Stephen Boppart has developed a novel system for use in the fight against disease.
Stephen Boppart understands better than most researchers the importance of technology in the fight against disease. As a cancer survivor for more than 12 years, Boppart’s research into biomedical imaging as a tool for disease detection has extra meaning. Boppart began working on a system using optical coherence tomography (OCT) before coming to the Beckman Institute. Now, as head of the Biophotonics Imaging Laboratory and in collaboration with other Beckman researchers and a local hospital, his work with OCT has gone from theory to practice. A member of the Nanoelectronics and Biophotonics (NB) group, Boppart has developed an OCT system that detects breast cancer cells either non-invasively or less invasively than a traditional biopsy. In the coming months, breast cancer specialists at Urbana’s Carle Hospital will introduce Boppart’s portable, functional, optical biopsy system as a diagnostic tool for the first time in a clinical setting. “This is really the first step in being able to do this in patients in, perhaps, the operating room, without the delays of pathology and having to take out tissue,” Boppart said. The system employs OCT technology, a high-resolution imaging technique using light, to perform “optical biopsies” of tissues, cells, and someday perhaps even molecules. By using light to explore tissue close to the skin and contrast agents, catheters, probes, and a light needle for deeper areas, there is no need to remove tissue, and results are known immediately. This provides doctors with high-resolution, real-time imaging capabilities, in addition to benefits such as portability and lower cost.
By performing ‘optical biopsies’ of tissues, cells, and perhaps, someday even molecules, the system – with its high resolution, real-time information capabilities, portability, and lower costs – provides a new tool in the fight against disease. Boppart believes in the future this technology will be as common as MRI. “In terms of resolution, it’s a much higher resolution than CT, and even ultra-sound,” he said. With the system, there is no need to remove tissue, and results are known immediately. The system could have future applications in surgical guidance and tissue engineering, and has shown promise for revealing important details at the cellular and even molecular level.
Attacking disease at the molecular level has great potential in terms of prevention and early detection. Scientists in the Molecular and Electronic Nanostructures Research Initiative (M&ENS) are doing research into DNA sequencing that could expand our understanding of genetics and have tremendous implications for medicine and science in general.
Jean-Pierre Leburton uses computational methods for simulation and modeling.
Beckman researchers Gregory Timp (NB) , Jean-Pierre Leburton and Narayana Aluru of the Computational Electronics (CE) group and Klaus Schulten of the Theoretical and Computational Biophysics (TCB) group are developing a new technique to read DNA sequences. They are trying to read electrical traces left by DNA molecules passing through artificial nanopores in a very thin silicon capacitor just a few atoms wide. If the DNA leaves an electrical trace, then the sequencing of everything from cancer cells to antibiotics is possible, with concurrent benefits of lower cost, and greater dependability and efficiency. One possible outcome of this work is a gene chip that could determine DNA 'on-the-fly' without the time and expense of a laboratory setting. Leburton said this project could be a crucial breakthrough in genome science. “It is so fundamental we would certainly have an impact on the Genome Project. If we are 100 percent successful in this project, this would be a totally new way to read DNA. Not only new, but faster, cheaper, and more reliable.” While ultra-fast recording of DNA sequences is a future goal, manufactured nanopores have already been used to size short strands of DNA. This technique uses electron beams to push single molecules of DNA through a nanopore in an effort to detect the electrical traces. This type of single molecule approach is used in a variety of important research areas.
Joseph Lyding (NB) uses scanning tunneling microscope (STM) technology he developed to not only study nanostructures such as single-walled carbon nanotubes (SWCNT), but also to manipulate them at the atomistic scale for applications like integration with silicon surfaces. Lyding’s group has developed a system called Dry Contact Transfer (DCT) as a reliable way to deposit nanotubes onto a surface without the drawbacks of a wet chemical deposition process. Ultimately, ultra-fast carbon nanotube transistors may replace silicon in electronics, but integration with silicon is still a key research theme. Lyding’s efforts in another area, the Protein Logic Project, seek to merge silicon electronics with biology for parallel processing of information. In these types of systems, a protein array acts as a chemical processor, producing a chemical output that is then sensed by a periphery of silicon transistors. These systems could lead to biosensors based on a bio-chemical environment interacting with an electronic environment for such uses as ultra-fast image recognition or disease detection. “So you get this conversion between a biological, bio-chemical environment and an electronic environment,” Lyding said. “And the idea is that you could make cellular neuro-networks out of regular arrays out of any type of device, whether it’s a protein that switches chemically or a transistor that switches electronically, you can do ultra-fast image processing.”
