Infuse Bone Graft

RECOMBINANT HUMAN BONE MORPHOGENETIC PROTEIN-2 (rhBMP-2)

Infuse^TM Bone Graft contains a manufactured bone graft material that is approved for use as a bone graft in sinus augmentation and localized alveolar ridge augmentation. It provides an alternative to bone-harvest surgery, a secondary procedure which can be painful for some patients and lengthens the healing process. Infuse Bone Graft provides proven, predictable bone formation and is supported by extensive research and clinical results.

THE MECHANISM OF ACTION AND INFUSE BONE GRAFT*

Bone morphogenetic proteins (BMP) play a role in the formation of bone and cartilage, the healing of fractures, and the repair of other musculoskeletal tissues.²

The preferred method for obtaining BMP is to manufacture a recombinant version of a naturally occurring BMP using well-established molecular biology technique (e.g., recombinant insulin). This production method results in pure solutions of a single BMP. Recombinant production offers the advantage of tightly controlled manufacturing processes to ensure purity, consistency and sterility.

The mechanism of action includes six steps. Table 1 includes an overview of the steps, and each step is described in detail below.

Step 1: Implantation
When rhBMP-2 is placed on an absorbable collagen sponge (ACS) and implanted in the body, it produces new bone tissue at the site of implantation. Neither the rhBMP-2 nor the ACS can produce new bone tissue independently. Only when they're used together do they initiate the bone induction process.

Step 2: Chemotaxis
Bone-forming cells migrate to the area of the rhBMP-2/ACS implant. This cell migration stimulated by a chemical response is called chemotaxis. Mesenchymal stem cells (MSC) move from bleeding bone, muscle, and the periosteum to infiltrate the implant.

Step 3: Proliferation
The mesenchymal stem cells around the rhBMP-2/ACS implant increase in number. In-vitro studies have shown that rhBMP-2 can increase the proliferation of several multipotent cell lines, which can differentiate into osteoblasts, or bone-forming cells.^3-7

Step 4: Differentiation
Binding to specific receptors on the surface of the MSC, rhBMP-2 causes them to differentiate into bone-forming cells.^{2, 7} In-vitro studies of rhBMP-2 support the fact that differentiation of mesenchymal stem cells into bone-forming osteoblasts plays an essential role in the induction of new bone.^4,6 Pre-clinical studies have shown that rhBMP-2 can cause the differentiation of precursor cells into osteoblasts.^3-19.

A 2003 in-vitro study compared the bone-forming activity of fourteen recombinant human bone morphogenetic proteins.²⁰ Three cell lines, representing the different stages of osteoblast differentiation, were each tested. Alkaline phosphatase activity — a measure of the amount of new bone formation — was significantly increased in all three cell lines by BMP-2, BMP-6, and BMP-9. The researchers concluded that BMP-2, BMP-6, and BMP-9 may be the most potent agents to induce osteoblast lineage-specific differentiation of mesenchymal stem cells.

Step 5: Bone formation
As the sponge degrades or dissolves; these stem cells differentiate into osteoblast and begin to form trabecular bone and/or cartilage. Blood vessel formation (angiogenesis) is observed at the same time. The bone formation process develops from the outside of the rhBMP-2/ACS implant towards the center until the entire implant is replaced by trabecular bone.

Preclinical studies support that the bone formation started by rhBMP-2/ACS is self-limiting, forming a predictable amount of bone at the site of implantation. The ability of rhBMP-2 to induce new bone formation depends on its concentration. The rate of bone formation, the amount of bone formed, and the density of the resulting bone are positively correlated with both the concentration of rhBMP-2 and the length of time that rhBMP-2 is present at the implant site.¹

Step 6: Remodeling
Remodeling of the trabecular bone induced by rhBMP-2 is consistent with the biomechanical forces placed on it. Radiographic, biomechanical, and histologic evaluation of the induced bone indicates that it functions biologically and biomechanically as native bone. Pre-clinical studies also indicate that the induced bone can repair itself, if fractured, in a manner indistinguishable from native bone healing.¹

BRIEF SUMMARY

INDICATIONS, CONTRAINDICATIONS, WARNINGS, AND PRECAUTION FOR INFUSE BONE GRAFT FOR CERTAIN ORAL MAXILLOFACIAL AND DENTAL REGENERATIVE USES

INFUSE^® Bone Graft is indicated as an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets.

The INFUSE^® Bone Graft consists of two components–recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) placed on an absorbable collagen sponge (ACS). These components must be used as a system for the prescribed indication. The bone morphogenetic protein solution component must not be used without the carrier/scaffold component or with a carrier/scaffold component different from the one described in the package insert.

INFUSE^® Bone Graft is contraindicated for consumers with a known hypersensitivity to recombinant human Bone Morphogenetic Protein-2, bovine Type I collagen or to other components of the formulation and should not be used in the vicinity of a resected or extant tumor, in consumers with any active malignancy or consumers undergoing treatment for a malignancy, in pregnant women, or consumers with an active infection at the operative site.

There are no adequate and well-controlled studies in human pregnant women. In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies that are capable of crossing the placenta. Women of childbearing potential should be warned by their surgeon of potential risk to a fetus and informed of other possible dental treatments. The safety and effectiveness of this device has not been established in nursing mothers. Women of childbearing potential should be advised to not become pregnant for one year following treatment with this device.

INFUSE^® Bone Graft has not been studied in patients who are skeletally immature (<18 years of age or no radiographic evidence of epiphyseal closure).

Please see the package insert for the complete list of indications, warnings, precautions, adverse events, clinical results, and other important medical information.