March 12, 2004
Aerogels may spawn life-like lab-on-a-chip devices and better model membranes
By Dawn Levy
It's the tale of the princess and the pea, science-style. Proteins sitting on a glass microscope slide can have a hard time getting comfortable. Atop a bed of compact silica, they can become confined, contorted and damaged -- and may even lose their biological functions.
If the princess had had a waterbed instead of a hard mattress, she'd never have been kept awake by the discomfort of a pea. Similarly, embedding proteins in a lipid bilayer creates a comfy environment a lot like the protein's natural resting place in a cell membrane. And laying that protein-studded lipid bilayer on a hydrated cushion may allow the proteins to better keep their natural forms and functions.
Thanks to Stanford inventors, proteins now have their waterbed. It's created from a novel aerogel -- a light, porous silica material that can be formulated to be between 50 percent and 98 percent empty. When its pores are filled with a biological buffer, the resulting substrate may support cell membranes just as a cell body would, allowing researchers to study functional components under life-like conditions.
The Stanford researchers have succeeded in creating lipid membranes on the surface of extraordinarily porous liquid-filled aerogel. This technology is now available for licensing through Stanford's Office of Technology Licensing. Next, the researchers hope the substrate will allow integral membrane proteins to remain as intact and functional in experimental systems as they are in living cells. Doing so may improve model membranes for research and enable the creation of novel biosensors and lab-on-a-chip devices, arrays for screening drugs that bind to membrane-embedded receptors and libraries that display membrane proteins in their natural shapes.
"If we're successful in the entire construction, we'll be able to put proteins in an environment in which they'll remain functional, and we can have access to them for analytical techniques as well as provide the proteins with any other sort of environmental conditions that are appropriate," says Chemical Engineering Department Chair Curtis Frank, the W. M. Keck, Sr. Professor in Engineering. Frank recently filed a patent for the aerogel technology with visiting Professor Subhash Risbud from the University of California-Davis, graduate student Kevin Weng and postdoctoral fellow Johan Stalgren. The researchers collaborate in the Center on Polymer Interfaces and Macromolecular Assemblies (CPIMA), a National Science Foundation-sponsored partnership among Stanford, IBM Almaden Research Center, UC-Davis and UC-Berkeley.
Maintaining proteins in a physiological state is a major engineering challenge. While engineers have made lipid bilayers stand up on compact silicon wafers before, the Stanford invention is the first to allow assembly of bilayers on a porous and hydrated silicon substrate. The atomically rough, corrugated surface of the Stanford material and its abundance of water-loving hydroxyl chemical groups make it possible for the lipids to essentially walk on water. "It's sort of like having matchsticks stand on ocean," Risbud says.
Membrane-bound proteins represent the single most important class of drug targets, Weng says. Approximately 50 percent of current targets are membrane-bound molecules. Keeping the components of these molecules functional with supported lipid bilayer systems may improve biochemical and biophysical studies of antibody binding, drug binding and other interactions. Drug target screening is an important potential application of such systems.
The CPIMA group collaborates with Assistant Professor of Medicine William Robinson and graduate student Jennifer Lynn Radosevich, both of whom study autoimmune diseases, such as multiple sclerosis. Many membrane components, such as glycolipids and proteins, can induce dysfunctional immune-system cells to attack. Aerogel technology may increase the chances of membrane components behaving naturally during experiments.
Aerogels also facilitate the production of patterned (and hydrated) lipid bilayers useful in multiple chemical assays of biological samples. Microarrays created with the technology may someday find use in high-throughput assays. Patterned bilayers may also aid tissue engineering, allowing researchers to direct cell growth to make, say, an artificial retina.
Aerogel also allows experimenters first-time access to both sides of the cell membrane -- the outer membrane, where drugs bind to embedded receptor proteins, as well as the inner membrane, where signals trigger physiological events, such as neurochemical communication. Scientists could also study the transport of substances through the membrane, such as ions traveling through a protein channel. Compact silica glass slides, in contrast, allow researchers access to only one side of a membrane.
Just as a jellyfish retains its shape after it washes up on a beach and dries, so too do aerogels retain their structure as they're being produced in the lab -- despite the fact that they are more air than gel. That structure is an amorphous network of small molecules -- in the case of the Stanford substance, silicon dioxide with attached organic groups. The key to creating the Stanford aerogel is a process that allows the gel solution to dry without shrinkage. Called supercritical drying, it exchanges carbon dioxide with the solvent used to prepare the gel solution. Under a scanning electron microscope, the resulting structure resembles haphazardly interlacing strings of pearls. To the naked eye, the macroscopic material looks like Jell-O. A dry chunk of aerogel, translucent and fragile, feels lighter than Styrofoam.
Scientist Samuel S. Kistler made the first aerogel in 1931 and patented it in 1937. The history is unclear about whether he accomplished this while at Stanford or the College of the Pacific in Stockton. His first aerogels were made of silica, but he also made aerogels of alumina, tungsten, iron and tin oxides, nickel tartrate, cellulose, gelatin, egg whites and rubber.
While hydrated aerogels have important biological applications, dry aerogels show promise, too. They have been components of particle detectors in high-energy physics. Their high porosity means their thermal conductivity is about 100 times less than that of fully dense silica glass, paving the way for use in superinsulating spacers in windows and in shields to trap solar energy. As sound moves slower through aerogels than air, they may improve efficiency of devices that emit ultrasonic waves to gauge distances, such as auto-focusing cameras and some robots.