Nanotechnology, VLSI fabrication, genetic engineering and drug design intersect in the rapidly developing field of BioMEMS, a curious blend of organic and inorganic systems that is seeing explosive growth in the lab and may soon do the same in innovative new applications. Chip makers are eyeing BioMEMS research developments as a promising supplement to an oversupplied electronics market.
Indeed, silicon fab expertise is in demand by biotechnology companies attempting to target a wide variety of potential applications in areas such as DNA sequencing, biometrics, genetically engineered drugs, point-of-care instruments and a host of military applications in the detection of chemical and biowarfare agents. But the list of potential applications stretches much further, with new entrants constantly springing up in biological research labs.
How to capitalize on all this potential? It probably will not be a smooth road to profitability for the average semiconductor house, cautions Robert LeFort, president of Infineon Technologies North America Corp. The San Jose, Calif., company has just introduced a DNA analysis chip designed in conjunction with MetriGenix Inc. (Gaithersburg, Md.), a biotechnology firm specializing in DNA analysis microarrays. "The human-consequences factor make this kind of development difficult,"LeFort said.
Typically, medical applications require a long sequence of trials followed by government approval. For example, the genetic engineering of drugs would seem to have a large market potential, but "only one out of 5,000 attempts gets to the commercialization stage and even then, they are only effective 50 percent of the time," LeFort said.
Still, LeFort is impressed with the pace of the field. "We went from a skunkworks operation to a mass-market introduction in only two months. There is a clear business case to be made for DNA analysis chips." With test tubes, he said, "you have a serial, one-at-a-time system. But with a DNA analysis chip, you can do 128 trials at a time with far less reagent."
MetriGenix first approached Infineon two years ago with a new approach to chips using DNA chemistry that promised to be more efficient and faster than existing technology. Today's DNA analysis chips use tiny, shallow wells to contain the DNA and reagents. The MetriGenix design uses a capillary flow-through technique whose prime advantage is to speed up the reactions.
MetriGenix needed a semiconductor company with VLSI fabrication expertise to realize this lab-on-a-chip system. After two years of work to thrash out the fabrication issues, the Infineon and MetriGenix team says it has fielded "several dozen" of the newly introduced chips to drug companies.
Infineon has now embarked on a second BioMEMS development project: an electronic cell-culture system that gives biological researchers the ability to grow neurons on an electronic substrate and record their electronic behavior. The neuron chip was presented at the International Solid-State Circuits Conference in February.
Others in the BioMEMS field agreed with LeFort's assessment of the market dynamics. "The road to market penetration and profitability is complicated," said Carl Meinhart, a professor in the department of mechanical and environmental engineering at the University of California at Santa Barbara. "Many companies are currently in these spaces, but few have achieved profitability. As in many high-technology fields, the path to profitability becomes clear only after the opportunity has passed."
Meinhart recently achieved a BioMEMS research breakthrough by integrating a tunable-laser cavity into a biochip that can be used as a sensor for immunoassays. The sensor is a pair of distributed Bragg reflector lasers that incorporate a reaction chamber. Antigen-antibody binding events alter the modal index of the laser cavity, resulting in a sensor with very high sensitivity.
The new sensor approach could result in products for areas such as field-portable biosensors, distributed sensors, and medical screening and diagnostics, Meinhart said. "However, there are many practical issues that need to be addressed before it can be used in the field," he said, citing sample preparation steps and reliability as examples. "The laser structures are relatively complicated. Therefore, commercialization would most likely leverage strengths from two companies-a semiconductor laser manufacturer and a biotechnology company-for assay development and distribution."
Another complication for companies seeking to play in this new field is that BioMEMS lacks technological standards that would help to stabilize the development of new products. This is particularly true at the nanoscale on which molecular-biological processes take place, said Jeeseong Hwang at the Optical Technology Division of the National Institute of Standards and Technology. Hwang and his colleagues at NIST are working on characterizing surfaces at the resolution of single molecules using techniques such as near-field scanning optical microscopy (NSOM) and chemical-force microscopy (CFM).
Hwang and his associates are employing these advanced imaging techniques in an effort to image individual molecules on polymer surfaces. NSOM is is a technique for moving beyond the resolution limits of conventional optics, and is considered ideal for small-scale systems. Lori Goldner at the Optical Technology Division pioneered the so-called "polarimetric" approach to NSOM. The method has been employed in a new single-molecule metrology approach that should help to establish standards for BioMEMS research and development. Tinh Nguyen, Mark VanLandingham and Xiaohong Gu of NIST's Materials and Construction Research Division are developing CFM as an alternative imaging technique.
"I am convinced that there will be a great thrust toward development of BioMEMS platforms for the use of single-molecule analysis and on-chip capillary electrophoresis," said Hwang. "Immediate applications will be bioterrorism detection and single-cell-based infectious-disease analysis."
Nanotechnology visionaries are fond of pointing out that life itself is an existence proof of the viability of molecular-scale machines. The emergence of BioMEMS has now set off not only theoretical speculation on the extension of MEMS into the realm of nanotechnology, but also ambitious technology development projects. An example is the recently formed Institute for Cell Mimetic Space Exploration, a joint project involving a team of scientists from UCLA, NASA, Arizona State University, the California Institute of Technology, the Jet Propulsion Laboratory and the University of California, Irvine.
Projected development work will explore the connection between nanotechnology, biotechnology and information technologies. The researchers hope to learn how to implement what are called bionanotechnology electromechanical systems, or BioNEMS, by looking at the way cells adapt and grow to create complex organisms. The result could have "immense impact in the aerospace, medical, defense and energy fields, to name a few," according to a statement from the institute. The project kicked off with a five-year, $15 million grant from NASA, with an option to renew funding at the same level for another five years.
