Evaluation of bone healing using rhBMP-2 soaked hydroxyapatite in ridge augmentation: a prospective observational study

Adequate bone volume is one of the important factors to obtain osseointegration in dental implants. In 1986, Lekholm et al. reported that for the implant success, a minimum of 1 mm or more of the buccal and lingual bone was necessary surrounding the implant surface. Clinicians often encounter patients with deficient vertical or horizontal alveolar bones. Reasons may vary from trauma, periodontal disease, tooth extraction, and to tumor. Under such circumstances, the implant surface may not be entirely covered by the bone, and this could increase the risk of infection, gingival recession, non-esthetic appearance, poor oral hygiene maintenance, and peri-implantitis [1].

The ideal bone graft material should have no immune response and include growth factors that facilitate rapid bone formation and re-vascularization. It should also be able to maintain space for new bone infiltration and readily available in clinics.

Autografts are known to be the ideal material for the reconstruction of bone defects. Autografts have osteogenesis, osteoconduction, and osteoinduction abilities that enable rapid bone healing without inducting immune responses. They are, however, difficult to obtain in sufficient quantities without causing complications in the donor site and a large amount of the transplanted grafts often get absorbed. To overcome the problems, other bone substitutes such as allografts, xenografts, and alloplasts have been developed and used. However, allografts and xenografts could be problematic due to the risk of infection and high price. The alloplasts are cheap and have no risk of infection, but they lack osteogenesis and osteoinduction abilities to form viable bone tissue [2].

Bone morphogenetic protein (BMP), the leading osteoinductive growth factor, has been studied since 1995 and extensively in the 2000s. Animal studies focused on discovering roles of BMP in guided bone regeneration (GBR) when delivered with drug carriers [3, 4]. In general, osteoinductive capabilities should be given to osteoconductive bone graft materials for bone graft material development. Various proteins, such as BMP-2, 4, 7, and 14, have been reported to have osteoinductive abilities in animal experiments.

In particular, BMP-2 act as a growth and differentiation factor in the body and promotes the new bone formation by acting extensively at the entire stage of osteogenesis ranging from mesenchymal stem cells-osteoprogenitor-preosteoblast-osteoblast-osteocytic osteoblast-osteocyte [5].

BMP-2 also showed potential for bone regeneration through various studies including sinus augmentation [6, 7], alveolar bone preservation [8], bone augmentation [9], and periodontal recovery [10]. Ike and Urist reported that BMP-2 contained in dentin exhibited osteoinductive abilities important for osteogenesis [11]. Jung et al. showed that GBR with combination of the xenograft (Bio-Oss) with rhBMP-2 can enhance the maturation process of bone regeneration [12].

Similar to other growth factors, BMP-2 requires a carrier system that could provide optimal cellular and vascular growth, cellular attachment, and release kinetics [13, 14]. Highly soluble, BMP-2 requires robust scaffolds over long periods that act as drug carrier at the implant site to exert osteoinductive effects [15, 16]. Ideal scaffolds should control-release growth factors and prevent degradations. Various materials have been proposed, and absorbable collagen sponge (ACS) has been the most documented carrier for rhBMP-2 because of its high binding and retention capacities for the rhBMP-2. According to a study by Hwang, the use of rhBMP-2 with ACS could result in accelerated bone formation compared to conventional bone grafting in postoperative bone defects [17]. However, collagen lacks osteoconductivity as well as structural integrity in transplanted sites. Therefore, calcium phosphates, such as hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), have been considered as suitable candidates for rhBMP-2 delivery system because of their space-providing properties [18].

The goal of this study is to evaluate effectiveness and complication of alveolar ridge augmentations using a hydroxyapatite-based alloplastic bony substitute with rhBMP-2.

Postoperative complications were not found in all subjects.

Despite possessing good biocompatibility and osteoconductive potential, most of commercially available graft materials lack osteoinductive potential. Much research thus has been focused on graft materials mixed with additives that could promote osteogenic potentials such as bone morphogenetic protein (BMP).

Kim et al. studies showed that demineralized dentin matrix (DDM) could act as an effective rhBMP-2 carrier [4, 13]. Kim also had reported that HA or DDM scaffolds could be combined with rhBMP-2 and promote bone formation [19].

A study from Kim et al. showed that low-dose Escherichia coli–derived rhBMP-2 with HA is as effective as anorganic bovine bone xenografts in early stages for enhanced bone formation after maxillary sinus floor augmentation without any major intraoperative or postoperative complications [7]. The soft tissue and residual graft areas showed no significant differences between the groups and rhBMP-2 antibody in the serum after BMP-2/H grafting did not increase significantly.

A study by Burkus et al. showed that formation of anti-BMP-2 antibodies are low and transient in patients treated with rhBMP-2 [20]. Moreover, small formation of antibodies did not affect fusion success and had no visible affect clinical sequelae.

Many studies support that BMP-2 is an effective osteoinducer, and there is no evidence that administration of rhBMP-2 at the time of surgery links with an increased risk of cancer [21, 22]. However, rhBMP-2 could induce adverse clinical effects, including ectopic bone formation and tissue inflammation when used in high concentrations [23, 24].

NOVOSIS®-Dent is a graft material used in combination with rhBMP-2 and HA carrier in alveolar bone defect areas. In order for rhBMP-2 to exert its effects, it must act locally at the site where new bone formation is required, and for this reason, it is commonly used with carriers capable of releasing from local sites. The carrier of NOVOSIS®-Dent is HA, a material that occupies 65% of the bone and 98% of the dental enamel, and it provides osteoconduction by providing a porous structure (83% porosity, 300 μm pore size). NOVOSIS®-Dent provides osteoconduction by using HA as a carrier and osteoinduction capability by utilizing BMP-2 to form a new bone at the bone defect site.

In this study, HA+rhBMP-2 showed relatively good bone formation compared with ABB. Although HA+rhBMP-2 had less volume of bone augmentation (widths ABB 2.52 ± 0.18 mm, HA+rhBMP-2 1.75 ± 0.85 mm; heights ABB 1.68 ± 0.17 mm, HA+rhBMP-2 1.57 ± 0.28 mm) and more resorptions over 4-month periods (widths ABB 29.7 ± 8.8%, HA+rhBMP-2 31.5 ± 7.4%, p = 0.841 and heights ABB 39.2 ± 21.8%, HA+rhBMP-2 52.6 ± 6.5%, p = 0.548), it showed relatively more bone formation in histomorphometric assessments (ABB 28.9 ± 10.3%, HA+rhBMP-2 35.2 ± 19.7%; p = 0.886). This suggests that HA+rhBMP-2 group may provide new bone formation through osteoinductive abilities provided by the osteogenic protein. This characteristic observation might be consistent with the in vivo and in vitro studies that the delivered rhBMP-2-activated dentin resorption that was associated with giant cells, ultimately promoting the bone formation and remodeling capacity in later stage [13, 25]. However, even though the average bone formation was higher in HA+rhBMP-2 group, the statistical difference was marginal because of the limited number of the cases. Therefore, the result needs to be confirmed by the more number of the cases in the future study.

Bone graft material including rhBMP-2 showed good bone formation and remodeling capabilities. Within its limitation, this study suggested that ridge augmentations using rhBMP-2 soaked HA could be clinically useful to supplement implant placements in edentulous regions. Additionally, serious postoperative complications related to the graft material did not occur.