Evaluation of safety and efficacy of autologous oral mucosa-derived epithelial cell sheet transplantation for prevention of anastomotic restenosis in congenital esophageal atresia and congenital esophageal stenosis.

BACKGROUND: We performed the first autologous oral mucosa-derived epithelial cell sheet transplantation therapy in a patient with refractory postoperative anastomotic stricture in congenital esophageal atresia (CEA) and confirmed its safety. In this study, patients with CEA and congenital esophageal stenosis were newly added as subjects to further evaluate the safety and efficacy of cell sheet transplantation therapy. METHODS: Epithelial cell sheets were prepared from the oral mucosa of the subjects and transplanted into esophageal tears created by endoscopic balloon dilatation (EBD). The safety of the cell sheets was confirmed by quality control testing, and the safety of the transplantation treatment was confirmed by 48-week follow-up examinations. RESULTS: Subject 1 had a stenosis resected because the frequency of EBD did not decrease after the second transplantation. Histopathological examination of the resected stenosis revealed marked thickening of the submucosal layer. Subjects 2 and 3 did not require EBD for 48 weeks after transplantation, during which time they were able to maintain a normal diet by mouth. CONCLUSIONS: Subjects 2 and 3 were free of EBD for a long period of time after transplantation, confirming that cell sheet transplantation therapy is clearly effective in some cases. In the future, it is necessary to study more cases; develop new technologies such as an objective index to evaluate the efficacy of cell sheet transplantation therapy and a device to achieve more accurate transplantation; identify cases in which the current therapy is effective; and find the optimal timing of transplantation; and clarify the mechanism by which the current therapy improves stenosis. TRIAL REGISTRATION: UMIN, UMIN000034566, registered 19 October 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039393 .

Fate of Costochondral Grafts for Micrognathia: 3D Analysis of Postoperative Length, Position, and Graft Take.

PURPOSE: Costochondral grafting is performed in the reconstruction of severe micrognathia. In this study, we report our experience with graft take, as well as unique findings that have not been focused on in the past literature such as postoperative position and changes in the shape of the graft and thinning of the skull base in contact with the graft. METHODS: Between 2002 and 2019, costochondral grafting was performed on 15 sides of 10 patients with micrognathia. Graft take and other detailed findings such as growth, position, and changes in the shape of the grafts and skull base in contact with the grafts were evaluated using computed tomography images. RESULTS: Graft take was obtained in all cases, and subsequent distraction could be performed in 8 of 10 graft sites as planned. Six of 15 grafts were displaced anterior to the preoperative planned position. However, there were no cases with complications due to deviation such as trismus. Concave deformity of the skull base in contact with the graft was observed in 9 graft sites. The thinning and bending deformation were observed in 2 grafts. CONCLUSIONS: Costochondral grafting was considered a reasonable method for first-line treatment of severe micrognathia. Several unique findings that have not been focused on in the past literature were observed. These should be kept in mind when performing costochondral grafting. Several modifications to the present protocol are suggested to improve the quality of graft take.

First-in-human autologous oral mucosal epithelial sheet transplantation to prevent anastomotic re-stenosis in congenital esophageal atresia.

BACKGROUND: Congenital esophageal atresia postoperative anastomotic stricture occurs in 30-50% of cases. Patients with severe dysphagia are treated with endoscopic balloon dilatation (EBD) and/or local injection of steroids, but many patients continue to experience frequent stricture. In this study, we investigated the transplantation of autologous oral mucosa-derived cell sheets (epithelial cell sheets) as a prophylactic treatment for congenital esophageal atresia postoperative anastomotic stricture. METHODS: Epithelial cell sheets were fabricated from a patient's oral epithelial tissue, and their safety was confirmed by quality control tests. The epithelial cell sheets were transported under controlled conditions from the fabrication facility to the transplantation facility and successfully transplanted onto the lacerations caused by EBD using a newly developed transplantation device for pediatric patients. The safety of the transplantation was confirmed by follow-up examinations over 48 weeks. RESULTS: The dates that EBD was performed were recorded for one year before and after epithelial cell sheet transplantation, and the intervals (in days) were evaluated. For about 6 months after transplantation, the intervals between EBDs were longer than in the year before transplantation. The patients were also aware of a reduction in dysphagia after transplantation. CONCLUSIONS: These results suggest that cell sheet transplantation may be effective in preventing anastomotic stricture after surgery for congenital esophageal atresia, but the effect was temporary and limited in this case. Although we chose a very severe case for the first human clinical study, it may be possible to obtain a more definitive effect if the transplantation is performed before the disease becomes so severe. Future studies are needed to identify cases in which cell sheet transplantation is most effective and to determine the appropriate timeframes for transplantation. TRIAL REGISTRATION: UMIN, UMIN000034566, registered 19 October 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039393 .

