When William Murphy, an associate professor of biomedical engineering and orthopedics and rehabilitation at University of Wisconsin-Madison works with some of the most powerful tools in biology, his approach is to develop tools that fit together. The structures are similar to socket wrenches that are put together to turn a three-quarter-inch nut in a confined space, or to loosen a one-inch bolt with a very persuasive lever that has rusted tightly.

Murphy’s tools however are not socket wrenches but proteins, which are much more flexible than socket wrenches and also about 100 million times smaller and whilst one end of his modular tool may connect to bone, the other end may stimulate growth of bone, cartilage or blood vessels.

Darilis Suarez-Gonzalez and Jae Sung Lee of the Murphy lab will present their findings at the Orthopedic Research Society meeting in San Francisco, which show that orthopedic implants “dip-coated” with modular growth factors can stimulate bone and blood vessel growth in sheep.

For years, medical scientists have been intrigued by growth factors, i.e. proteins that can stimulate tissue growth, however, these factors can either be too effective or not sufficiently specific, and therefore result in cancer instead of controlled growth needed for healing.

Murphy wants to use the unique benefits of this modular approach to heal or regenerate bone, tendon, and ligaments, and especially in replacement surgery after an artificial joint has loosened or failed. By placing growth factors near a new implant through temporary stimulation of the bone physicians can potentially achieve shorter healing times and a good tight fight.

Another option could be to reattach ligaments to bone following sports injuries and healing large bone defects during spinal fusion, facial reconstruction or trauma. Murphy works in collaboration with two associate professors of orthopedics and rehabilitation at the School of Medicine and Public Health and says:

“Ben Graf focuses on knee injuries in sports medicine and David Goodspeed, a lieutenant colonel in the Army who has seen blast injuries during multiple tours in Iraq, is working on the kind of major traumatic wound we think is potentially treatable using this approach.”

Murphy says that the functioning end of the modular structure may feature a fragment of a growth factor, however not the entire protein. He continues:

“Often, you just want the specific regions that activate the signaling pathways, because that can reduce the chances of stimulating unwanted growth, even cancer.”

At the opposite end, Murphy may place an anchoring molecule, which binds to the bone and prevents the modular structure from migrating away from the wound.

He explains the modular approach, saying, that, “you might be able to stimulate bone formation without the side effects. We are trying to decrease stimulation outside of the bone defect, trying to design these molecules to specifically generate new bone in a defect, and to stay there.”

Murphy conducted animal tests together with Mark Markel, a professor of veterinary medicine, which demonstrated that the bone is denser around the implant, and that the amalgamation between implant and bone is more durable than the latest modern produced orthopedic techniques. Furthermore, the added growth factors have not been detected elsewhere in the animal.

Engineering each section of the molecule individually allows that their properties can be tailored as required. Murphy says:

“We can take similar protein structures and modulate them. If we want a molecule that binds very strongly to the surface of a bone graft, we can do that. If we want one that releases over controllable time-frames, we can do that as well.”

Murphy is aware that many obstacles need to be overcome when taking a key step in moving from the lab to the clinic and says:

“We have shown that this can work in a large, clinically relevant animal model, but realistically, I don’t see this being used in the clinic within the next five years.”

Murphy’s approach is inspired by biology. He does not try to precisely copy normal communication between cells and tissues, stating:

“We are not interested in specifically mimicking a particular structure or function, but nature uses a variety of fundamental mechanisms during development and regeneration, and we are taking lessons from them and designing synthetic systems to achieve similar outcomes. We are not repeating nature, but we are inspired by nature.”

Written by Grace Rattue