The repair of segmental mandibula defects by a bone morphogenetic protein bone device in man

Abstract

Bone induction with naturally sourced BMPs has been demonstrated repeatedly in heterotopic and orthotopic sites of non-human primates. This has spawned the investigation of bone regeneration in mandibular defects of human patients. This was compared to osteogenesis in patients treated with autologous bone grafts, considered the gold standard for the reconstruction of skeletal defects.

The osteogenic device was formulated as a combination of human demineralized bone matrix as a carrier and naturally sourced BMPs. BMPs were extracted from bovine bone with chaotropic agents and subsequently purified by a sequential chromatographic process. BMPs (quantified as alkaline phosphatase units of activity) were loaded onto human demineralized bone matrix. The device was combined with sterile saline and applied to the defects as a paste. Autologous bone was obtained from the iliac crest and prepared as a particulate cancellous bone and marrow graft in a bone mill. These were loaded into perforated titanium mesh trays secured to the remaining mandible. Patients were followed-up clinically and radiographically at 1, 6 week, 3, 6, 12 month intervals. A trephine biopsy of the implants was performed at 3 months post-implantation and the specimens examined on undecalcified bone sections.

The osteogenic device induced bone formation in 2 of 6 patients treated.Histological examination of successful implanted BMP devices exhibited mineralised bony trabeculae with copious osteoid seams. These were lined by contiguous osteoblastic layers. Bone deposition directly onto non-vital matrix provided unequivocal evidence of osteoinduction. Bone induction occurred without a chondrogenic phase. Of the 7 patients grafted with autologous bone " had histological evidence of osteogenesis. Morphometric analysis of the histological sections showed that, when successful, BMP treated defects had highly active osteogenesis compared to autologous bone. However, the high proportion of inactive BMP implants indicates the need for further development to produce an osseoinductive system which performs reliably in this clinical context. Surprisingly, 2 autologous bone grafts also failed. This may be as a result of the more advanced age of the patients and the incl usion of periosteum in the surgical resection Moreover, all the autologous implants demonstrated volumetric decline over the follow-up period. Histomorphometric analysis showed that in all patients successful grafts had a far higher fibrovascular tissue content than the failed grafts. This suggests that the titanium mesh system may be biologically flawed and act as a barrier to angiogenesis. These results provide the first histological evidence of the ability of naturally sourced BMPs to induce bone formation in mandibular defects in human subjects.