Scientists Report Early Progress in Tissue Engineering Mandibular Condyle

Researchers have long dreamed of engineering new knees, hips and other body joints in the laboratory from a person's own bone and cartilage producing adult stem cells. The challenge has been to figure out how to manipulate these cells and get them to form tissues that precisely mirror the natural three-dimensional structure and mechanical strength of our normal, healthy joints.

Now, in an important first step toward realizing this dream, scientists report in this month's issue of the Journal of Dental Research that they have created a mandibular condyle from rat adult stem cells that is the precise three-dimensional shape of the human joint. A mandibular condyle is the knobbed ending of the lower jaw; it joins the lower jaw to the temporal bone of the skull on both sides of the head at the temporomandibular joint, or TMJ.

Stressing that their findings are preliminary and significant scientific challenges lie ahead, the researchers said the results are hopeful because they produced their structure from a single population of stem cells and prompted them to form two distinct layers of bone and cartilage, a characteristic feature of a condyle and a first in the field of tissue engineering. According to Jeremy Mao, D.D.S, Ph.D., a scientist at the University of Illinois at Chicago and an author on the study, this work is instructive in learning to engineer not only mandibular condyles but those of other joints throughout the body.

"The TMJ is a synovial, or free-moving, joint," said Mao, whose work is supported by NIH's National Institute of Dental and Craniofacial Research (NIDCR). "So are the knee, hip, and shoulder joints, all of which include rounded, moveable condyles. We certainly hope our results will be applicable to other synovial joints."

Coined in 1987, the term "tissue engineering" combines principles from engineering and the life sciences in a bold attempt to use the body's own biological materials to repair, regenerate, and ultimately replace damaged organs and tissues, including bone and cartilage. If successful, tissue engineering would eliminate the need for bone grafts and avoid problems associated with artificial replacement joints, such as donor site defects, immunorejection, abnormal wear and tear, and transmission of pathogens.

As tissue engineers have studied the hips, knees, and other joints, most of their work to date has focused on the initial step of repairing a small area of damaged tissue. According to Mao, while studies in this area have tremendous therapeutic potential, he and his colleagues realized that these strategies might be somewhat limited in people with severe arthritis. "People with very severe osteoarthritis or rheumatoid arthritis often have large condyle defects, so the entire condyle needs to be replaced," said Mao.

About two years ago, Mao and his team of clinicians, dentists, surgeons, cell biologists, and materials scientists decided to take the next step and engineer a mandibular condyle. "Why the mandibular condyle?" answered Adel Alhadlaq, D.D.S., M.S., a coauthor on the paper and also a scientist at the University of Illinois at Chicago. "We began our research using mice that were no larger than a human hand, and, obviously, it wasn't possible to engineer a large human tibia or femur that way. Because the mandibular condyle is smaller and could be transplanted into a mouse, it was just a practical structure to try and engineer."

At the same time, Mao said his research team has had a long-standing research interest in temporomandibular joint disorders. These sometimes painful conditions affect an estimated 90 million Americans, and, for those with severe damage to the joint itself, a tissue-engineered mandibular condyle one day could have tremendous clinical benefits.

As reported this month in the Journal of Dental Research, Mao's group succeeded in their efforts. The group isolated adult mesenchymal stem cells from rat bone marrow, then treated them in the laboratory to differentiate into either bone or cartilage producing cells called osteoblasts and chondrocytes. Each adult mesenchymal stem cell can produce thousands of individual osteoblasts or chondrocytes.

Thereafter, the group seeded the differentiated cells into a hydrogel polymer solution, and placed their creation into a polyurethane mold made from a human mandibular condyle. The scientists then implanted three small molded structures just below the skin of severe combined immunodeficient (SCID) mice. Each implant now was encapsulated in a hydrogel coat that was subdivided into layers seeded either with osteoblasts or chondrocytes, an attempt to engineer distinct layers of bone and cartilage.

Eight weeks later, Mao and colleagues harvested the three tissue-engineered condyles from the mice. They found the implants had formed on their own into "firm" structures that retained the precise shape and three-dimensional structure of the molded human mandibular condyle.

Importantly, within the layer of the implants seeded with osteoblasts, the scientists detected mineral deposits in island structures, a sign that the osteoblasts had followed their biological program and produced bone. In the other layer, they identified "sparse chondrocyte-like cells within abundant extracelluar matrix" that expressed certain proteins characteristic of cartilage.

In future work, Mao said he and his team will attempt to enhance the biological and mechanical properties of the tissue-engineered condyles. However, Mao stresses that these results are just the start of a much steeper scientific challenge. "It is no small task by any measure to recapitulate what nature does perfectly during development," he said. "Although we understand many of these cues during natural development, we need to learn how to utilize them to tissue engineer mandibular condyles."

"But we have designed several approaches to solving the problems, and enhancing the tissue-forming capacity of engineered mandibular condyles. This will be the central focus of our NIDCR grant over the next few years," added Mao.

The NIDCR, part of the National Institutes of Health, is the federal government's lead agency in the conduct and support of dental research. For more information about NIDCR, please visit http://www.nidcr.nih.gov or call (301) 496-4261.