. The first materials (Appl. Phys. Lett. 85, 4561) were slow (several seconds) and the diffraction efficiency was small (around 3 percent). With better designed composites (Appl. Phys. Lett. 87,171105) the diffraction efficiency reached a value of 40% with a response time of 35ms. Another important advantage of using two-photon sensitization was that, when CW reading beams were used the holograms were immune to erasing by the reading beams, a property called "non-destructive readout". The natural dark decay of the photorefractive gratin could be stopped by use of thermal fixing, which require a heating-cooling cycle to freeze the non-linear chromophores after recording the holograms. This resulted in writing, storing and erasing (if necessary) very efficient holograms in a single material at the optical communication wavelength, which was a first in these material systems. (Click here for the TRN magazine article about these results)
Left: Femtosecond four-wave mixing setup used to characterize photorefractive polymers. Middle: Diffraction efficiency vs. applied field at 1550nm Right: Temporal dynamics of PR response and TBC gain at 1550nm.
This project was highly interdisciplinary spanning the fields of organic photonics, non-linear optics, ultrafast spectroscopy and holography. I helped design and fabricate complex organic composites and devices. I characterized them with a variety of tools such as photoconductivity, ellipsometry, interferometry, two-photon spectroscopy and most importantly four-wave mixing in the femtosecond time scales. Building complex optical setups and measuring very weak signals was a part of this work.
During this time I have also been involved in other work within the group. We have developed high efficiency composites at 980 nm through linear absorption sensitization (Appl. Phys. Lett. 85, 1095) . We have demonstrated real-time correction of atmospheric aberrations of free-space beams using phase conjugation in photorefractive polymers, better known as " beam clean-up" in both 633nm (Appl. Phys. Lett. 86, 161103) and 1550nm. As a result of developing better composites and using more efficient geometries, we have reduced (Opt. Lett. 31, 1408) the operation voltage of photorefractive devices from several kV's to only around 1000V, while maintaining high speed and efficiency. Single nanosecond pulse operation of PR polymers with sub-millisecond response time (Appl. Phys. Lett. 89, 114105) and efficient PR polymers operating in reflection geometry (in preparation) were demonstrated, which are critical for applications such as updateable 3D displays. We have used our materials for injection locking of broad area laser diodes (published in Optics Express). (see the last page on OPN paper and this review article for a summary of PR polymer research).
In addition to the published results, we have made important improvements in two other fields. In particular, we have demonstrated very efficient third-harmonic generation in organic the composites we developed. The IR femtosecond pulses focused in the materials were creating light in green, which is a third order non-linear effect and was very useful for characterization of the ultrafast pulses. The THG efficiency was as high as the best results reported at that time in an organic material, but we simply did not have the time to continue working on this direction. However, there is now (as of Oct, 2007) a possibility to revive this work as the combination of photonic crystal fibers, which allow precise control over dispersion, and THG polymers offer some exciting possibilities in fiber-lasers and amplifiers.
Also during this time, we pursued the idea to demonstrate a true free-space optical communication system which employed our photorefractive polymers for adaptive optical correction of atmospheric aberrations. Most of the free-space laser systems work at 830nm or 1550nm due to the low absorption of these wavelengths in the atmosphere. We have designed an experiment to show reduction in the bit-error rate (BER) in a free-space system and built the setup to demonstrate the concept. We have succeeded in real-time correction of aberrations at 830 nm using our newly developed photorefractive polymers. The results were almost as good as the 633nm results. However, it was obvious that the demonstration of BER reduction was further ahead and due to time constraints we had to postpone this project. However, I plan to write up at least part of our results showing real-time aberration correction (above) at this important wavelength.
Contact me for any questions regarding this work.
Follow this link to learn more about the work in our broader group: (Peyghambarian Group)
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