Long-term skeletal stability in the treatment of mandibular prognathism with a physiological positioning strategy.

Our aim was to evaluate the long-term skeletal stability of the mandible in 21 patients after orthognathic surgery with physiological positioning. The measurement points SNB, B point (X, Y), Pog (X, Y), and the angle of the ramus were measured on cephalometric photographs to assess skeletal stability preoperatively, immediately after operation, and one and two years postoperatively. In addition, we evaluated the clinical symptoms of disorders of the temporomandibular joint (TMJ). The analysis of the cephalometric photographs showed that SNB, B point X, and Pog X showed no significant differences among the postoperative time points. On the other hand, B point Y and Pog Y showed no significant differences throughout the study period. We compared the angle of the ramus before operation and two years postoperatively, and no significant difference was found. In addition, no cases showed any pathological symptoms of disorders of the TMJ two years postoperatively. The long-term stability after orthognathic surgery with physiological positioning was confirmed, and it seems to be a reliable orthognathic treatment in patients with mandibular prognathism.

Clinical application of autogenous partially demineralized dentin matrix prepared immediately after extraction for alveolar bone regeneration in implant dentistry: a pilot study.

The aim of this study was to examine the efficacy and safety of autogenous partially demineralized dentin matrix (APDDM) prepared onsite, for clinical application in bone regeneration procedures related to implant dentistry, including socket preservation, alveolar ridge augmentation, and maxillary sinus floor augmentation. In this study, 16 patients underwent dental implant placement using APDDM transplantation. There were no systemic or local complications (including surgical site infection) in any of the cases, and oral rehabilitation using dental implants was successful in all cases for at least 2 years after attachment of the suprastructure. This report describes the clinical application of APDDM prepared immediately after tooth extraction to bone augmentation, taking advantage of the relatively short preparation time due to partial demineralization. APDDM, as introduced in this study, is an efficient, safe, and reasonable bone substitute. Consequently, this material has the potential to become one of the options as a bone substitute in implant dentistry.

Administration of teriparatide improves the symptoms of advanced bisphosphonate-related osteonecrosis of the jaw: preliminary findings.

Teriparatide is a synthetic polypeptide hormone that contains the 1-34 amino acid fragment of the recombinant human parathyroid hormone that stimulates bone formation. Currently, it is approved only for the treatment of osteoporosis. The outcomes of daily teriparatide injections for the treatment of bisphosphonate-related osteonecrosis of the jaw in 10 patients are reported here. Two of the 10 cases dropped out due to adverse events. Of the remaining eight cases, seven exhibited clinical improvement of the jaw-related symptoms of osteonecrosis and progression of the sequestration, while one case did not show improvement of the symptoms. Administration of teriparatide in patients with osteonecrosis of the jaw promotes bone formation and subsequent sequestration over a short period of time. These results suggest that adjunctive teriparatide therapy is a viable and effective option for treating osteonecrosis of the jaw.

A clinicopathological study of perineural invasion and vascular invasion in oral tongue squamous cell carcinoma.

The risk factors for recurrence of head and neck cancer are classified as being of high or intermediate risk. Those of intermediate risk include multiple positive nodes without extracapsular nodal spread, perineural/vascular invasion, pT3/T4 primary tumours, and positive level IV/V nodes. However, little evidence is available to validate these intermediate risk factors. We analyzed perineural/vascular invasion in 89 patients who underwent radical surgery for oral tongue squamous cell carcinoma, whose records were reviewed retrospectively. Perineural invasion was found in 27.0% of cases and vascular invasion in 23.6%; both had a strong relationship with histopathological nodal status (P = 0.005). The 5-year disease-specific survival (DSS) and overall survival rates of patients with perineural invasion were significantly lower than those of patients without perineural invasion (P < 0.001 and P = 0.002, respectively). The 5-year DSS of UICC stage I and II cases with perineural/vascular invasion was significantly lower than those without (P < 0.001 and P = 0.008, respectively). Perineural invasion and vascular invasion are risk factors for regional metastasis and a poor prognosis. We recommend elective neck dissection when perineural/vascular invasion is found in clinical stage I and II cases. The accumulation of further evidence to consider intermediate risks is required.

Bone Marrow-derived Cell Therapy for Oral Mucosal Repair after Irradiation.

