A microchip with an array of 64 nanosensors. The nanosensors appear as small dark dots in an 8 x 8 grid in the center of the illuminated part of the backlit microchip.
A new biosensor microchip that could hold more than 100,000 magnetically sensitive nanosensors could speed up drug development markedly, Stanford researchers say. The nanosensors analyze how proteins bond – a critical step in drug development. The ultrasensitive sensors can simultaneously monitor thousands of times more proteins than existing technology, deliver results faster and assess the strength of the bonds.
A microchip with a nanosensor array (orange squares) is shown with a different protein (various colors) attached to each sensor. Four proteins of a potential medication (blue Y-shapes), with magnetic nanotags attached (grey spheres), have been added. One medication protein is shown binding with a protein on a nanosensor.
Stanford researchers have developed a new biosensor microchip that could significantly speed up the process of drug development. The microchips, packed with highly sensitive “nanosensors,” analyze how proteins bind to one another, a critical step for evaluating the effectiveness and possible side effects of a potential medication.
A single centimeter-sized array of the nanosensors can simultaneously and continuously monitor thousands of times more protein-binding events than any existing sensor. The new sensor is also able to detect interactions with greater sensitivity and deliver the results significantly faster than the present “gold standard” method.
“You can fit thousands, even tens of thousands, of different proteins of interest on the same chip and run the protein-binding experiments in one shot,” said Shan Wang, a professor of materials science and engineering, and of electrical engineering, who led the research effort.
“In theory, in one test, you could look at a drug’s affinity for every protein in the human body,” said Richard Gaster, MD/PhD candidate in bioengineering and medicine, who is the first author of a paper describing the research that is in the current issue of Nature Nanotechnology, available online now.
The power of the nanosensor array lies in two advances. First, the use of magnetic nanotags attached to the protein being studied – such as a medication – greatly increases the sensitivity of the monitoring.
Second, an analytical model the researchers developed enables them to accurately predict the final outcome of an interaction based on only a few minutes of monitoring data. Current techniques typically monitor no more than four simultaneous interactions and the process can take hours.
“I think their technology has the potential to revolutionize how we do bioassays,” said P.J. Utz, associate professor of medicine (immunology and rheumatology) at Stanford University Medical Center, who was not involved in the research.
It is the increased sensitivity to detection that comes with the magnetic nanotags that enables Gaster and Wang to determine not only when a bond forms, but also its strength.
“The rate at which a protein binds and releases, tells how strong the bond is,” Gaster said. That can be an important factor with numerous medications.
“I am surprised at the sensitivity they achieved,” Utz said. “They are detecting on the order of between 10 and 1,000 molecules and that to me is quite surprising.”
The nanosensor is based on the same type of sensor used in computer hard drives, Wang said.
“Because our chip is completely based on existing microelectronics technology and procedures, the number of sensors per area is highly scalable with very little cost,” he said.
Although the chips used in the work described in the Nature Nanotechnology paper had a little more than 1,000 sensors per square centimeter, Wang said it should be no problem to put tens of thousands of sensors on the same footprint.
“It can be scaled to over 100,000 sensors per centimeter, without even pushing the technology limits in microelectronics industry,” he said.
Wang said he sees a bright future for increasingly powerful nanosensor arrays, as the technology infrastructure for making such nanosensor arrays is in place today.
“The next step is to marry this technology to a specific drug that is under development,” Wang said. “That will be the really killer application of this technology.”
GMR nanosensor and nanoparticle system for kinetic analysis. Schematic representation of antibody–antigen binding. On the left, antibody labelled with a magnetic nanoparticle tag in solution at concentration Cs approaches the GMR sensor surface.
Visualization of spatiotemporal resolution of the sensor array.
Schematic representation of a two-compartment model as applied to GMR sensor (orange) for kinetic analysis of labeled antibody binding to antigen. The kinetics of binding between a ligand in solution and a capture agent on a surface is typically modeled as a two-compartment reaction36 to allow for both reaction and transport kinetics to be incorporated. In the model, the soluble ligand in the surface compartment (reaction zone) reacts with the surface and is gradually replenished by diffusion, flow, and convection from the bulk compartment (bulk zone).