Status: approved; marketed

Organizations involved:

Straumann USA – USA mark.

Staumann AG – Manuf.; R&D; Tech.; Intl. mark.; Parent

Biora AB – Former

Karolinska Institute – R&D; Tech.

Biodenix Technologies Inc. – Canada mark.

UEDA Espanola S.A – Europe mark.

Seikagaku Corp. – Japan mark.

Yoshida Dental Trade Dist. Co. – Japan mark.

MediMix S.A. – Latin Amer. mark.

Description: Enamel Matrix Derivative or Emdogain is a sterile lyophilized (freeze-dried) formulation of porcine (pig) teeth-derived enamel matrix (amelogenin; lower molecular weight fraction) proteins for topical application to the roots of loose teeth to facilitate their reattachment. The porcine amelogenin proteins are extracted from the preemergent teeth of young slaughtered pigs. Emdogain contains various porcine proteins that self-assemble into a resorbable and implantable hydrophobic matrix and act as growth factors for reattachment of teeth in persons with severe periodontitis (gum disease).

The proteins of teeth enamel matrix (hard outer covering) of humans and other animal species are composed of a high molecular weight part (enamelin) fraction and a low molecular weight part (amelogenin) fraction, the active constituent. This low molecular weight component of enamel matrix proteins consists of acetic acid extractable proteins generally referred to as amelogenins. Amelogenins have a molecular weight of up to about 40,000 (40 kDa), but mainly a molecular weight within the range of about 5,000 to about 25,000 (5-265 kDa).

The enamel matrix protein (amelogenin) in Emdogain facilitates development of all necessary tissues for true functional tooth reattachment in patients with moderate to advanced periodontitis. Prior to use, the porcine proteins are dissolved in a high viscosity solution of Propylene Glycol Alginate to facilitate application to the exposed tooth root surfaces during periodontal flap surgery (gum is cut to expose the tooth root). The porcine enamel proteins adsorb to hydroxyapatite (the major mineral component of teeth), collagen and exposed dental roots. The adsorbed amelogenin forms matrix which essentially mimics physiologic processes that take place during the formation of the developing tooth root and surrounding periodontal tissues. Emdogain proteins are resorbed naturally during the normal healing process, leaving only a residue of enamel matrix proteins on the debrided root surface. This natural and insoluble surface layer encourages repopulation of cementum-forming cells from the surrounding tissues. The newly created surface also functions as an interface between the tooth and the surrounding tissues, preventing downgrowth of epithelial tissues.

Emdogain is manufactured from teeth extracted from slaughtered pigs. Slaughtering is often performed at an age of about one-half year (while the teeth still are under development). The lower jaw is cut out, frozen, and the teeth are removed. The porcine matrix proteins are prepared by steps including acid extraction, filtration, and lyophilization. The manufacturing process with its harsh acidic conditions and lack of presence of cellular material substantially reduces (eliminates) the risk for porcine virus contamination. There have been no reports of viral contamination with Emdogain.

Emdogain (amelogenin fraction) is packaged as a kit with two vials intended for use on one patient only – an Enamel Proteins (amelogenin fraction) vial containing either 30 mg (original packaging) or 10 mg of protein (more recently introduced) powder, along with a vial containing Propylene Glycol Alginate (vehicle solution) and application needles. Mixing of the Enamel Proteins vial (30 mg) with the supplied Propylene Glycol Alginate vial contents results in a viscous, syringeable gel, enough for treatment of three teeth, while mixing of the 10 mg vial with the supplied Propylene Glycol Alginate vial is enough for one tooth. When mixed, a viscous, easy to use, syringeable gel is formed that is applied quickly and easily during normal periodontal flap surgery.

Emdogain has also been developed as a premixed gel filled in a syringe delivery system, which is easy to use and saves time for the dentist. Emdogain Gel is distributed in Europe and in the U.S. A new version of the gel, EmdogainGel TS, provides treatment for wider intrabony defects where additional tissue support is desired and is only approved in Europe.

Nomenclature: Tooth Enamel Proteins [BIO]; Emdogain [TR]; Enamel Matrix Derivative [FDA]; EMD [SY]; tooth enamel proteins, porcine [SY]

Biological.: Amelogenin proteins are growth factors associated with the early stages of tooth enamel (hard outer surface) formation and in the development of acellular cementum and its associated tooth attachment structure. Amelogenin constitutes about 90% of the enamel matrix protein of human teeth. Amelogenin is a family of structurally related proteins which together form supra-molecular hydrophobic aggregates (matrix) which appear to stabilize newly formed tooth enamel crystals. Enamel matrix proteins, including amelogenin, are practically insoluble at physiologic pH and temperature (one reason why teeth don’t dissolve in the mouth). The structure of amelogenin is conserved and functionally consistent among many animal species. Amelogenin proteins have been found in very early animals (back to 100 million years before the dinosaurs). The porcine amelogenin proteins in Emdogain are recognized as “self” by the human immune system, i.e., they are not rejected.