Materials with autonomic, or self-healing, properties are another key area of investigation within M&ENS. An ongoing line of research has involved the development of self-healing polymers that consist of microcapsules with a healing agent, a polymerizing agent, and a catalyst. When a crack ruptures one of these microcapsules, the healing agent contacts the catalyst, and then polymerizes and bonds the crack face closed. Nancy Sottos and her colleagues Scott White, Jeffrey Moore, and Philippe Geubelle in the Advanced Chemical Systems (ACS) group focus on these materials, with some of the research into self-healing polymers headed toward the application phase. A grant from NASA and the Jet Propulsion Laboratory is funding a new line of research led by Sottos into developing microencapsulated systems for space-based applications. In addition, Sottos and White are working with Moore on a molecular-based approach to self-healing systems that involves mechano-chemical triggering. These materials feature a mechano-chemical link in the polymer backbone that would, when stressed, use that energy to create a chemical reaction leading to repair or strengthening of the material.
Paul Braun’s group created a glucose sensor using self-assembly techniques.
Biosensors are a key focus of research in ACS and involve a wide range of projects.
Using self-assembly techniques, Paul Braun’s (ACS) group created a pH sensor in 2004 with a sensitivity of 0.01 pH units. Now, the group has shown that a self-assembled, three-dimensional photonic crystal-based glucose sensor has the ability to detect physiological glucose levels in buffers similar to blood serum. The technique of templating colloidal crystals that created the glucose sensor is general in nature, and therefore should allow the detection of other compounds such as those found in pesticides and nerve gas agents.
“This is another one of those sensors where you can almost drop in the active piece,” Braun said. “So we can convert this from a glucose sensor to a pH sensor to another kind of sensor just by changing one molecule in the sensor design. We can basically dial in the molecules we want to detect. And you can define the sensitivity by how much of the active sensing group you put in.”
Braun said the porosity of the glucose sensor design allows it to be integrated into microfluidic devices like microelectromechanical systems (MEMS).
“We can integrate them into lab-on-a-chip designs. That is what is truly unique about ours as compared to any other design out there,” Braun said. “The way that we designed our structure, it’s going to be quite resistant from bio-fouling, so other things in the bloodstream don’t really interfere with it. And, because it contains porosity, fluids rapidly go into the structure, so it has a fairly rapid response time.”
Paul Bohn’s (ACS) group focuses on controlling the movement of fluids in microfluidic devices for use in biosensors and other technologies. One such device receiving increasing attention is the molecular gate , an externally controllable fluidic interconnect useful in micro- and nanofluidics. Bohn’s work in the micro- and nanofluidics area analyzes attomole and subattomole masses for preparative chromatography, the isolation of very small particles, for a variety of uses. Bohn, in collaboration with Mark Shannon and Jonathan Sweedler of the Biological Intelligence Research Initiative worked on a nanofluidic device based on a molecular gate to detect attomolar concentrations of neurotoxins. Their research focused on serotypes of botulism, a toxin with serious consequences for humans at only a femtogram of exposure. That amount can’t be detected by current methods, but molecular gate technology has the capability of metering and delivering amounts down to million trillionths of a liter of fluids containing target chemicals or molecules. The research into molecular gate technology has reached the engineering phase as part of a new nano-chemical-electrical-mechanical system for manufacturing at the nanoscale. This system utilizes the molecular gate for metering attoliters of chemical reactants used in the manufacturing process.
Interfaces between the biological and the electronic are a key focus of MENS research. Describing how nature works at the nanoscale level is an important tool for researchers trying to mimic nature in artificial nanodevices.
Umberto Ravaioli uses molecular simulations in a variety of research topics.