Investigation of maxillofacial morphology and oral characteristics with Turner syndrome and early mixed dentition.

Turner syndrome is associated with an X chromosome abnormality in women and is characterized by infantilism, congenital webbed neck, and cubitus valgus. The aim of this study was to determine the maxillofacial morphology and oral characteristics of Japanese girls (mean age, 8.5 years) with Turner syndrome and early mixed dentition. Lateral cephalograms obtained at the first visit were used to analyze maxillofacial morphology. Oral characteristics were identified using orthopantomograms, intraoral photographs, and study casts. All patients received growth hormone. Lateral cephalograms showed a retrognathic maxilla and mandible and a small gonial angle. Nine patients had a high-arched palate. Nine patients had class II first molar relationship occlusion and one had mesial step-type occlusion. Three patients showed ectopic eruption of the maxillary first permanent molar accompanied by resorption of the maxillary second primary molar. Eruption of the permanent teeth tended to occur early. The median mesiodistal diameter of the maxillary central incisor was smaller than the Japanese norm. Ectopic eruption of the maxillary first permanent molar may be caused by lack of eruption space and a discrepancy between bone growth and timing of tooth maturation.

Clinical study of dentocraniofacial characteristics in patients with Williams syndrome.

Williams syndrome (WS) is a rare congenital anomaly that is characterized by distinctive facial features, congenital heart disease, and behavioral characteristics that include mental retardation. However, only a few reports have documented the dentocraniofacial morphological characteristics of WS in Japanese individuals. The aim of this study was to analyze the dentocraniofacial morphology and growth patterns in a group of nine Japanese subjects (two males and seven females; mean age at admission, 10.1 years) with WS. The analytical methods included an initial medical questionnaire, lateral cephalography, panoramic radiography, dental casts, and oral examinations. The dental findings showed congenitally missing teeth, microdontia, and peg-shaped teeth. Regarding cranial morphology, microcephaly occurred at high frequencies, and a short posterior cranial base and thick calvarial bones, including frontal, parietal, and occipital bones, were seen in patients with WS. An analysis of maxillofacial morphology showed the large gonial angles and lingual inclination of the lower incisors in patients with WS. In addition, the chin button was deficient and in three of four growing subjects the maxillofacial growth pattern demonstrated a downward and backward tendency. The results of this study provide important information that will improve our understanding of the characteristics of patients with WS.

Measurement of Distraction Force in Cleft Lip and Palate Patients During Le Fort I Maxillary Advancement With Rigid External Distraction.

OBJECTIVE: Maxillary distraction osteogenesis (DO) is a mainstream surgical technique for patients who have severe maxillary hypoplasia associated with craniofacial syndromes and cleft-related deformities. However, limited information about the biomechanical aspects of maxillary DO is available limiting broad utilization and improvements to the procedure. The objective of this study was to analyze force levels during the active distraction process and to investigate the relationship between distraction force and maxillary movement during Le Fort I maxillary DO using a rigid external distraction (RED) system. PATIENTS: Microtension gauges were integrated into the distraction wires on each side of the RED system. Six patients with cleft lip and palate aged 12.8 to 23.5 years underwent strain gauge measurements during maxillary advancement with DO using an RED system. Lateral cephalograms were taken to measure maxillary horizontal, vertical, and linear movements after DO. RESULTS: The average linear maxillary movement was 11.2 mm (range 8.5-15.9 mm). The applied forces ranged from 13.4 to 26.8 N. The distance of maxillary movement was proportional to the distraction force. CONCLUSIONS: The measurement of distraction forces during DO provides important information with which to establish appropriate protocols. Patients requiring more advancement may require more distraction force. However, other factors such as scarring, patient anatomy, surgical freedom of the osteotomized maxilla, and the like, may affect the required force during DO with the RED system.

