By Dean A. Haycock

Special to BioWorld Today

There are few fields in which the familiar saying "use it or lose it" applies as often or as well as it does to biomedicine.

Some neuroscientists, for instance, suggest that mental stimulation - "using your brain" - may be a way to delay or postpone the neurodegenerative effects of Alzheimer's disease. Less cerebral examples are skeletal muscle and bone. Moving them regularly, as anyone who has managed to stick to an exercise program can attest, changes them. The principle also applies to blood vessels and smooth muscles.

David Mooney, of the University of Michigan in Ann Arbor, provided an example:

"It has been well documented in the past," he told BioWorld Today, "that if tissue containing smooth muscle is cyclically stretched, you see upregulation of gene expression for different growth factors. This provides one explanation for how tissues that are being mechanically stimulated interact with their surroundings."

The same mechanism, he added, may promote release of growth factors. In other words, mechanical stimulation produced by moving and pressing tissues may be a mechanism by which tissues in our body naturally regulate growth factor signaling.

Currently, drug delivery systems implanted in the body deliver drugs on a regular basis. That is, they are designed to work in a static environment. But, the body moves. And that movement generates mechanical force. Cartilage, bones, tendons, muscles, blood vessels and skin are pressed, pulled and stretched. Today, artificial materials referred to as polymeric matrices, which are packed with growth factors and implanted in the body, can stimulate the growth of new tissues.

Polymeric Matrices Offer New Approach

Perhaps tomorrow, Mooney and his collaborators reason, "polymeric matrices, which release growth factors in response to mechanical signals, might provide a new approach to guide tissue formation in mechanically stressed environments."

Mooney and his colleagues describe their approach in a letter titled "Controlled growth factor release from synthetic extracellular matrices" that appears in the Dec. 21/28, 2000, issue of Nature. They describe a model delivery system that responds to mechanical signaling by upregulating the release of vascular endothelial growth factor (VEGF), a substance that promotes blood vessel formation.

As Mooney explained, "In the context of tissue engineering . . . it is potentially of great interest to allow the tissue to modulate the host response."

The researchers therefore loaded a type of polymeric matrix called an alginate hydrogel with VEGF. These hydrogels are widely used for drug delivery, cell transplantation, wound dressing, dental impressions and other applications. The inspiration for polymeric matrices was the natural extracellular matrices of tissues that appear to serve as depots for a variety of growth factors. When released from extracellular matrices, these factors induce changes in many different cellular processes in nearby tissues.

The artificial matrices, the hydrogels, can be repeatedly deformed after being compressed. That means they can be "squeezed" repeatedly. After demonstrating the ability of these gels to repeatedly release growth factor with mechanical compression in vitro, the scientists applied the approach to living animals. They implanted hydrogels loaded with VEGF under the skin in severe combined immunodeficient mice. Hydrogels without VEGF served as controls. While hydrogels alone produced no signs of increased vascularization near the implant even with mechanical stimulation, hydrogel implants containing VEGF did. Most significantly, VEGF-loaded hydrogels that were subjected to cyclic mechanical stimulation "showed a statistically significant increase in granulation layer thickness and in vascularization, as compared with non-stimulated VEGF-releasing gels."

The experimenters next turned to non-obese diabetic mice, which are often used to study wound healing. In this case, cyclic mechanical stimulation significantly increased, compared to controls, blood vessel formation near the femoral arteries that the scientists had tied off.

"One of the key things necessary for this approach," Mooney said, "is that you have to have a depot for the drug within the [drug delivery] device. If all the drug is freely soluble, you are going to drive most of it out in the first mechanical perturbations. In this particular case, we focused on a growth factor that would have a reversible interaction with the material.

"A small fraction [of the drug] would be floating around in soluble form," he continued. "That could be driven out quickly. But what allows the system to keep responding to multiple signals is the fact that you then get a re-equilibration of some of the growth factor that is bound to the matrix. When the concentration of the soluble growth factor goes down because it has been driven out, some of the drug will come off the matrix to replenish the soluble pool, which is the pool you are basically driving out and using to modulate the delivery."

Controlling Release Of Factors A Possibility

The authors said their findings may suggest a new way to manipulate drug delivery.

They propose - although they did not investigate it in this paper - that their approach potentially could be useful for controlling the release of different factors in the body. This would involve a sensor connected to a feedback system that would monitor drug concentration and produce a mechanical signal to the implanted device that would release the drug when needed.

The University of Michigan researchers do quite a bit of work in cell transplantation. They are interested in cartilage and bone tissue engineering. Naturally, they are now looking at ways of combining this concept with some of their cell transplantation models so they can perhaps promote, in a controllable and responsive way, blood vessel formation as they grow bone tissue in the body.

"We are also beginning to investigate this [procedure] purely from the drug delivery perspective," Mooney reported. "And we are trying to see if this concept can really explain how tissues interact and signal each other."

While Mooney has some interactions with biotech companies, he said this project is not tied to any specific company. The work was supported by funds provided by the National Institutes of Health in Bethesda, Md., and The Whitaker Foundation in Rosslyn, Va.