In a development that one day may revolutionize spinal and knee-replacement surgery and the treatment of osteoporosis, researchers at Vanderbilt University in Nashville, Tennessee, have demonstrated for the first time that healthy new bone can be grown in one part of the body to repair bony defects at another location.

This grow-your-own-bone, or in vivo bioreactor, technique was tested successfully to treat bone defects in a rabbit model, according to a new study published in the Proceedings of the National Academy of Sciences.¹

"This is the first demonstration of engineering any tissue on demand within the human body," says lead researcher V. Prasad Shastri, PhD, assistant professor of biomedical engineering at Vanderbilt University and lead author of the study. "We can control how much we grow and grow large volumes of fully functional human bone that is identical to natural bone," he tells CIAOMed. "As this technology develops further, we will develop simple tools for the surgeon to use."

The new technology involves creating an in vivo bioreactor space between the membrane that covers the long bone and bone itself. Dr. Shastri and his colleagues created the space by making a tiny hole in the periosteum and injecting saline water to loosen and inflate the layer from the underlying bone. Next, they remove the water and replace it with a gel that is approved by the US Food and Drug Administration (FDA) for transplantation of cartilage cells. The gel, called calcium-alginate, contains calcium, which is important for forming cells to create bone.

"This engineered bone can then be used as a natural bone bridge to treat fractures," he says. "The required cells and the growth factors are all found in the bioreactor space naturally. All the ingredients necessary for bone formation are right there; we just create space and inject material."

Dr. Shastri maintains that the new bone is very similar to native bone and can be used elsewhere in the body.

The potential for bone banking?

"There are several applications for the new technology," he says. It may possible to grow new bone for all types of repairs, including spinal fusion and high tibia fractures that are close to the joint and difficult to treat. "In people who have problems where bone quality changes with age, such as osteoporosis, we [may be able to] bank healthy bone to replace old bone," Dr. Shastri says.

But, he says, it's not just conducive to bone growth. "We can also grow cartilage and the cartilage we get is very identical to cartilage on the articular surface of knee." When cartilage cells are put in the in vivo bioreactor, "we snuff out air and make an environment depleted of oxygen by cutting off the blood supply," he says. After the growth begins, "the doctor can follow what happens in the space with micro-computed tomography (Micro-CT) or CT and say, ‘When do I want to get this out?'"

According to Dr. Shastri and colleagues, the new bone can be detached easily before it fuses with the old bone, leaving the old bone scarred but intact.

"For spinal fusion, we don't need the bone to be very mature. This provides a tremendous level of control for the clinician," he says.

"This research has important implications not only for engineering bone, but for engineering tissues of any kind," says study co-author Robert S. Langer, ScD, professor at the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts. "It has the potential for changing the way that tissue engineering is done in the future."

 

Researchers anticipate few, if any, FDA hurdles

Given that the new technique involves autologous tissue and that the gel is already approved by the FDA, Dr. Shastri maintains that he expects few regulatory hurdles for the approval of the technique. "We are working with materials that are not perceived by the FDA as problem," he says.

The new findings are based on studies in rabbits with mature skeletons. "The effects are real and should nicely correlate with what people see in humans," Dr. Shastri says. "The next step is larger animal studies to determine if the procedure will work in humans and, if it does, to get it approved for evaluation in humans."

That may occur in the near future. "Since the chips seem to be in place, if everything goes as planned in about 1.5 years, we will have preliminary data to allow clinicians to explore more readily," Dr. Shastri says.

Less invasive than the gold standard for grafts: harvesting from the iliac crest

While autologous bone harvesting from the iliac crest remains the gold standard for grafts, this new bone engineering procedure will enable surgeons to grow bone for grafts within a patient's body. As a result, it is less invasive and associated with significantly less postoperative pain. "Isolation of bone from the iliac crest is extremely painful and very invasive," Shastri says. "A recent study found that 4 or 6 years after spinal fusion, over 30% of patients complained of pain in the donor site, but not the recipient site."

Dr. Shasti maintains that it is difficult to harvest autologous bone in abundance, but the new technology allows surgeons to grow as much as 15 ml on demand.

Bioreactor versus bone morphogenetic proteins

Much attention has been focused on the potential of bone morphogenetic proteins (BMPs) and delivery of these molecules using collagen and ceramic scaffolds. "They help bones form but are not bone; some [patients] cannot bear weight right away," Dr. Shastri says. "While we wait for bone to form [with the new technology], we know what we are working with and can amass large volumes."

"Many orthopaedic surgeons are still not comfortable with BMPs because they don't know what the outcome will be," he says. Several BMPs are being studied for orthopaedic applications, including human BMP-2, which can be administered laparoscopically, and which is currently approved as a bone graft replacement for anterior lumbar spinal fusions. BMP-7 and BMP-14 are being investigated for similar indications.

Molly Stevens, PhD, a reader at Imperial College, London, UK, who conducted most of the research as a post-doctoral fellow at MIT, adds that "the new bone actually has comparable strength and mechanical properties to native bone, and since the harvested bone is fresh, it integrates really well at a recipient site."

Reference

Stevens MM, Marini RP, Schaefer D, et al. In vivo engineering of organs: The bone bioreactor. Proc Natl Acad Sci. 2005; scheduled to appear online before print. Will be available at: http://www.pnas.org/.