Systemic and maxillofacial characteristics of 11 Japanese children with Russell-Silver syndrome.

Russell-Silver syndrome (RSS) is a congenital anomaly characterized by intrauterine and postnatal growth retardation, typical facial features, fifth-finger clinodactyly, and skeletal asymmetry. Although data on intrauterine and postnatal growth retardation have been reported, there are few reports concerning the typical maxillofacial morphology in individuals with RSS. The aim of this study was to describe the details of this systemic condition and to characterize maxillofacial morphology based on cephalograms in 11 Japanese patients (age range, 3.9-12.0 years) with RSS. All 11 individuals had intrauterine and postnatal growth retardation. In addition, most showed mandibular retrognathia and relative macrocephaly. Lateral cephalogram measurements showed that mandibular retrognathia resulted from short mandibular body length, whereas the depth of the cranial base was close to normal. Although asymmetry of hand, foot, and limb length were present in most individuals, obvious facial asymmetry was not common. Differences between left and right skeletal and dental age were not observed, indicating that children with RSS might show asymmetry because of quantitative differences in skeletal growth rather than delayed growth rate. Our findings not only provide important information about the maxillofacial characteristics of RSS, but also help to clarify the association between these characteristics and genetics, which will add to the body of information on clinical symptoms.

Investigation of maxillofacial morphology and dental development in hemifacial microsomia.

Objective : Hemifacial microsomia (HFM) is a congenital anomaly characterized by unilateral underdevelopment of the mandible and ear. This study was conducted to characterize maxillofacial morphology and dental development in Japanese patients with HFM. Design : This is a retrospective hospital-based study. Patients : The subject population comprised 12 boys and 12 girls (average age, 9.3 years) diagnosed with HFM. Main Outcome Measures : We used posteroanterior (PA) and lateral cephalograms obtained at the first visit to analyze maxillofacial morphology and orthopantomograms to compare dental development between the affected and unaffected sides. Dental development was graded according to Nolla's stages of tooth calcification. Results : PA cephalogram analysis showed that the occlusal plane inclined upward on the affected side in each patient. The mandibular body and ramus were smaller on the affected side than on the unaffected side. Lateral cephalogram analysis showed that the patients tended to have steep mandibles, large gonial angles, and a slightly convex facial structure. The affected side/unaffected side ratio of the mandibular body and ramus correlated with SNB, ANB, convexity, and mandibular plane. The difference in dental development between the affected and unaffected sides was significant at the mandibular molars and the mandibular canine. Conclusions : This study demonstrates a correlation between lateral and frontal measurement parameters in patients with HFM. The data also showed delayed calcification in the mandibular molars on the affected side.

Dentomaxillofacial characteristics of ectodermal dysplasia.

The aim of this retrospective hospital-based study was to elucidate the dentomaxillofacial characteristics of ectodermal dysplasia. Six Japanese individuals (one male and five female; age range, 12.7-27.2 years) underwent comprehensive examinations, including history recording, cephalometric analysis, panoramic radiography, and analysis of dental models. All the subjects had two or more major manifestations for clinical diagnosis of ectodermal dysplasia (e.g., defects of hair, teeth, nails, and sweat glands). They presented hypodontia (mean number of missing teeth, 9.5; range, 5-14), especially in the premolar region, and enamel dysplasia. Five subjects had bilateral molar occlusion, whereas one subject had unilateral molar occlusion. The common skeletal features were small facial height, maxillary hypoplasia, counterclockwise rotation of the mandible, and mandibular protrusion. Interestingly, the maxillary first molars were located in higher positions and the upper anterior facial height was smaller than the Japanese norm. The results suggest that vertical and anteroposterior maxillary growth retardation, rather than lack of occlusal support due to hypodontia, leads to reduced anterior facial height in individuals with ectodermal dysplasia.

