NIST Industrial Impact

Company: Aastrom Biosciences, Inc., Ann Arbor, Michigan
Business: Medical product development
Number of Employees: 80

Mother Nature is a tough act to follow, a designer of elegant systems that are rarely surpassed. But scientists at a small biotechnology company in Michigan did it, building a small device that acts just like human bone marrow and in some ways is even better.

Relying on co-funding from NIST's Advanced Technology Program (ATP), scientists at Aastrom Biosciences, Inc., designed and built an experimental system that successfully grows therapeutic amounts of functional human stem cells, which normally reside in the bone marrow of healthy individuals and mature into blood and immune system cells.

Stem cells harvested from patients and other donors currently are used to treat approximately 12,000 U.S. patients annually (and the number is growing) whose own stem cells are missing or damaged, often because of radiation or chemical treatments for cancer. The Aastrom bioreactor may offer significant advantages over traditional cell-harvesting techniques to both patients and the U.S. economy:

• The new approach could reduce the cost of stem cell therapy by an estimated 25 percent.

• Cancer may be less likely to recur, based on studies in which cultured cells were less contaminated with tumor cells than the patients' own bone marrow before culture.

• Up to 96 percent less tissue needs to be harvested, reducing donor pain and expanding the utility of stem cells from other sources, such as umbilical cord blood (UCB).

Moreover, in the future, the technology could provide new approaches to blood replacement, gene therapy, wound repair, and other medical treatments. "We have found that the device, as a platform, is applicable to other cell types beyond bone marrow and UCB," notes Alan Smith, vice president for research.

The world has taken due notice. The Aastrom approach to cell therapy, now in clinical trials with more than 70 patients at six sites in the United States and Europe, has generated considerable excitement among private investors, who have poured more than $70 million into the company since the two-year ATP project began in 1992. Aastrom already has a marketing alliance with a company that hopes to distribute and service the devices for stem cell therapy.

The scientific importance of the advances generated in the ATP project is reflected by more than 100 papers and 14 patents that Aastrom either owns or licenses exclusively, including a patent on the basic stem-cell replication method. "To use an analogy: We invented the car; everyone else is coming up with turbochargers or some other accessory to the original invention," the company's patent lawyer told The New York Times in July 1997.

At the center of all this excitement is a desktop-sized device that, like a videocassette recorder, is designed to hold disposable cassettes. A small amount of harvested tissue is injected into a cassette--which is about the size of a large pizza--in which growth factors, oxygen, and proprietary processes stimulate production.

Unlike the typical bioreactor, which relies on an external source of oxygen requiring recirculation of the growth medium at a high rate (generating uneven concentrations of materials), the Aastrom device achieves consistent culture conditions through internal oxygenation and a slow, radial perfusion process, Smith says.

The challenging design task required an interdisciplinary team with expertise in cell biology; biochemistry; chemical, electrical, and mechanical engineering; software design; and other fields. The ATP funding enabled the company to accelerate by up to two years the design and construction of a prototype cell-culturing device and the instrumentation for automated operations.

If the clinical trials are successful and the Food and Drug Administration approves the bioreactor for clinical use, then the technology would compete against two traditional cell-therapy approaches: direct harvesting of bone marrow tissue and peripheral blood progenitor cell (PBPC) collection after stem cells are induced by drugs to move into the bloodstream.

Aastrom estimates that its procedure would require only 1 to 3 hours of patient time, compared to 16 hours of total procedure time for bone marrow harvesting and 39 hours for PBPC. Moreover, Aastrom's approach requires the cell donor to undergo only one skin puncture to withdraw approximately 40 milliliters (ml) of bone marrow, whereas direct harvesting requires up to 140 painful skin punctures to withdraw 1,000 ml. Aastrom's approach also eliminates the drug used in the PBPC process.

The Aastrom technology may expand the therapeutic use of UCB, which is the blood that remains in the umbilical cord and placenta after childbirth. UCB is becoming increasingly popular for cell therapy because it is easy to collect, tumor free, and potentially less subject to issues of tissue incompatibility between donor and recipient. However, the amounts of UCB available for transplantation are severely limited.

The Aastrom system has passed initial safety and efficacy tests, and the results of preclinical trials are promising. In one study at Loyola University Medical Center, six breast-cancer patients not only recovered vital cell function but also exhibited a very low incidence of side effects. In an expanded study with 19 patients, bone marrow cells underwent about a sixfold median expansion over 12 days in the bioreactor, providing sufficient stem cells for transplantation. This is no small achievement, because only a fraction of 1 percent of bone marrow cells are stem cells.

Of particular significance to patients, both the Loyola research and a separate study by Aastrom and Duke University Medical Center showed that cells grown outside the body were less contaminated with tumor cells than the patients' own bone marrow, suggesting that cancer may be less likely to recur after treatment.

In the ongoing clinical trials, bone marrow cells are being cultured to treat breast cancer patients, and UCB cells are being expanded to treat adults and children with a variety of conditions, such as leukemia, single-gene defects, and immune deficiencies, Smith says. In the latter cases, the patients could not be treated using traditional approaches unless a suitable donor could be found.

The Aastrom technology has intrigued the National Institutes of Health, which recently awarded the company two grants, including one to develop a novel AIDS therapy. Aastrom is collaborating with University of Colorado researchers to insert cell-destruction genes into AIDS patients' stem cells, which then would be expanded in the bioreactor and transplanted back into the patient. The idea is to cause cells infected with the AIDS virus to die before the virus can replicate.

June 1998