New Technique Builds Microscopic Medical Devices For Transplants

Mauro Ferrari, professor of biomedical engineering at Ohio State, has devised a method for implanting tiny silicon capsules -- about the size of a pinhead -- beneath a patient's skin. Such capsules would carry healthy transplant cells that would take the place of the patient's malfunctioning cells by producing needed chemicals for the body. For example, capsules in diabetics could allow patients to produce insulin again, Ferrari explained.

Today, doctors suppress patients' immune systems with drugs to keep antibodies from destroying transplanted tissue, leaving patients open to infections. Ferrari's technique eliminates the need for immunosuppression, and for transplanting an entire organ when a few grams of healthy cells will do.

"If you can't beat the immune system, you hide from it," said Ferrari. He and his colleagues are working to nanomachinecapsules with holes that are just the right size -- big enough to let the needed chemicals get out, but small enough to keep the antibodies from getting in.

In their latest study, Ferrari and his colleagues were able to create 2-millimeter capsules, each containing millions of channels only 18 nanometers -- approximately 50 atoms -- across.

The researchers simulated the capsule's use in treating insulin-dependent diabetes. The 18-nanometer holes allowed glucose and insulin molecules to pass through, but blocked the antibody immunoglobulin G (IgG), which attacks transplanted cells.

These results were published in a recent issue of the Journal of Membrane Science. Ferrari began this work before he became director of Ohio State's Biomedical Engineering Center, while still on the faculty of the University of California at Berkeley. He is continuing the work at Ohio State. Co-authors Tejal Desai and Derek Hansford are former students of his at Berkeley; Desai is now assistant professor of Bioengineering at the University of Illinois at Chicago, and Hansford joined the Ohio State faculty as an assistant professor of biomedical engineering in August 1999.

Other researchers have tried to construct similar capsules from plastic, but the materials were incompatible with the body, and couldn't provide immunoisolation for a sufficiently long period of time, Ferrari explained. He and his colleagues chose silicon because it wouldn't react with the body, and because the computer industry had already developed methods for creating precise surface features with the material.

Ferrari's patented method employs photolithography, a technique in which microchip manufacturers take a smooth layer of silicon atoms and eat away portions of the surface with chemicals. The holes that result are all the same size, down to an atom. "If we want to make 18-nanometer holes, we make 18-nanometer holes," said Ferrari, "millions and millions of them, all exactly the same."

Insulin-dependent diabetes develops when the body fails to recognize cells in the pancreas that respond to glucose and produce insulin. One possible therapy is to transplant even just a few grams of healthy pancreatic cells, Ferrari explained. A capsule containing the cells could be inserted under the skin anywhere in the body. Molecules of glucose would enter the capsule, and the transplanted cells would release insulin, which would flow back out.

Determining the right hole diameter was difficult, Ferrari said, because nobody knows the size of these molecules for sure. Initial tests revealed that both insulin and glucose could pass, though with difficulty, through 18-nanometer holes.

Ferrari and his colleagues then inserted a silicon membrane containing 18-nanometer holes between two chambers of liquid, one containing IgG. Over the next four days, they measured the amount of IgG that penetrated the membrane.

After one day, the concentration of IgG in the second chamber was less than 0.4 percent. After four days, the concentration had grown to just over 1 percent.

Ferrari characterized this rate as several times slower than capsules made of plastic. He cited a similar study in which a perforated plastic membrane allowed an IgG concentration of 1 percent to accumulate in the second chamber after only 24 hours.

He added that keeping out 100 percent of all IgG may be impossible. Researchers think the molecule is not spherical, and if it enters an opening with its narrow end, it can squeeze through. "These molecules twist and turn and find their way into small passageways -- that's what makes them good antibodies," said Ferrari.

As to cost, Ferrari said that one capsule could produce all the insulin a patient needed for a year for about $20. He hopes to be able to test his capsules in clinical trials within the next three years.

Ferrari and his colleagues recently received a $1.4 million grant from the State of Ohio Board of Regents to continue this work in a consortium. Member institutions include Ohio State, Case Western Reserve University, University of Cincinnati, University of Akron, the Cleveland Clinic Foundation, and the Battelle Memorial Institute.