Long-term maxillomandibular changes after maxillary distraction osteogenesis in growing children with cleft lip with or without palate.

Objective : To evaluate the long-term maxillomandibular changes after maxillary distraction osteogenesis in growing children having cleft lip with or without cleft palate. Patients : Eight Japanese patients with cleft lip with or without cleft palate aged 9.3 to 13.1 years. Measures : The maxillary and mandibular positions before (T0), immediately after (T1), and 1, 3, and 5 years after distraction osteogenesis (T2, T3, and T4, respectively) measured on cephalograms superimposed at the sella turcica with the Frankfort horizontal plane as the horizontal reference. The anterior nasal spine (x, y), pogonion (x), and menton (y) were used for linear measurements, and sella turcica-nasion-point A, sella turcica-nasion-point B, and point A-nasion-point B angles were used for angular measurements. Results : The mean horizontal maxillary advancement (anterior nasal spine [x]) was 12.3 mm during T0 to T1, but -2.7, -1.1, and -0.1 mm of the posttreatment changes were observed during T1 to T2, T2 to T3, and T3 to T4, respectively. Anterior nasal spine (y) shifted 2.3 mm downward during T0 to T1, and further downward changes were observed during T1 to T2 and T2 to T3 (P < .05). Pogonion (x) did not show distinct changes due to individual variance, but menton (y) shifted downward from T1 to T4. Sella turcica-nasion-point A significantly decreased during T1 to T2 and T2 to T3 but not during T3-T4. Point A-nasion-point B significantly decreased only during T2 to T3, and sella turcica-nasion-point B did not show any distinct change. Conclusions : There was no further maxillary advancement after distraction osteogenesis in the growing children with cleft lip with or without cleft palate. Therefore, long-term observation and management of occlusion in case of the mandibular growth pattern are important.

Dental and maxillofacial characteristics of six Japanese individuals with ectrodactyly-ectodermal dysplasia-clefting syndrome.

Objective : Ectrodactyly-ectodermal dysplasia-clefting syndrome is a congenital anomaly characterized by ectodermal dysplasia, ectrodactyly, cleft lip and palate, and lacrimal duct anomalies. Because this syndrome is frequently accompanied by a congenital lack of teeth, narrow palate, and malocclusion, comprehensive orthodontic intervention is required. Design : To highlight the specific dental and maxillofacial characteristics of ectrodactyly-ectodermal dysplasia-clefting syndrome, six Japanese individuals diagnosed with the syndrome are described here. Patients : The subjects consisted of two boys and four girls (age range, 6.0 to 13.9 years) diagnosed with ectrodactyly-ectodermal dysplasia-clefting syndrome by medical and dental specialists. Their conditions included ectodermal dysplasia (hypodontia, microdontia, enamel hypoplasia, and abnormalities in hair and nails), cleft lip and/or palate, and ectrodactyly. Cephalograms, panoramic x-rays, and dental casts were taken; systemic complications were recorded at the first visit to our dental hospital. Results : All individuals had severe oligodontia with 9 to 18 missing teeth. The missing teeth were mainly maxillary and mandibular incisors and second bicuspids, arranged in a symmetrical manner. Cephalometric analysis showed retruded and short maxilla due to cleft lip and/or palate. It is interesting that all individuals showed a characteristically shaped mandibular symphysis with a retruded point B. It is likely that this unusual symphyseal morphology is due to the lack of mandibular incisors. Conclusions : This study demonstrates the presence of severe oligodontia in the incisal and premolar regions and describes a characteristic maxillary and mandibular structure in Japanese individuals with ectrodactyly-ectodermal dysplasia-clefting syndrome.

