Photo by Daniel Dubois
Prasad Shastri inspecting newly grown bone under the microscope.

New method proves it's possible to grow bone for grafts within a patient's body

By David F. Salisbury
Published: July 29, 2005

An international team of biomedical engineers has demonstrated for the first time that it is possible to grow healthy new bone reliably in one part of the body and use it to repair damaged bone at a different location.

The research, which is based on a dramatic departure from the current practice in tissue engineering, is described in a paper titled "In vivo engineering of organs: The bone bioreactor" published online this week by the Proceedings of the National Academy of Sciences.

"We have shown that we can grow predictable volumes of bone on demand," says V. Prasad Shastri, assistant professor of biomedical engineering at Vanderbilt University who led the effort. "And we did so by persuading the body to do what it already knows how to do."

Courtesy of Robert Langer  
Robert Langer is one of the pioneers of the field of tissue engineering.

"This research has important implications not only for engineering bone, but for engineering tissues of any kind," adds co-author Robert S. Langer, Institute Professor at the Massachusetts Institute of Technology and a pioneer in the field of tissue engineering. "It has the potential for changing the way that tissue engineering is done in the future."

The approach currently used by orthopedic surgeons to repair serious bone breaks is to remove small pieces of bone from a patient's rib or hip and fuse them to the broken bone. They use the same method to fuse spinal vertebrae to treat serious spinal injuries and back pain. Although this works well at the repair site, the removal operation is extremely painful and can produce serious complications. If the new method is confirmed in clinical studies, it will be possible to grow new bone for all types of repairs instead of removing it from existing bones. For people with serious bone disease, it may even be possible to grow replacement bone at an early stage and freeze it so it can be used when it is needed, says Prasad.

Courtesy of Molly Stevens and Prasad Shastri
Formation of new bone over a four week period

Despite the fact that living bone is continually growing and reshaping, the numerous attempts to coax bone growth outside of the body— in vitro —have all failed. Recent attempts to stimulate bone growth within the body— in vivo —have had limited success but have proven to be extremely complex, expensive and unreliable.

Shastri and his colleagues took a new approach that has proven much simpler. They decided to take advantage of the body's natural wound-healing response and create a special zone on the surface of a healthy bone in hopes that the body would respond by filling the space with new bone. The approach lived up to their highest expectations. Working with mature rabbits, a species with bones that are very similar to those of humans, the researchers were delighted to find that this zone, which they have dubbed the "in vivo bioreactor," filled in with healthy bone in about six weeks. And it did so without having to coax the bone to grow by applying the growth factors required by previous in vivo efforts. Furthermore, they found that the new bone can be detached easily before it fuses with the old bone, leaving the old bone scarred but intact.

Photo by Molly Stevens
Molly Stevens, now on the faculty at Imperial College in the UK, performed most of the research on the in vivo bioreactor as a post-doctoral fellow at MIT

"The new bone actually has comparable strength and mechanical properties to native bone," says Molly Stevens, currently a reader at Imperial College in the United Kingdom who did most of the research as a post-doctoral fellow at MIT, "and since the harvested bone is fresh it integrates really well at a recipient site."

Long bones in the body are covered by a thin outer layer called the periosteum. The layer is a little like scotch tape: the outside is tough and fibrous but the inside is covered with a layer of special pluripotent cells which, like marrow cells, are capable of transforming into the different types of skeletal tissue. So Shastri and his collaborators decided to create the bioreactor space just under this outer layer.

They created the space by making a tiny hole in the periosteum and injecting saline water underneath. This loosened the layer from the underlying bone and inflated it slightly. When they had created a cavity the size and shape that they wanted, the researchers removed the water and replaced it with a gel that is commercially available and approved by the FDA for delivery of cells within the human body. They chose the material because it contained calcium, a known trigger for bone growth. Their major concern was that the bioreactor would fill with scar tissue instead of bone, but that didn't happen. Instead, it filled with new bone indistinguishable from the original.

Courtesy of Molly Stevens and Prasad Shastri
The two radiographs on the left show the left and right tibias of the same animal. The bioreactor was created on the tibia on the right and the new bone shows up as a bulge in the area inside of the rectangle. The three images on the left show how newly grown bone can be used to repair normal bones. The radiograph at the top shows a normal bone. The second image shows the same bone after the researchers have created a small defect. The third image shows the area around the defect six weeks after surgery has been performed to patch the defect with new bone.

The scientists intend to proceed with the large animal studies and clinical trials necessary to determine if the procedure will work in humans and, if it does, to get it approved for human treatment. At the same time, they hope to test the approach with the liver and pancreas, which have outer layers similar to the periosteum.

Other contributors to the study include the late Dirk Schaefer, who was an orthopedic surgeon at Kantonsspital-Basel in Switzerland; Robert P. Marini, chief of clinical surgical facilities of MIT's division of comparative medicine; and Joshua Aronson, an undergraduate student at MIT.

The research was funded by a grant from Smith and Nephew, Endoscopy.

V. Prasad Shastri's home page

Vanderbilt Center for Matrix Biology

Robert S. Langer's home page

Langer Lab website

Molly Stevens home page

 


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