Normal mammalian teeth are anchored in special cavities, alveoli, in the jaw bone. The periodontal membrane lies between the roots of the teeth and the jaw bone. This membrane has a thickness of about 0.2 mm and consists of collagen fibers and vessels and nerves. The roots of the teeth, primarily composed of dentin, are covered by a thin (0.01 to 1 mm) layer of cementum. Collagen fibers extend from the cementum through the periodontal membrane and are anchored in the jaw bone. The cementum is extremely important for the attachment of teeth to the jaw bone. In the part of the root which is not covered by jaw bone fibers, root cementum extends out into the surrounding tooth gum, the gingiva. These fibers assist in anchoring the tooth and stabilize the gums. The tooth gum, as well as the whole oral cavity, is covered by a thin layer of epithelium. This epithelium forms a dense collar or sleeve around the teeth. Natural tooth attachment requires root cementum; fiber bundles connecting the root cementum and jaw bone; and the jaw bone. Each of these starts to regrow after application of Emdogain, with the porcine growth factor matrix mimicking human growth factors involved in tooth reattachment.

Periodontitis or loosening of the teeth, is a common disease affecting about 10% of the world’s population. It is caused by bacterial growth between the teeth and gums. Bacteria may collect and form plaque or uneven hard surfaces on the teeth, if not removed by regular brushing or other cleaning and flossing. The gums become red, swollen, sensitive, and prone to bleeding. If left unchecked, periodontitis leads to inflammation that can destroy the fibers that anchor teeth to the jaw bone, and eventual tooth loss. In patients with periodontitis, bacteria on the surface of the teeth cause chronic inflammation in the tooth gum around the teeth. Inflammatory cells excrete enzymes intended to kill the bacteria, but these also attack the collagen fibres attaching the tooth to gingiva and jaw bone. The cells on the surface of the tooth root or cementum become subject to destruction, and epithelium from the oral mucous membrane grows downwardly along the teeth and produces a “gingival crevice” or sac. In this crevice, new bacteria encounter find growth conditions and new inflammatory cells invade this area, accelerating the decomposition of the tissues of the periodontal membrane. The cementum cells die and the bone of the alveolar area is destroyed. After some time, the teeth may completely lose their attachment to the jaw bone.

Experimental studies in a marginal dehiscence model in primates show that Emdogain creates a suitable surface for the colonization of cementum-forming cells. The proteins only exert effects locally at the sites of application. Two weeks after application, 75% of the dentin surface is covered with cementum-forming cells. After cementum formation, the periodontal ligament and alveolar bone are established. Bone formation occurs along the treated root surface and, in time, defects fill with new alveolar bone. Reformation of tooth attachment (cementum) and jawbone starts immediately after application and continues for an extended time, over one year in some cases.

The safety and efficacy of Emdogain has been demonstrated. A thorough toxicology program, including acute and chronic studies, in vitro mutagenicity studies, reproductive toxicology tests, and several additional toxicology studies have been carried out. The potential for sensitization and other immunological reactions in humans were also examined. No immunological or allergic reactions were found.

Companies.: Emdogain was initially developed by the Department of Oral Pathology, Karolinska Institute (Stockholm, Sweden). It was commercially developed and manufactured by Biora AB (Malmo, Sweden), and was marketed in the U.S. by Biora, Inc.

In early 2004, Staumann AG acquired Biora AB. Staumann USA markets Emdogain in the U.S., and the parent company markets it internationally.

Seikagaku Corp. (Biora-division) markets Emdogain in Japan, and it is co-marketed by Yoshida Dental Trade Distribution Co., one of the largest distributors of dental products in Japan. Emdogain is marketed in Canada by Biodenix Technologies Inc. (Vancouver, BC); in Mexico by MediMix S.A.; and in Spain by UEDA Espanola S.A.

Manufacture: Emdogain is manufactured from tooth enamel mechanically scraped from mandibular (lower jaw bone), non-erupted, developing premolars and molars obtained from slaughtered six-month old pigs. The soft cheese-like enamel matrix is removed, homogenized, frozen, and stored. Acid extracts of the enamel matrix are prepared using cold ascetic acid solution, centrifugation, and dialysis of the supernatant (e.g., with cut off of 3.5 kDa). SDS-polyacrylamide gel electrophoresis (SDS-PAGE) of the resulting protein shows predominating bands at 20, 13, and 5 kDa (typical of amelogenin). Emdogain is prepared from this acidic extract by further purification and lyophilization (protein content 85% w/w). The final product exhibits SDS-PAGE peaks at a ratio of 80/8/12 for the 20, 13, and 5 kDa amelogenin protein bands, respectively. See also the Tech. transfer section for further information.

