The multiwelled microplate, long a standard tool in biomedical research and diagnostic laboratories, could become a thing of the past for some applications thanks to new electronic biosensing technology developed by a team of microelectronics engineers and biomedical scientists at the Georgia Institute of Technology. The researchers hope to replace microplates with modern microelectronics technology, including disposable arrays containing thousands of electronic sensors connected to powerful signal processing circuitry. This new electronic biosensing platform could help realize the dream of personalized medicine by enabling real-time disease diagnosis -- even in doctor's offices -- for selection of individualized therapeutic approaches.

"This technology could help facilitate a new era of personalized medicine," said John McDonald, chief research scientist at the Ovarian Cancer Institute in Atlanta and a professor in the Georgia Tech School of Biology. "There are a lot of potential applications for this that cannot be done with current analytical and diagnostic technology." Fundamental to the new system is its ability to electronically detect markers that differentiate between healthy and diseased cells. These biomarkers can be differences in proteins, mutations in DNA, or even specific levels of ions that differ in cancer cells.

"We have put together several novel pieces of nanoelectronics technology to create a method for doing things in a very different way than what we have been doing," said Muhannad Bakir, an associate professor in Georgia Tech's School of Electrical and Computer Engineering. "What we are creating is a new general-purpose sensing platform that takes advantage of the best of nanoelectronics and three-dimensional electronic system integration to modernize and add new applications to the old microplate application. This is a marriage of electronics and molecular biology." The three-dimensional sensor arrays are fabricated using conventional low-cost, top-down microelectronics technology. Existing sample preparation and loading systems may have to be modified, but the new arrays should be compatible with existing workflows in research and diagnostic labs.

"We want to make these devices simple to manufacture by taking advantage of the advances made in microelectronics," said Ramasamy Ravindran, a graduate research assistant in Georgia Tech's Nanotechnology Research Center and the School of Electrical and Computer Engineering, "while at the same time not significantly changing usability."

The system will use low-cost, disposable components, with information processing done by reusable conventional integrated circuits connected temporarily to an array. Ultrahigh-density, spring-like, mechanically compliant connectors and advanced "through-silicon vias" will make the electrical connections, allowing technicians to replace arrays without damaging the underlying circuitry. Separating the sensing and processing portions allows fabrication to be optimized for each type of device, notes Hyung Suk Yang, a graduate research assistant also working in the Nanotechnology Research Center. Otherwise, the types of materials and processes that could be used to fabricate the sensors would be severely limited. Sensitivity of these tiny electronic sensors can be greater than that of current systems, potentially allowing earlier disease detection. The substantially smaller sample wells could permit more testing to be done with a given sample volume. This technology could also facilitate ligand-based sensing that recognizes specific genetic sequences in DNA or messenger RNA.

So far, the researchers have demonstrated a biosensing system with silicon nanowire sensors in a 16-well device built on a 1-cm by 1-cm chip. The nanowires, just 50 nm by 70 nm, differentiated between ovarian cancer cells and healthy ovarian epithelial cells at a variety of cell densities. Silicon nanowire sensor technology can be used to simultaneously detect large numbers of different cells and biomaterials without labels. Beyond that, the platform could accommodate a range of other sensors, including technologies that don't yet exist.

"Our platform idea is really sensor agnostic," said Ravindran. "It could be used with a lot of different sensors that people are developing. It would give us an opportunity to bring together a lot of different kinds of sensors in a single chip."

Mapping single nucleotide polymorphism (SNP) variations that account for ~90% of human genetic variation could help determine a patient's propensity for a disease or likelihood of benefitting from a given intervention. These biosensors could enable caregivers to produce and analyze SNP maps at the point of care. Although many technical challenges remain, the ability to screen for thousands of disease markers in real-time has many biomedical scientists excited. "You could theoretically put all possible combinations on the array," Ravindran said. "This has not been considered possible until now because making an array large enough to detect them all with current technology is probably not feasible."

Papers describing the biosensing device were presented at the Electronic Components and Technology Conference and the International Interconnect Technology conference in June 2010. The research has been supported in part by the National Nanotechnology Infrastructure Network (NNIN), Georgia Tech's Integrative BioSystems Institute (IBSI) and the Semiconductor Research Corporation.

John Toon is manager of the research news and publications office at the Georgia Institute of Technology, 75 Fifth Street, NW, Suite 314, Atlanta, GA 30308; 1-404-894-6986; www.facebook.com/gtresearchnews; Twitter @gtresearchnews.