If the physical and chemical laws that govern the biology of living systems are the same as those that govern inanimate objects, isn’t it logical that the quantitative skills engineers bring to the table can substantially add to the biological revolution taking place? For years while ethicists, theologians, human rights groups, and the medical and insurance professions have been debating when life starts, how it should end, or even the quality of life, engineers, biologists, and physicians have been working together to solve some of the most pressing physical needs of society. Researchers in Notre Dame’s College of Engineering focus their bioengineering efforts in the areas of biomechanics, biomaterials, bioinstrumentation, bioinformatics, and bioremediation. Their successes promise to be at the forefront of innovations in medical treatment plans and surgical procedures, the development of chemical and optical sensors for medical applications, and the invention of new drug-delivery systems.
Targeting Radiation Therapies
While X-rays and other imaging techniques have long been used to identify broken bones or help locate tumors, new technologies developed at Notre Dame are being used to improve the quality of medical images and provide more accurate diagnoses, radiation dosage assessments, and therapeutic radiation treatments. Professors Danny Z. Chen and X. Sharon Hu — along with their research team in the Department of Computer Science and Engineering and in conjunction with researchers at the University of Iowa, the University of Maryland School of Medicine, the University of New Mexico, the University College of London, and several U.S. medical companies — have been solving problems in radiation cancer treatment and medical imaging. The algorithms they have developed for radiation cancer treatment planning and delivery produce radiation therapy plans that deliver a more accurate dosage in a shorter time period (60 percent faster) than current commercial treatment planning systems and other algorithms. Delivering accurate dosages more quickly allows hospitals to treat more cancer patients, reduces treatment costs for both hospitals and patients, and decreases the risk of over dosage.
Tanyel Kiziltepe, research assistant professor in the Advanced Diagnostics and Therapeutics (AD&T) initiative at the University of Notre Dame, and Basar Bilgicer, assistant professor of chemical and biomolecular engineering, are working to address one of the side effects of Trastuzumab, an antibiody used in breast cancer treatment.
Also known as Herceptin®, Trastuzumab, targets and kills the HER2 (Human Epidermal Growth Factor Receptor 2) positive cells found in one of every three breast cancer patients. When used in conjunction with chemotherapy, it has been shown to reduce cancer recurrence up to 50 percent. However, Trastuzumab can also lead to congestive heart failure because the receptor molecules in breast cancer cells that attract the Trastuzumab (so that it can attach to the cancer cells and kill them) are the same molecules located around heart tissue.
The Notre Dame team is working to improve the selectivity of Trastuzumab, so that when it is in the body it can better identify HER2 cancer cells as opposed to healthy ones that have the same receptors, so that the antibiody can become safer and more effective. Their initial results will be tested first in vitro and then in animal studies.
Imagine a handheld device that could identify a bacterial contaminant in a food source while it was still in a processing plant, detect apollutant in water at the source in real-time, or isolate a virus or infectious disease in a country with limited medical and diagnostic resources. These are actual scenarios where current lab-on-a-chip technology provides fast and accurate diagnostics when time and information are critical. But even these micro labs cannot process exceedingly small (mass limited) samples effectively. The incorporation of nanofluidic elements into lab-on-a-chip technology as demonstrated by Notre Dame researchers expands this technology and its functionality.
Small fluid samples need careful handling to preserve sample integrity. Some samples, like pheromones or neurotransmitters, are available only in limited quantities, and they can be destroyed during multi-step procedures. Others are small due to an aspect of the substance itself. For example, toxins must be handled in minute quantities to minimize potential harm to the diagnostician.
A team of University of Notre Dame researchers, led by Paul W. Bohn, the Arthur J. Schmitt Professor of Chemical and Biomolecular Engineering and concurrent professor of chemistry and biochemistry, has successfully addressed this challenge. They have developed platforms to capture individual molecules of interest in mass-limited quantities and created intelligent chemical reaction chambers in the space of a nanopore. Information can now be extracted from samples consisting of a few hundred-thousand molecules and manipulated as needed.
The team accomplished this by designing hybrid microfluidic/nanofluidic networks with nanoporous membranes in layered (3D) architectures. In previous studies at other research universities, devices had been limited to two microfluidic layers using a single layer of nanofluidic interconnects. Bohn’s hybrid networks with 3D architecture combine the advantages of traditional microfluidic devices with integrated-circuit-like capabilities, such as the ability to maintain separate, chemically unique environments within a single interconnected device, as well as the ability to transfer fluid between these two environments at will.
Each nanopore of a nanocapillary array membrane (NCAM) in the 3D hybrid microfluidic/nanofluidic system works as an intelligent chemical reaction chamber where substances can be loaded or unloaded externally via fluidic manipulation. The ability to confine mass-limited reactants within a nanopore also significantly increases the probability of a desired reaction. The use of chemical reaction chambers speeds up the reaction rate in cases where the kinetics is transport limited.
Notre Dame researchers’ success offers several possibilities for future lab-on-a-chip devices. For instance, a gated injection could be performed from a microchannel filled with a complex sample mixture into another channel where a preparative electrophoretic separation would be carried out. A specific component band could then be collected from this separation, transferred to yet another spatial plane and into a channel filled with a chiral separator where, after an additional separation, a specific enantiomer could be transferred to a final microchannel interface and a mass spectrometer for detection. Another possibility is an antibody-modified NCAM capturing a specific property from a complex sample mixture, thus performing a combined preparatory separation and de facto preconcentration, prior to an on-demand release by fluidic manipulation for further analytic steps.
Iannacone, J., Kim, B.-Y., Sweedler, J.V., King, T.L., and Bohn, P.W., “Manipulating Mass Limited Samples Using Hybrid Microfluidic/ nanofluidic Networks,” Biological Applications of Microfluidics, F.A. Gomez, ed., John Wiley & Sons, New York, 2008, Ch. 23, pp. 451-472.
Gatimu, E.N., Sweedler, J.V., and Bohn, P.W., “Nanofluidics and Mass-limited Chemical Analysis,” Analyst, 2006, 131, 705-709.
Kuo, T.C., Cannon, D.M. Jr., Feng, W., Shannon, M.A., Sweedler, J.V, and Bohn, P.W., “Gateable Nanofluidic Interconnects in Multilevel Microanalytical Systems,” Analytical Chemistry, 2003, 75, 1861-1867.