Patient Photos
Before Before	After After

Replacement of missing bone presents a daunting challenge for the reconstructive surgeon. Traditional techniques have involved grafts and flaps. A bone graft is transferred from a donor site such as the hip or rib into a surgically created pocket, or recipient site.The graft cells must quickly get nutrition from the surrounding pocket or they will die.Thus, there are intrinsic limitations to the amount of free bone graft that can be expected to survive after transplantation.  Bone flaps are tissue units that are transferred along with their own blood supply. 

The artery and vein of the bone flap must be connected to similar vessels near the recipient site.  Such grafts can be much larger in size because the blood supply is re-established at the new location.  The operative procedure, involving microsurgical re-connection, is lengthy, requires observation in an intensive care unit, and has a finite rate of failure.  Regardless of location, donor sites for bone are painful.  Transfer of bone flaps such as the fibula (the small bone of the leg), although necessary, represent a definite sacrifice of valuable tissue for the patient.

Re-creation of bone within a recipient site using molecular methods offers an entirely novel approach to these difficult problems. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is now available and offers significant clinical advantages for the reconstructive surgeon.  Bone morphogenetic proteins are a group of endogenous proteins involved in embryologic development and skeletal formation.  BMPs found in the mature skeleton are likely involved in bone maintenance and fracture healing.  Marshall Urist, a pioneering orthopedic surgeon at UCLA, conducted basic research on the role of these substances.  As part of another experiment, he coincidentally observed that demineralized segments of bone matrix implanted into rabbit muscle caused bone formation.

The concept that undiscovered agents, contained in bone matrix, had the capacity to cause osteogenesis (bone formation) without the introduction of bone cells was absolutely revolutionary.  Urist reported his findings in 1971 and coined the term bone morphogenetic protein.  Of the more than 15 human BMPs now known to exist, BMP-2 is the most potent. It causes undifferentiated mesenchymal stem cells found normally in bone marrow, muscle and periosteum (the soft tissue membrane surrounding bone) to convert themselves into osteoblasts (bone-forming cells).  In 1988, Wozney sequenced and cloned rhBMP-2.  Recombinant technology now allows production of large, pure quantities of rhBMP-2 that can be produced clinically and in the laboratory.

Orthopedic research demonstrated the safety and efficacy of rhBMP-2 for spinal fusion and long bone fracture non-union.  This material and others are now available for human use.  In the past two years more than 100,000 orthopedic cases have been performed, mostly in hip and spine.  All bones outside the skull form first via cartilage, ie. via chondral ossification.  Facial bones, on the other hand, form directly within a membrane, ie. via membranous ossification. Clinical studies in maxillofacial surgery have been oriented toward the use of dental implants via reconstitution of bone in the maxillary sinus and augmentation of edentulous gums.  Thus rhBMP-2 is capable of forming bone using either the chondral or membranous mechanism depending upon the nature of the soft tissues into which the rhBMP-2 is implanted.

When placed into an appropriate environment rhBMP-2 causes bone formation de novo.  The introduction of bone-forming cells from the host is not necessary to initiate this process.  Instead, rhBMP-2 acts in situ to attract and concentrate host stem cells at the site.  These cells subsequently undergo differentiation into osteoblasts.  Effective doses of BMP-2 are species-specific.  Humans respond best to a concentration of 1.5 mg per milliliter.  This dose is 200,000 times the estimated physiologic concentration of natural BMP-2 found in bone.  Boyne and Chin showed that rhBMP-2 improved healing of primate alveolar (gum) distraction sites. Carstens and Chin demonstrated ability of rhBMP-2 to resynthesize 10 cm of pig mandible.  Chin subsequently demonstrated the use of rhBMP-2 in human alveolar distraction.  Chin and Carstens showed that rhBMP-2 was effective in establishing osseous union across discontinuity defects in major facial clefts.

One of the most unique features of rhBMP-2 is its ability to create from the local tissue environment the type of bone native to that environment.  This has major implications for facial bones because the original cells of origin for these bone come from an embryonic source (neural crest) that is very different from that of the rest of the skeleton (paraxial mesoderm).  Resynthesis of facial bone using the local cell population has theoretical advantages over placement of bone grafts obtained from non-facial donor sites.  Membranous (facial) bone formation with rhBMP-2 is quite rapid.  Laboratory studies and clinical observations demonstrate bone framework essentially laid down by three months. By six months, remodeling is largely complete.

Clinical work at St. Louis University School of Medicine and SSM Cardinal Glennon Children’s Hospital supports the concept that rhBMP-2 constitutes an effective means to achieve local bone formation, in situ osteogenesis (ISO). Maximum bone volume achieved to date is 12 cm of mandible. In accordance with work done by Chin and Carstens, alveolar (gum) clefts are effectively healed without recourse to hip graft.  Replacement of other membranous bones such as maxilla and cranium appears to follow the same principles and time course. The clinical potential of rhBMP-2 for facial bone defects will continue to be evaluated on a per-case basis.

For more references or clinical information regarding recombinant human bone morphogenetic protein-2, please email Debbie, our nurse coordinator - debbie_watters@ssmhc.com.