Oral mucositis (ulcer) is a serious and painful side effect for patients with head and neck cancer following radiation therapy. However, current clinical strategies cannot efficiently prevent the occurrence of oral mucositis. In this study, we investigated whether bone marrow-derived cells (BMDCs) prevented the occurrence and/or decreased the severity of radiation-induced oral mucositis. Fresh concentrated BMDCs from male C3H mice were transplanted intravenously into female mice after tongue irradiation. For 14 days postirradiation, the changes of body weight and the time courses of ulceration were observed. Until the ulcer reached maximum size (7 days postirradiation), macroscopic and histologic analyses of harvested tongues were performed to detect the behavior of donor BMDCs. Between 2 and 5 days postirradiation, BMDCs-transplanted mice showed more expression of stem cell markers (c-Kit, Sca-1) and EGFR and fewer apoptotic cells when compared with nontransplanted control mice (irradiation group). On day 7, there were fewer and smaller ulcers observed in the BMDCs-transplanted group. Tongues of these mice had preserved their epithelial thickness, and regenerative activities (blood vessels formation, cell proliferation) were higher than they were in the irradiation group. Fluorescently labeled BMDCs were not detected in tongue epithelium but rather in connective tissue (dermis) just below the basal cell layer. These findings suggest that exogenous BMDCs behave to reduce radiogenic oral mucositis in a paracrine manner.

Effects of postoperative chemotherapy and radiotherapy on patients with squamous cell carcinoma of the oral cavity and multiple regional lymph node metastases.

Nodal metastasis in oral squamous cell carcinoma (OSCC) is considered to be a predictor of a poor prognosis. The aim of this study was to investigate the relationship between the number of positive lymph nodes and the prognosis in OSCC patients with nodal metastases and to assess the effects of postoperative radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) on this patient group. A retrospective investigation of 98 patients with OSCC who underwent radical neck dissection and had at least three pathologically positive lymph nodes was performed. The 5-year disease-specific survival rate was 66.7% for patients with 3 positive nodes, while it was significantly lower for those with 4 positive nodes and those with ≥ 5 positive nodes (21.5% and 46.1%, respectively; P < 0.01). The loco-regional control and disease-specific survival rates for the surgery alone, surgery plus RT, and surgery plus CCRT groups were 46.2% and 40.5%, 66.3% and 54.4%, and 81.7% and 52.4%, respectively. For patients with ≥ 4 positive nodes, the loco-regional control rate after surgery plus CCRT was better than that observed after surgery alone (77.5% vs. 32.6%, P = 0.01). Postoperative RT and CCRT have positive impacts on the prognosis of OSCC patients with advanced stage neck disease.

Clinicopathological risk factors for local recurrence in oral squamous cell carcinoma.

Local recurrence of oral squamous cell carcinoma (OSCC) after primary surgery has been considered to be a poor prognostic entity in terms of survival rate. The purpose of this study is to evaluate the incidence of local recurrence and to identify significant risk factors for the local recurrence in OSCC. The authors retrospectively reviewed records for 187 patients who underwent radical surgery for OSCC. The local recurrence rate was 16.0% (30/187 patients) in this study. The survival rate of patients with local recurrence was 33.3%, which was significantly lower than that (94.3%) of patients without local recurrence. Pattern of invasion (POI), neoadjuvant chemotherapy (NAC), and the status of the surgical margin were identified as factors influencing local recurrence. In particular, NAC and the status of the surgical margin were independent risk factors by multivariate analysis. The deep margin was resected at a close site in many NAC-treated patients, suggesting that NAC may lead to local recurrence and poor outcomes. No efficacy of NAC was observed, suggesting that the standard treatment of oral cancers is surgery alone.

Formation of engineered bone with adipose stromal cells from buccal fat pad.

A robust method for inducing bone formation from adipose-derived stromal cells (ADSCs) has not been established. Moreover, the efficacy of strong osteogenic inducers including BMP-2 for ADSC-mediated bone engineering remains controversial. Meanwhile, the buccal fat pad (BFP), which is found in the oral cavity as an adipose-encapsulated mass, has been shown to have potential as a new accessible source of ADSCs for oral surgeons. However, to date, there have been no reports that define the practical usefulness of ADSCs from BFP (B-ADSCs) for bone engineering. Here, we report an efficient method of generating bone from B-ADSCs using rhBMP-2. The analyses show that B-ADSCs can differentiate in vitro toward the osteoblastic lineage by the addition of rhBMP-2 to culture medium, regardless of the presence of osteoinductive reagents (OSR), as demonstrated by measurements of ALP activity, in vitro calcification, and osteogenic gene expression. Interestingly, adipogenic genes were clearly detectable only in cultures with rhBMP-2 and OSR. However, in vivo bone formation was most substantial when B-ADSCs cultured in this condition were transplanted. Thus, B-ADSCs reliably formed engineered bone when pre-treated with rhBMP-2 for inducing mature osteoblastic differentiation. This study supports the potential translation for B-ADSC use in the clinical treatment of bone defects.

