ANN ARBOR---Using engineered skin and gingiva (gum tissue) cells, researchers at the University of Michigan School of Dentistry have produced complete bones with the same hard outer coating, spongy interior and marrow core as naturally produced bone. The researchers used the method to replace large areas of missing bone in living rats, raising the prospect of simpler, less painful bone grafts in human patients.
The experiments, published in the May 20 issue of Human Gene Therapy, also had a surprising result: the engineered cells not only delivered the bone-forming proteins they were designed to secrete, but they also participated directly in bone formation.
Current bone grafting methods involve harvesting a patient's bone marrow with a long needle or surgically removing a piece of bone, typically from the hip. With the new method, which is still in developmental stages, a tiny bit of skin or gum tissue is removed, cut into even smaller pieces, and placed in a culture dish. The cultured cells are then engineered to secrete BMP-7, a protein that induces bone formation. The engineered cells are seeded onto collagen sponges, which are placed in the area where bone repair is needed.
The research team---which included Bruce Rutherford, professor; Paul Krebsbach, assistant professor; Keni Gu, research investigator; and Renny Franceschi, associate professor---tested the system on rats that had large sections of bone missing from their skulls. New bone was produced from the rats' own skin cells, and the skulls were almost fully healed within just four weeks, "which was startling to me," says Rutherford.
The new bone looks just like naturally produced bone, and the researchers plan more experiments to find out whether it functions like natural bone. They also are experimenting with using a hydrogel---a material that changes from liquid to gel under certain conditions---instead of the collagen sponges. The particular hydrogel they use acts like "reverse Jell-O," remaining liquid when cool and firming up when warm, says Rutherford. Injected as liquid into a lesion of any size or shape, the material gels as it warms to body temperature, holding the engineered cells in the appropriate place.
In another set of experiments reported in the paper, the researchers implanted engineered human gingival cells into a strain of mouse that has no immune system and therefore does not reject foreign tissue. To their surprise, the new bone that formed in the mice was composed of both mouse and human tissue. "This suggests that the gingival cells were not just delivering BMP-7, but also responding to the protein and making bone themselves," says Rutherford.
Using a patient's own cells from easily accessed tissues that heal quickly is a major step toward an alternative to conventional bone grafts, Rutherford says. "If the implanted cells form bone directly, in addition to secreting BMP-7, these autografts would be useful in regenerating bone in the many cases where few cells capable of forming new bone remain in the injured bone. Such lesions are difficult to treat by conventional treatment."
The research was funded by the National Institute of Dental and Craniofacial Research.
The U-M School of Dentistry is one of the nation's leading dental schools engaged in oral health care education, research, patient care and community service. General dental care clinics and specialty clinics providing advanced treatment enable the School to offer dental services and programs to patients throughout Michigan. Classroom and clinic instruction train future dentists, dental specialists and dental hygienists for practice in private offices, hospitals, academia and public agencies. Research seeks to discover and apply new knowledge that can help patients worldwide. More information is available on the Web at http://www.dent.umich.edu.
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Journal
Human Gene Therapy