Umberto Ravaioli (CE), a professor of Electrical and Computer Engineering and full-time Beckman Institute faculty member, said comprehending natural processes is an essential component of this research. “We would like to understand how a biological system works so that we have an understanding in the future of how to connect them to electronics, to understand the dry-wet interface,” Ravaioli said. “If we can learn from biological systems then we can think of making artificial systems that have similar properties, perhaps based on carbon nanotubes, or some other kind of structure like a nanopore.”
Ravaioli uses particle simulation to explore systems with dry-wet interfaces that could lead to biosensors able to detect agents on a sample size of just a single molecule. Ravaioli’s group has taken its Monte Carlo method computer simulation program (MOCA) and adapted it for biology with a program called BIOMOCA. Ravaioli said the BIOMOCA simulation program makes it possible to conduct very long simulations (resolving up to micro- to milliseconds) so that the electrostatic behavior of the structure (average potential and charge distribution) can be mapped throughout and the current flow can be resolved reasonably well. He said BIOMOCA is not a substitute or competitor for molecular dynamics, “rather it provides an additional level in the model hierarchy necessary to probe the behavior of biological systems at different relevant time and space scales.
“BIOMOCA gives us a description of the biological system as if it were a device and indeed, the approach was patterned after our experience in solving comparable charge transport problems in electronics.”
They are also working with TCBG to investigate very large channels that are mechano-sensitive and useful in a variety of ways.
Aluru also works with molecular dynamic simulations, focusing on mechano-systems. Aluru's research combines quantum mechanical theories with atomistic and continuum theories to solve problems in nanofluidics, electrostatics, and mechanics. Because classical theories of physics often don't apply at the nanoscale, Aluru and his group have developed physical theories and computational design tools to aid in the modeling of nanoscale structures and systems. They are the first researchers to combine quantum mechanical theories for electrostatics with nanoscale mechanics. Aluru collaborates with researchers on both the computational side (Ravaioli, Karl Hess, Eric Jakobsson) and on the experimental side (Shannon, Bohn, Timp) to study systems and processes such as how molecules interact with nanostructures. This work is helping to bring an understanding of quantum mechanics into the world of mechanics, an important contribution to the fabrication of nanostructures.
The study of biological channels is one of the main missions of M&ENS research. This research may investigate calcium channels that send electrical signals to keep the heart pumping or membrane channels carrying water to maintain kidney function.
Ravaioli and M&ENS Co-chair Karl Hess (CE) have focused on the electronic properties of these ion channels. “Without these channels the heart would stand still,” Hess said. “We understand how electricity moves through these channels. At some point we could be able to find out why is it that your heart is pumping on a more regular rhythm when you take magnesium pills.”
Hess, well known for groundbreaking semiconductor theories, is extending those concepts to model ion channels. These models would allow the pioneering idea of rapid design of biomimetic (artificial materials which mimic natural ones) concepts. Hess said electron and hole transport in semiconductors shows great similarities to transport of ions in biological channels. The trapping and release of electrons and holes was explained by the well-known theory of Shockley, Read and Hall, but Hess said, “No such theory existed for ion channels.”
Hess and his colleagues modified the Shockley-Read-Hall method for ion channels and applied their modified approach successfully to several well-known channels, such as the antibody Gramicidin.
“We can simulate, therefore, very efficiently the trapping and release of ions as well as their continuum current,” Hess said. “This brings us a step closer to a multi-scale model that describes both microscopic events and macroscopic currents and voltages of systems involving both artificial and biological ion channels.”
The Theoretical and Computational Biophysics group investigates membrane proteins and membrane processes of biological cells by carrying out large-scale simulations at an atomic level. In addition to the work in DNA sequencing, TCBG research has resulted in discoveries of the physical mechanisms underlying several key cell functions, such as ion and water permeation in a bacterial toxin, and water permeation through aquaporin water channels. They discovered that a unique arrangement and an unexpected flipping motion of water molecules permeating the aquaporin channel explained how cells transport water through a membrane without allowing protons through at the same time. A snapshot image of the simulation by TCBG’s Emad Tajkhorshid was honored by the National Science Foundation and Science magazine.