Effective bone engineering with periosteum-derived cells.

Bone augmentation via tissue engineering has generated significant interest. We hypothesized that periosteum-derived cells could be used in place of bone marrow stromal cells (which are widely used) in bone engineering, but the differences in osteogenic potential between these 2 cell types are unclear. Here, we compared the osteogenic potential of these cells, and investigated the optimal osteoinductive conditions for periosteum-derived cells. Both cell types were induced, via bFGF and BMP-2, to differentiate into osteoblasts. Periosteal cells proliferated faster than marrow stromal cells, and osteogenic markers indicated that bone marrow stromal cells were more osteogenic than periosteal cells. However, pre-treatment with bFGF made periosteal cells more sensitive to BMP-2 and more osteogenic. Transplants of periosteal cells treated with BMP-2 after pre-treatment with bFGF formed more new bone than did marrow stromal cells. Analysis of these data suggests that combined treatment with bFGF and BMP-2 can make periosteum a highly useful source of bone regeneration.

Bone with a vascular flap induced from fat tissue with the use of rhBMP-2 in rats.

Here we report that successful bone formation with a vascular flap inside a cylindrical mold was induced from fat tissue with the use of recombinant human bone morphogenetic protein-2 in rats. Fat tissue connected to blood vessels was prepared to fit into the mold and implanted intramuscularly into the hind leg in Wistar rats. RhBMP-2 (20 micro g) was applied in a collagen sheet previously placed on the inside surface of the mold. Bone formation was confirmed radiologically and morphologically at 2, 4, and 8 weeks after the surgery. In the control group without rhBMP-2 or the group with ligation of the blood vessels before the implantation, bone formation was not observed. Our success in bone formation having a definite size, shape, and blood supply may lead to a therapeutic approach to effective bone reconstitution. The present study is the first report on bone induction from fat tissue by rhBMP-2 in vivo.

Prefabrication of vascularized bone flap induced by recombinant human bone morphogenetic protein 2 (rhBMP-2).

An experimental model for the prefabrication of a vascularized bone flap was developed in this study. To form vascularized bone in the desired configuration and to increase the survival rate of the grafted bone, a muscle vascularized pedicle (MVP) was transformed into vascularized bone by the inducer recombinant human bone morphogenetic protein 2 (rhBMP-2). The muscle flap (8 x 8 mm) raised on saphenous vessels in the rat thigh was sandwiched between same-size collagen (Terudermis) sheets in the presence or absence of impregnated 25 microg of rhBMP-2 for the experimental group and the control group, respectively. The flaps were harvested 1, 2 and 3 weeks postoperatively. Bone transformation was detected by gross examination, radiology, and histologic testing. No evidence of muscle tissue transformation was found in control flaps, whereas all of the experimental flaps produced new bone. Saphenous vessels were observed to supply the new bone upon harvesting, and the newly formed vascularized bone showed good configuration with shape of the Terudermis sheet. This study indicates that this model of effective bone reconstruction could be potentially applied in a therapeutic setting.

Functional reconstruction of the non-human primate mandible using recombinant human bone morphogenetic protein-2.

The purpose of this study was to evaluate the long-term functional properties of regenerated bone induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) in segmental bone defects of primate mandibles. The 30-mm defects were created in the mandibles of six young monkeys and the mandibles were fixed with titanium plates. Then 9 mg of rhBMP-2 permeating a poly-D, L-lactic-co-glycolic acid-coated gelatin sponge (PGS) was implanted into the bone defect. Dental implants were placed into the regenerated mandible 20 weeks after surgery, then suprastructures were placed and masticatory force loading was begun 8 weeks after the insertion of the dental implants. Bone formation and the quality of new bone were evaluated radiologically and histologically at 15 and 30 weeks after surgery, and 4 and 24 weeks after masticatory force loading. The resected mandibles were completely regenerated with the rhBMP-2-induced bone. Excellent remodelling and consolidation of new bone were observed after loading. This study demonstrated that the new bone induced by rhBMP-2 in large segmental defects was maintained and functional for at least 1 year. Bone regeneration induced by rhBMP-2 holds promise as a future therapy and may be an effective alternative to autogenous bone grafts for implant dentistry and reconstructive surgery.

