ARLINGTON, Va., -- Biomedical engineers at the University of Michigan have grown a healthy network of blood vessels in live animals using implants that deliver critical growth enzymes sequentially as in nature.
"To grow a replacement tissue cell by cell, you need a combination of growth factors delivered in the right sequence at the proper time and in the right place," said David Mooney, Ph.D., professor of biologic and materials science at Michigan and a Whitaker Investigator. "Just injecting a large amount of it with a needle doesn't work."
The experiments, reported in the current issue of the journal Nature Biotechnology, represent an early step toward growing new tissues in the human body, since all living tissues require blood circulation.
Possible medical applications include alternatives to heart bypass surgery, faster wound healing, and treatments for vascular disease in diabetics. The implants might also be used to deliver other drugs or therapeutic agents.
At least two enzymes or growth factors are needed for new blood vessels: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). VEGF initiates vessel growth, while PDGF promotes maturation by giving the vessels a strong interior lining. The continued presence of VEGF also prevents vessels from regressing as they mature.
The research group attempted to duplicate the sequential release of the growth factors by mixing them with a polymer in different ways and then melding everything into a porus scaffold to be implanted. As the scaffold dissolved, it released the growth factors one before the other with some overlap. The scaffold is designed to disappear altogether over time.
The Michigan group mixed VEGF with particles of the polymer for immediate and sustained release and encapsulated PDGF in polymer microspheres for slow release. The release rate and amount were controlled by the thickness and number of microspheres. Both the polymer-particle mixture and the microspheres were combined to make the scaffold.
The researchers conducted three experiments. First they confirmed the release rates of both growth factors in laboratory dishes, then implanted four types of scaffolds in healthy rats. One type contained VEGF alone, another PDGF, the third had both, the fourth neither. The rats were examined after two weeks and again in a month. Only rats that received both growth factors had grown new, mature blood vessels after four weeks.
In the third study, the researchers attempted to treat vascular disease in 16 diabetic mice using the same combination of four scaffold types. Again, only the dual-release scaffolds stimulated a mature vascular network.
Peter Carmeliet and Edward M. Conway of the University of Leuven in Belgium commented on the research in the same issue of Nature Biotechnology. They compared the Michigan approach to contemporary efforts to stimulate blood vessel formation using other methods, such as gene transfer, noting that none of the othermethods mimicked nature's timed-release delivery of multiple growth factors.
"Obviously, future work is needed to demonstrate the value of this system for [therapy]," they wrote. "Nonetheless, the exciting findings ... underscore the importance of paying attention to not only the type of angiogenic growth factor employed for therapeutic angiogenesis, but also how and when they should be delivered."
Mooney's group included postdoctoral student Thomas P. Richardson and graduate students Martin C. Peters, a Whitaker Fellow, and Alessandra B. Emmett. Mooney received a Biomedical Engineering Research Grant from the foundation in 1995 for tissue engineering research. Peters received a Whitaker Foundation Graduate Fellowship in 1996.
Journal
Nature Biotechnology