Gintuit will be used in dental care to correct gum pockets. Credit: Organogenesis

On March 12, the US Food and Drug Administration (FDA) approved a cell-based treatment for gum recession developed by Canton, Massachusetts–based Organogenesis. Dubbed Gintuit, the cell therapy was the FDA's first approval for regenerative medicine in dental care. Importantly, the FDA's Center for Biologics, Evaluation and Research (CBER) evaluation of the neonatal foreskin–derived fibroblast/keratinocyte therapy, delivered in a biodegradable scaffold under a Biologic License Application (BLA), provides important pointers for how the agency plans to evaluate other regenerative therapies and signals a shift from oversight by the Center for Devices and Radiological Health (CDRH). In 1998, a similar cell and scaffold therapy developed by the same company, Apligraft, was evaluated and approved by CDRH under a class III premarketing approval. “This was a practice run for what CBER will ask of other regenerative treatments coming down the line,” says Evan Snyder, chair of the FDA's Cellular, Tissue and Gene Therapies Advisory Committee, which deliberated over Organogenesis' Gintuit application.

Treatments for gum recession are unpleasant. Dentists typically patch receding gums with tissues sliced surgically off the palate—a painful procedure, called free gingival graft, that induces bleeding and other complications, often without cosmetically pleasing results. Gintuit is a new option, a regenerative treatment.

Gintuit has an identical sister product already on the market: Apligraf, approved in 1998 for wound healing by the FDA's Center for Devices and Radiological Health. The shift from devices to biologics reflects evolving regulatory processes on regenerative medicine, according to William Plavonic, managing director, equity research, medical devices at Canaccord Genuity, in Chicago. “As the science advances, so does the regulatory side,” he says.

Organogenesis makes Apligraf and Gintuit using the same process. Human foreskin from newly circumcised babies is collected and undergoes enzyme digestion. The resulting cells are separated by centrifugation into keratinocytes and fibroblasts, which are cultured, expanded and stored separately in master cell banks for future use. In the final product, the two cell types form a bilayer resting on a porous, polycarbonate membrane. Keratinocytes add structural strength to the product, whereas fibroblasts, in a matrix of bovine collagen, presumably secrete cytokines and growth factors involved in wound healing. Remarkably, approximately 450,000 individual treatments—virtually all of them Apligraf—have been produced from just 12 foreskin samples.

We're delivering millions of neonatal, prolific cells, and they all express varying levels of growth factors over time.

Organogenesis produces Apligraf in a size appropriate for treating skin wounds in venous leg and diabetic foot ulcers. Gintuit, on the other hand, comes as a much smaller construct— just 75 by 0.75 millimeters—for dentists to implant surgically at the base of the gum recession. Clinical testing results show that Gintuit regenerates 2 millimeters of gum tissue within six months, but precisely how isn't clear. “Fundamentally, this is 'systems biology',” says Geoff MacKay, Organogenesis' president and CEO. “We're delivering millions of neonatal, prolific cells, and they all express varying levels of growth factors over time.”

Larry Couture, the CDER advisory committee's outgoing chair, and a senior vice president in the Center for Applied Technology Development at the Beckman Research Institute, in Duarte, California, says Gintuit's mechanism of action ultimately isn't a big issue. “At the end of the day, patients do better, and that's what's important,” he says.

The clinical data required for Gentuit's BLA were similar to what was required for Apligraf's premarketing approval. Unlike Apligraf's medical device evaluation, however, CBER required more information in preclinical dossier and on the chemistry, manufacturing and controls. It also subjected Gintuit to potency evaluations designed to ensure that the cells are viable before they're released for clinical use. Organogenesis chose a histology assay as an endpoint to demonstrate a link between keratinocyte growth and development with fluctuating levels of vascular endothelial growth factor (VEGF). The assay shows that keratinocyte development fails when VEGF levels fall, and vice versa, but Snyder says this doesn't prove cause and effect. “You'd have to block VEGF and then look for effects on histology to be sure,” says Snyder, who is also a professor of stem cell and regenerative biology at the Sanford-Burnham Medical Research Institute, in La Jolla, California. CBER accepted the assay, Snyder says, on practical grounds—oral uses are easy to monitor, long-term history with Apligraf doesn't reveal safety problems, and moreover, Gintuit fulfills a real medical need as a less painful option for gum recession therapy.

“CBER broke the ice with this approval,” says Snyder. “The committee asked hard questions, but it was more flexible with the answers than it will be for new regenerative therapies heading for use in the brain, the heart or the spinal column.”