Bone regeneration using recombinant human bone morphogenetic protein-2 (rhBMP-2) in alveolar defects of primate mandibles.

The efficacy of bone morphogenetic protein (BMP) for bone reconstruction has been widely studied in numerous animal experiments, but insufficient information exists about its ability to regenerate bone in primates. The purpose of this study was to evaluate the effects of recombinant human BMP-2 (rhBMP-2) on bone formation in alveolar bone defects in the mandibles of young primates. Marginal bone defects were created in the mandibles of nine 5-year-old rhesus monkeys and rhBMP-2 permeated in a polylactic-co-glycolic acid-coated gelatin sponge (PGS) was implanted into the bone defects. The resected bone treated with rhBMP-2 regenerated completely at 12 weeks postoperatively, and remodelling and consolidation of new bone were seen histologically. This study provides evidence of considerable bone regeneration in alveolar defects after surgical implantation of rhBMP-2 in non-human primates. This technique may be an effective alternative to autogenous bone grafts for reconstructive surgery in clinical practice.

Prefabricated vascularized bone flap: a tissue transformation technique for bone reconstruction.

In this study, an attempt was made to transform a muscle vascularized pedicle raised on host vessels into a vascularized bone flap, using recombinant human bone morphogenetic protein 2 (rhBMP-2). The purpose of this study was to produce new bone vascularized in nature to increase the survival rate of the subsequently grafted bone and to fabricate the newly formed bone into the desired shape. Silicone molds in the shape of a rat mandible were used to deliver rat bone matrix impregnated with or without rhBMP-2. A muscle pedicle the same size as the mold was raised on the saphenous vessels in the rat thigh and then sandwiched in the center of the silicone molds. The molds were sliced in half and each section was filled with rat bone matrix that was impregnated either with 25 microg of rhBMP-2 for the experimental group or with diluting material alone for the control group. The sandwiched flaps were then secured by tying them to the adjacent muscles and were harvested at 2 and 4 weeks after surgery. Three and six rats were used in the control and experimental groups at each time point, respectively. Bone formation was assessed in the ex vivo specimens by macroscopic, radiologic, and histologic evaluation. Macroscopically, the continuation of the vascular pedicle was clearly visible for both the control and experimental muscle flaps. However, no evidence of muscle-tissue transformation was observed in the control flaps, whereas all the flaps treated with rhBMP-2 produced new bone that replicated the shape of the mold exactly and had saphenous vessels supplying the newly formed bone. This study demonstrates that this experimental model has the potential to be therapeutically applied for effective bone reconstruction.

Development of composite cultured oral mucosa utilizing collagen sponge matrix and contracted collagen gel: a preliminary study for clinical applications.

A new type of cultured mucosa was developed as a mucosal substitute. This composite cultured oral mucosa (CCOM) was composed of (1) a lamina propria in which fibroblasts were embedded in contacted collagen gel and honeycomb structured collagen sponge and (2) stratified epithelial cell layers on the surface of the cultured lamina propria. CCOM had a well-stratified and differentiated epithelial cell layer, and its involucrin and laminin expression resembled that of normal oral mucosa. Desmosomes were recognizable with transmission electron microscopic examination. In the lamina propria, contracted collagen gel had pooled away from the sponge wall, leaving a sparse structure inside the collagen sponge. Transplantation of CCOM to nude mice was performed by creating full-thickness wound and then applying CCOM (n = 12). Murine skin allograft (n = 4) and no-graft conditions (n = 5) served as controls. The mice were sacrificed for histological evaluation and assessed for wound contraction 28 days after transplantation. The epithelium of the CCOM-treated group had five to 10 cell layers, and the dermis contained many fibroblasts and a large amount of collagen bundles. The wound contraction of the CCOM-treated group was statistically less than that of the no-graft group. These results indicate that CCOM has barrier functions against various stresses and can induce a fibrovascular ingrowth from the surrounding wound bed, and that CCOM could be applied in a clinical setting.

Evaluation of ceramics composed of different hydroxyapatite to tricalcium phosphate ratios as carriers for rhBMP-2.