FDA class: Medical Device PMA

Approvals: Date = 19970400, first approval, PMA; Indication = for application as a gel on the tooth-root surface during periodontal flap surgery to promote the regain of tooth-supporting tissues and the reattachment of the tooth

Date = 19990820; PMA supplement; Indication = scaling and root planning procedures in periodontal aesthetic zones

Date = 20010202; PMA supplement; Indication = for treatment of periodontitis

Indications: [Full text of the "Indications” section from product monograph; prior to Feb. 2001 approval]:

Emdogain is indicated for topical application in conjunction with periodontal surgery to provide for regain of tooth support lost as a result of moderate to severe periodontitis.

It has proven to be effective in single wall, two wall and three wall intrabony defects without furcations.

Status: Emdogain was approved by FDA in April 1997 as a medical device (PMA). Emdogain is marketed in the U.S., most European countries, Canada, and Japan. It was first launched in 1996 in Scandinavia, Germany, and the Netherlands. It was approved in Japan in Dec. 2001.

Tech. transfer: The inventors of Emdogain are affiliated with the Department of Oral Pathology, Karolinska Institute (Stockholm, Sweden). Bioventures N.V. (Curacao, Netherlands Antilles), the assignee for Emdogain-related patents, is affiliated with the institute and/or is a company formed by the inventors. Biora has exclusively licensed this technology from Karolinska Institute/Bioventures N.V.

Patents covering aspects of Emdogain include U.S. 5,098,891, “Protein composition inducing a binding between parts of mineralized tissue,” March 24, 1992, assigned to Bioventures N.V. This patent includes descriptions of the preparation of enamel matrix proteins from an acid extract of porcine teeth extracted from the lower jaws of slaughtered pigs (about 6 months of age, weight about 80 kg). Lower jaw halves are removed and frozen. Suitable tooth germs are excised from the jaws after partial thawing, and low molecular weight enamel matrix is isolated by acid extraction, purified, sterile-filtered, and lyophilized (freeze-dried). See also U.S. 5,418,221, “Composition containing enamel matrix from tooth germs for inducing binding between living mineralized tissue parts,” May 23, 1995, assigned to Bioventures N.V.

Trials: Emdogain has been studied in a series of trials involving nearly 300 patients at 15 clinics in the U.S. and Sweden. Patients have been followed for over three years and have shown uniform improvement in Emdogain treated teeth compared to control surgery, by achieving statistical significance for probing pocket reduction, clinical attachment gain, and radiographic bone gain. Clinical trials have shown that Emdogain achieves clinical attachment and bone growth in 93% of cases. In comparison, untreated (control) patients continue to lose bone. Among patients with deep periodontal pockets (> 6 mm) of the 1- or 2-wall type, 60-70% achieve significant alveolar bone regain. In promoting rapid initial healing, Emdogain causes little or no associated postoperative pain and swelling.

Results from a controlled open-label Swedis study in 107 patients treated with Emdogain in connection with periodontal surgery were reported in J Clinical Periodontology (1997 Sep;24(9 Pt 2):697-704. A 2.5-3 mm increase in attachment and bone level was observed after treatment.

The Cochrane Collaboration, a leading source for cost-benefit reviews (evidence-based medicine), has concluded (The Cochrane Database of Systematic Reviews, 2006, Issue 2), “Emdogain might have some advantages over other methods of regenerating the tissue supporting teeth lost by gum disease, such as less postoperative complications, but has not been shown to save more compromised teeth or that patients noticed any aesthetic improvement 1 year after its application”

Medical: For the treatment of periodontitis and tooth reattachment, the collagen tissue (gingiva) adjacent to area of the tooth is incised to expose the surface of the root. Epithelium, if present, is removed. Biora recommends preconditioning the exposed tooth surfaces with PrefGel, a pH-neutral EDTA gel, which it also markets. The clean surface of the root is then coated with a layer of Emdogain, after which the collagen tissue (gingiva) is repositioned and optionally sutured so that healing can take place.

Market: The Average Wholesale Price (AWP) is not available (product not in 2007, 2005 or 2004 Red Book).           The Biora sales price (June 2000)for the 30 mg size package (≤ 3 teeth) was $159, and the price for the 10 mg package (1 tooth) was $119. PrefGel, often used in conjunction with Emdogain for site preparation, cost $30/package of 10 single-use pipettes.