Discovered in 1965 by Dr. Marshall Urist, Bone Morphogenetic Proteins (BMPs) are the only proteins known to induce new bone formation. More than 20 BMPs have been identified, but preclinical animal studies have shown that only certain BMPs are able to induce new bone formation. BMP-2 is a member of the BMP family that acts far upstream, directly on mesenchymal stem cells, leading to the growth of bone in situ.
BMP-2 has been shown in pre-clinical studies to be capable of inducing mesenchymal stem cells, which are osteoblast precursor cells, into migration, proliferation and differentiation in vitro. BMP-2 is a protein that is highly-conserved among all mammal species and has been shown in vivo to be required for bone growth and development.
INFUSE® Bone Graft is composed of rhBMP-2 on an absorbable collagen sponge (ACS) carrier. The "rh" stands for "recombinant human" and signifies that the BMP-2 protein is the exact amino acid sequence of the human version of BMP-2, but produced by recombinant technology so that no actual human products are involved. The recombinant production also guarantees an extremely pure protein product with a highly controlled and measurable bioactivity.
Over 200 potential carriers were evaluated to deliver rhBMP-2. The absorbable collagen sponge was chosen because of its ability to carry and deliver the rhBMP-2 at the appropriate level, to release the absorbed rhBMP-2 at the appropriate rate to induce bone formation, and to provide a scaffold for bone ingrowth. The collagen sponge has been shown to bind the rhBMP-2 quickly, 95% in approximately 15 minutes of soaking time, elutes the protein for a period of approximately 8-10 days, and is fully resorbed in 4-10 weeks. The figure below depicts how important the binding and release kinetics are in the choice of a carrier for rhBMP-2. Implanted into a bone-deficient site, INFUSE® Bone Graft works with the body's own biology to restore normal function and esthetics.
Mechanism of Action
Normal bone formation and healing involves the coordinated interaction between bone-forming cells and biologic signals, within a protected healing environment.
rhBMP-2 is different from other biologic products that claim to grow bone because it is a signaling protein with chemotactic properties that also induces the body's own cells to form bone. rhBMP-2 initiates the body's own bone healing cascade:
INFUSE® Bone Graft is implanted in the surgical site.
Chemotaxis, or attraction of mesenchymal stem cells to the site, occurs.
Mesenchymal stem cells proliferate, or increase rapidly in number, in the site due to the presence of the rhBMP-2.
Mesenchymal stem cells differentiate, or begin to change from stem cells to osteoblast cells, due to the binding of rhBMP-2 molecules to cell-surface receptors on the stem cells.
Mineralized bone tissue begins to form around the osteoblasts, supported by an increased presence of angiogenicsignaling proteins such as VEGF, which have been shown to be upregulated by rhBMP-2.
Mechanical forces on the mineralized bone tissue causes the de novo bone created in the rhBMP-2 implantation site to mature and remodel, just like any other bone would be expected to respond.
Clinical Evidence
To show the safety and efficacy of rhBMP-2, clinical researchers have studied rhBMP-2 in models of increasing difficulty, from athymic rats to non-human primates, to large, randomized human clinical studies. 32 early pre-clinical safety studies provided the foundation for the rhBMP-2 development. 28 separate pre-clinical studies were conducted in lower to higher animal species, in increasing order of complexity, from rats to feline, goat, canine and non-human primate studies. The preclinical data, which included 8 non-human primate studies, enabled human clinical trials to begin in 1994. In human clinical trials, five prospective clinical studies provide the evidence to support the use of INFUSE® Bone Graft in dental regenerative bone grafting procedures.
INFUSE® Bone Graft human clinical trials included a histology endpoint. Core trephine biopsies were taken at time of implant placement from 96 INFUSE® Bone Graft treated patients, and compared to histological samples from 70 autograft treated patients. These trephine core biopsies were judged by an independent reviewer to be equivalent. The histology showed that INFUSE® Bone Graft grew new, viable bone for implant placement. The amount of bone versus unremodelled material is an important factor for surgeons to consider when choosing a grafting option. Only INFUSE® Bone Graft has been shown by histology to grow new bone in multicenter randomized Level 1 human clinical trials