We have investigated pellet-shaped implants prepared from biphasic calcium phosphate (BCP) ceramics with five different ratios of hydroxyapatite (HAP) to beta tricalcium phosphate (beta-TCP). The purpose of this study was to evaluate these BCP ceramics as carriers for rhBMP-2. BCP ceramics impregnated with the different doses of recombinant human bone morphogenetic protein 2 (rhBMP-2) (1, 5 and 10g) were used for the experimental purpose and the ceramics without rhBMP-2 were used as control. The pellets were placed into subcutaneous pockets on the dorsum of 4-week-old male Wistar rats. The animals were sacrificed 2 and 4 weeks after implantation. Bone induction was estimated by alkaline phosphatase (ALP) activity measured at 2 weeks after implantation. Pellets were also examined radiologically, histologically and histomorphometrically. The results showed that all experimental pellets exhibited new bone formation whereas the control pellets produced only fibrous connective tissue. Here, 100% HAP ceramic showed most amount of bone formation, whereas 25% HAP to 75% TCP ceramic produced the bone least in amount among different BCP ceramics at the end of 4 weeks. This study indicates that formation of new bone depends on the ceramic content with high HAP-TCP ratio and high dose of rhBMP-2.

Reconstruction of the primate mandible with a combination graft of recombinant human bone morphogenetic protein-2 and bone marrow.

PURPOSE: This study evaluated whether recombinant human bone morphogenetic protein-2 (rhBMP-2) can be used to regenerate a resected part of the mandible in a primate model. MATERIALS AND METHODS: Segmental bone defects were created surgically in the mandible of Japanese monkeys. rhBMP-2 was suspended in a solution of polyglycolic co-lactic acid (PGLA) and lyophilized to make a BMP/PGLA complex. The rhBMP-2/PGLA complex and autogenous bone marrow in ratios of 3:0, 2.5:0.5, or 2:1 (vol:vol) were each implanted into the bone defects in 3 monkeys. Bone marrow or P(GLA alone were each implanted in 1 monkey as a control. The animals were killed 16 weeks after surgery, followed by radiologic and histologic evaluation. RESULTS: The implantation of bone marrow alone succeeded in reconstruction of the mandible, but the implantation of the rhBMP-2/PGLA complex showed only a small amount of bone formation. The combination graft of rhBMP-2/PGLA and bone marrow resulted in a greater degree of bone formation; especially the 2:1 combination showed the same result as only bone marrow implantation. CONCLUSION: The combination graft of rhBMP-2 and bone marrow, which requires only a small amount of bone marrow, was a reliable method for reconstruction of mandibular segmental defects in this animal model.

Comparative study of biphasic calcium phosphate ceramics impregnated with rhBMP-2 as bone substitutes.

We investigated pellet-shaped implants prepared from biphasic calcium phosphate (BCP) ceramics with five different ratios of hydroxyapatite (HAP) to beta-tricalcium phosphate (beta-TCP) to evaluate these ceramics as bone substitutes. BCP ceramics impregnated with different doses of recombinant human bone morphogenetic protein 2 (rhBMP-2) (1, 5, and 10 microg) were used for experimental purposes and ceramics without rhBMP-2 were used for control. The pellets were implanted under the pericranium in adult Wistar male rats and were harvested 8 weeks after implantation. The retrieved pellets were then examined radiologically, histologically, and histomorphometrically. The results revealed that the pellets treated with rhBMP-2 exhibited new bone and bone marrow, whereas control pellets produced fibrous connective tissues. The formation of new bone induced by rhBMP-2 was dose dependent. The extent of bone and bone marrow formation and the degree of resorption of the ceramic particles were significantly higher in the pellets composed of 25% HAP-75% TCP. In this study, bioresorption of the ceramic produced favorable conditions for rhBMP-2-induced bone formation.

Congenital midline sinus of the upper lip: case report and review of literature.

A case report of a congenital midline sinus of the upper lip in a 5-year-old girl is presented. The patient complained of intermittent swelling around the frenulum of the upper lip. The sinus was located on the midline of the philtrum just below the base of the columella. Excision of the sinus tract via an intraoral approach gave a satisfactory result. Microscopic examination of the resected sinus revealed it to be lined by stratified squamous epithelium with sebaceous glands and hair follicles. Fifteen other cases have been reported in the English literature and are reviewed. There are two postulates that can account for the formation of the upper lip sinus based on two major theories of the development of the face: the fusion theory and the merging theory. However, the etiology of this rare congenital sinus remains obscure.