In emergency, flu vaccine could be made quickly in existing facilities

In an emergency such as a pandemic outbreak or last year’s vaccine shortage, the influenza vaccine could be produced twice as fast using cell cultures in existing biopharmaceutical manufacturing facilities, according to Henry Wang, professor of biomedical and chemical engineering.

Wang and graduate student Lyle Lash proposed a system for retrofitting existing biopharmaceutical buildings to produce the flu vaccine using cell cultures.

With traditional vaccine manufacturing, the virus is injected and incubated in a chicken egg, killed and extracted, then bottled and sold. The process takes more than four months.

Wang and Lash considered the cell culture approach, or when the flu virus incubates in cell cultures rather than in eggs. Researchers say the approach is promising because it is more flexible and quicker than the current egg culture method. Building a separate cell culture facility and shipping the cells to the existing bio-manufacturing plants, the production cycle could be cut in half to two months, Wang says.

Lash and Wang identified about a dozen potential facilities around the world that could be modified to manufacture flu vaccines in a pinch. Many biopharmaceutical facilities use mammalian cell culture already to produce their drug products so they easily could be switched to producing flu vaccine using the same bioreactors, the researchers say.—By Laura Bailey, News Service

Polymers with copper show promise for implanted sensors

U-M researchers have promising preliminary results with new polymer coatings that eventually may be used on chemical sensors that can be placed in the bloodstream or under the skin to continuously monitor oxygen, acidity (pH) or glucose levels.

Developing such sensors has been problematic because the body responds to these foreign objects in ways that interfere with their ability to accurately measure blood chemistry. In the bloodstream, clots form on the surface of implanted sensors or blood vessels contract around them. Sensors implanted under the skin may become walled off by cells that flock to the site as part of the inflammatory response.

U-M chemistry professor Mark Meyerhoff and collaborators previously coated intravascular sensors with nitric oxide-releasing polymers, which improved accuracy and reduced clots. However, Meyerhoff says, these polymers can be sensitive to moisture and heat, making commercialization a challenge. In addition, the polymer coatings must be very thin for most biomedical applications, which limits the amount of nitric oxide that can be stored and released from the thin coating on the sensor surface.

The researchers’ new approach is to make polymers that generate nitric oxide from compounds called nitrosothiols found in the bloodstream. The key to doing this, the researchers found, is copper. Copper ions can act as catalysts to take nitrosothiols and generate nitric oxide from them, says Meyerhoff, the Philip J. Elving Collegiate Professor of Chemistry. The researchers have shown that copper ions work as expected when incorporated into polymers. Next, they plan to test the new polymers to see if they are as effective at preventing clots as the nitric oxide-releasing polymers they developed earlier.—By Nancy Ross-Flanigan, News Service

Taking aim with nanoparticle PEBBLEs

Nanoscale polymer beads, initially developed as sensors to explore and monitor cellular processes, show promise for diagnosing and treating cancer, says Raoul Kopelman, the Kasimir Fajans Collegiate Professor of Chemistry, Physics and Applied Physics.

Kopelman and collaborators have encouraging preliminary results using the polymer spheres, known as Photonic Explorers for Biomedical use with Biologically Localized Embedding (PEBBLEs), to treat a virulent form of brain cancer in rats.

PEBBLEs typically are 20 to 200 nanometers in diameter—about the size of a virus. The spheres carry an assortment of molecules on their surfaces, some to guide the PEBBLEs to their targets inside the body, some to enhance their visibility on MRI images, and others to deliver a deadly cargo to cancer cells when triggered by exposure to light.

In recent experiments with a small number of rats that had a type of brain cancer called 9L-gliosarcoma, PEBBLE-based treatment significantly increased survival time. Kopelman and coworkers plan to tinker with the PEBBLEs a bit more before trying them on larger numbers of rats, and PEBBLE-based cancer treatments for people are a long way off. But “there’s no doubt,” says Kopelman, “that nanoparticles such as PEBBLEs can do a fantastic job for therapy, diagnostics and a combination of the two.”

Collaborators include Martin Philbert, professor of toxicology and associate dean for research in the School of Public Health; Brian Ross, a professor of biological chemistry and of radiology in the Medical School; Alnawaz Rehemtulla, an associate professor of environmental health sciences, radiation oncology and radiology with joint appointments in the Medical School and the School of Public Health; and Yong-Eun Lee Koo, a research associate in the chemistry department, LSA.—By Nancy Ross-Flanigan

Probing the promise and perils of nanoparticles

For all its promise, the prospect of using nanoparticles in biomedical applications and consumer products has raised concerns about possible harmful effects of the miniscule materials.

Scientists at the University are addressing those concerns by investigating how certain kinds of nanoparticles damage cell membranes—enough to cause cell death in some cases—and how the damage can be prevented.

Mark Banaszak Holl, professor of chemistry and of macromolecular science and engineering, in collaboration with other researchers at the Center for Biologic Nanotechnology, has been studying nanoparticles known as dendrimers, tiny spheres whose width is 10,000 times smaller than the thickness of a human hair. Dendrimers have shown promise for precisely delivering drugs to their targets inside the body, but high concentrations of these nanoparticles can be toxic.

In earlier work, U-M researchers discovered that dendrimers punch nanoscale holes in cell membranes, making the membranes more permeable. At high enough concentrations, they can completely destroy the membranes, killing cells in the process. But the damage can be prevented by engineering dendrimers in particular ways, such as modifying their surfaces to make them neutral instead of charged, the scientists found.

More recently, graduate student Pascale Leroueil studied other types of charged nanoparticles—already being used to deliver drugs and genes—to see if they behaved like dendrimers and found that they caused similar damage. Both that work and the dendrimer work used model membranes to probe the effects of nanoparticles. Now, the research group is exploring their interactions with living cells.

Collaborators on this work include Dr. James R. Baker, Jr., the Ruth Dow Doan Professor of Biologic Nanotechnology; Bradford Orr, professor of physics and director of the Applied Physics Program; research associate Jennifer Peters and research investigators Anna Bielinska and Istvan Majoros.—By Nancy Ross-Flanigan

U-M team makes synthetic mother of pearl

It’s possible to grow thin films of mother of pearl in the laboratory that are even stronger than the super-strong material that naturally lines the inside of abalone shells. The trick is to add compounds normally found in insect shells and fungi cell walls to the recipe.

Mother of pearl, also known as nacre, has fascinated materials scientists because it is several times stronger than nylon, says Nicholas Kotov, associate professor at the College of Engineering.

Kotov’s team has succeeded in making artificial nacre even stronger.

“We think this material will be tremendously important because different sensors, different electronic materials, space shuttles, airplanes and even cars require thin sheets of ultra-strong material,” says Kotov.

Seeking a way to strengthen the artificially made nacre, researchers substituted a material called chitosan, which is a naturally occurring compound in insect shells and the cell walls of fungi. The nanocomposite films are made by layering molecules on top of each other. Scientists dip a substrate into a solution of electrolytes, which carries electrical current, then into a clay solution. During this process, molecules bind to the substrate and begin to form layers. The dipping is done in a specific sequence to control different properties of the film as it is layered.

Graduate students Paul Podsiadlo and Zhiyong Tang also collaborated.—By Laura Bailey