Research involving carbon nanotubes continues to cut across a wide range of disciplines within the Beckman Institute, and shows the value of these structures in such diverse areas as microfluidics, medicine, and electronics. While Lyding and others investigate nanotubes at the most elemental levels, Materials Science and Engineering Professor John Rogers (NB) studies them for use at the micro and macro levels in search of ways to make electronics cheaper, faster and more lightweight.
With prolific results and numerous interdisciplinary collaborations, Rogers researches ‘soft’ materials such as biological tissue, polymers, and liquid crystals for imaginative electronics applications. Rogers explores using plastics, or polymers, and organic, or biological, systems for uses in electronic devices that could one day replace silicon-based devices and the clean-room manufacturing process they require. Based on the Rogers group’s work, flexible macroelectronics such as paper-like displays (for example, digital wallpaper or wearable electronics) are made possible. By carving specks of single crystal silicon from a bulk wafer and casting them onto sheets of plastic, Rogers’s group demonstrated it is possible to create thin-film, high performance transistors. Their research realm includes not only investigating technologies like those involving single-walled carbon nanotubes (SWCNTs), but also using lithographic techniques to pattern these materials into practical applications such as consumer electronics.
As electronics and the silicon-based devices that power them grow increasingly smaller, the influence of quantum mechanics on their performance becomes greater. Beckman researchers are dealing with this issue in novel ways, including harnessing the potential of an electron’s spin, and using photonic crystals for the purpose of converting information transported by photons to the information-processing electrons on computer chips.
Pierre Wiltzius (NB), Jennifer Lewis (ACS) and Braun are investigating self-assembly of photonic devices for possible integration with electronic components. This method has advantages over lithographic techniques for making three-dimensional photonic crystals, which are excellent materials for producing simpler, faster chips that complement smaller devices. Wiltzius said the wedding of photonics and electronics is in its early stages as researchers try to understand the materials and make photonic crystals that are usable in electronic devices. He compared work on photonic crystals to the development of today’s integrated circuit microelectronics, which required advances in semiconductor technology to reach their current form.
“We don’t have the equivalent of a semiconductor for light,” Wiltzius said. “The big goal is to develop materials that will allow us to deal with light in a very novel and qualitatively different way.”
Although applications for photonic crystals are a future goal, the research is already paying off in terms of basic science.
“What excites is, it is truly interdisciplinary,” Wiltzius said. “It takes expertise all the way from theoretical understanding of these materials to simulation, to physics, but goes very readily into materials science.”
Another line of research in the quantum world of electronics is investigating the under-used power inherent in an electron’s spin. Spintronics (spin-based electronics, or magnetoelectronics) are devices that rely on an electron’s spin to perform their functions. Many feel this field has a chance to radically change the way chips and semiconductor electronic devices are made by using a new type of computer memory, magnetic random-access memory (MRAM) that can include a multiplicity of functions on a single chip.
Spintronics also have great potential for use in quantum computing – what many consider to be the next great leap in the processing of information. The conventional unit of computation, the bit, contains binary information for sequential computation. But a spin-supported quantum bit (qubit) uses vectors (an ensemble of two numbers) to do computations in a two-dimensional space. This allows for parallel computations, or computations done at the same time instead of sequentially. This would have tremendous security applications in terms of better data encryption, as well as many other uses, such as much faster data searching. Leburton has reported a new simulation paradigm in the area of nanospintronics that could be used for quantum computing, as well as the sequencing of DNA.
Quantum computing has the potential to help us understand the quantum world much better than the tools provided by classical computing. Hess, in collaboration with Walter Philipp (CE), is investigating how far quantum information can take us. Is it possible to transmit information at the quantum level without wires or optics? Current physics says it is not, but pure science follows wherever the research points, and this line of investigation promises to be interesting.
At the Beckman Institute, there is always an eye toward application that goes along with the science. Doing research with real-world applications in mind has always been a guiding principle of the Institute and of Arnold Beckman himself.
When M&ENS was formed a decade ago, nanotechnology was in its infancy. Today, it is a growing industry that promises to transform everything from medical laboratories to electronics. M&ENS was unique 10 years ago in its focus on nanostructures, but even as this technology becomes more common, this Beckman Institute research thrust remains a central point of reference in what many believe will be a new technology revolution.