An experimental growth-factor method developed by University of Wisconsin-Madison biomedical engineer William Murphy for securing implants to bones produced strong, healthy bone as it healed around a metal implant in an animal model (right). The implant on left was performed with conventional surgery techniques and produced less bone and more scar tissue (white areas). Implants are the large black areas.
When William Murphy works
with some of the most powerful tools in biology, he thinks about making
tools that can fit together. These constructions sound a bit like
socket wrenches, which can be assembled to turn a half-inch nut in tight
quarters, or to loosen a rusted-tight one-inch bolt using a very
tools used by Murphy, an associate professor of biomedical engineering
and orthopedics and rehabilitation at University of Wisconsin-Madison,
however, are proteins, which are vastly more flexible than socket
wrenches—and roughly 100 million times smaller. One end of his modular
tool may connect to bone, while the other end may stimulate the growth
of bone, blood vessels or cartilage.
Feb. 4th and 6th, at the Orthopedic Research Society meeting in San
Francisco, Darilis Suarez-Gonzalez and Jae Sung Lee of the Murphy lab
are reporting that orthopedic implants “dip-coated” with modular growth
factors can stimulate bone and blood vessel growth in sheep.
many years, medical scientists have been fascinated by growth
factors—proteins that can stimulate tissues to grow. But these factors
can be too effective or not specific enough, leading to cancer rather
than the controlled growth needed for healing.
wants to start applying the manifold benefits of the modular approach
to healing or regenerating bone, tendon, and ligaments, and in
particular to replacement surgery after an artificial joint has loosened
or failed. Temporarily stimulating bones to grow by placing growth
factors near the new implant could shorten healing time and ensure a
good, tight fit.
approach could also be used for reattaching ligaments to bone after
sports injuries and healing large bone defects during spinal fusion,
facial reconstruction or trauma. In this work, Murphy collaborates with
two associate professors of orthopedics and rehabilitation at the School
of Medicine and Public Health.
Graf focuses on knee injuries in sports medicine,” he says, “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.”
The working end of the modular structure may feature a fragment of a growth factor, but not the entire protein.
you just want the specific regions that activate the signaling
pathways, because that can reduce the chances of stimulating unwanted
growth, even cancer,” he says.
the other end, Murphy may place an anchoring molecule that binds to the
bone and prevents the modular structure from migrating away from the
the modular approach, he says, “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.”
tests, performed in collaboration with Mark Markel, a professor of
veterinary medicine, have shown that the bone is denser around the
implant, and that the union between the implant and the bone is stronger
than produced by state-of-the-art orthopedic techniques. The added
growth factors have not been detected elsewhere in the animal, Murphy
each section of the molecule separately allows their properties to be
tailored as needed. “We can take similar protein structures and modulate
them,” Murphy says. “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.”
from the lab to the clinic is a major step, and Murphy knows that many
hurdles remain. “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.”
says his approach is inspired by biology without trying to exactly
duplicate normal communication between cells and tissues. “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.”