Systemic and maxillofacial characteristics of patients with Beckwith-Wiedemann syndrome not treated with glossectomy.

INTRODUCTION: Beckwith-Wiedemann syndrome (BWS) is a genetic disorder characterized by exomphalos, macroglossia and gigantism. Previous studies reported a wide variation in the skeletal and occlusal characteristics in individuals affected by BWS. However, these studies were performed by analyzing both individuals who had and those had not received a glossectomy, which has a high impact on the jaw growth and occlusion. To highlight the intrinsic characteristics of BWS, 7 Japanese affected individuals without glossectomy were analyzed in this study. METHODS: Seven individuals who had been diagnosed with BWS by medical specialists and had not undergone glossectomy were analyzed. Cephalograms and dental casts were taken and systemic complications were recorded at the first visit. RESULTS: Individuals uniformly showed a higher birth height and weight, macroglossia, large anterior cranial base, and mandibular body. They exhibited a wide dental arch and an anterior open bite due to the undererupted and proclined anterior teeth. A wide variation was seen in the gonial angle, but the facial height was large overall. CONCLUSIONS: As intrinsic characteristics of BWS, individuals exhibited macroglossia resulting in an anterior open bite and a wide dental arch. A long facial height and an enlarged anterior cranial base and mandibular body were also noted.

Amount of bone lengthening affects blood flow recovery and bone mineralization after distraction osteogenesis in a canine cleft palate model.

OBJECTIVES: Distraction osteogenesis has been applied to the craniofacial region. To reduce the cleft width of patients with cleft lip and palate, alveolar bones are distracted toward the cleft. However, no reports have described limitations to the amount of lengthening that can be achieved by distraction osteogenesis in this area. Therefore, we investigated the healing process following different extents of distraction osteogenesis using a canine cleft palate model. METHODS: A 10-mm bone defect was made in the palates. A bony segment including the canine was prepared and translocated into the defect area at a rate of 1 mm/d for 6 or 10 days, resulting in two groups (6- and 10-mm groups). Canine pulpal blood flow was monitored for 100 days with Doppler flowmetry. Then, the animals were sacrificed and the regenerated bone area was evaluated radiologically and histologically. Statistical significance was confirmed with the Mann-Whitney rank test. RESULTS: Pulpal blood flow in the 6-mm group recovered to original levels earlier than in the 10-mm group. Cortical bone density in the regenerated bone, measured by peripheral quantitative computed tomography, was significantly greater in the 6-mm group than in the 10-mm group. The amount of regenerated bone in histologic sections was also significantly greater in the 6-mm group. CONCLUSION: We clearly showed that healing progress depends on the extent of distraction osteogenesis, highlighting the importance of limited distraction osteogenesis in the alveolar area.

The effects of hyperbaric oxygen on tooth movement into the regenerated area after distraction osteogenesis.

OBJECTIVE: To analyze the effect of hyperbaric oxygen on newly formed bone in distracted areas surrounding the root of a moving tooth by histological and radiological analysis. It was hypothesized that the application of hyperbaric oxygen to a tooth moving into the distracted area would accelerate ossification and vascularization of newly formed bone in the distracted space. DESIGN: Ten dogs were used. After creating a 10-mm-long bone defect, a bony segment was prepared and translocated into the defect area at a rate of 1 mm/d for 10 days. Following the distraction period, tooth movement was started and the dogs were divided into two groups. The HBO group received hyperbaric oxygen; whereas, the control group did not. At 150 days after tooth movement, the distracted area around the moving tooth was evaluated radiologically and histologically. Differences between groups were confirmed by a Mann-Whitney U test. RESULTS: Trabecular bone density and cortical and subcortical bone areas measured by peripheral quantitative computed tomography in the HBO group were significantly higher than those in the control group. Histological observations revealed regenerated bone and blood vessels formation in the tension site of the moving tooth in the HBO group. The regenerated bone structure measured by bone histomorphometry was larger and more active in bone formation in the HBO group than in the control group. CONCLUSIONS: Applying hyperbaric oxygen to tooth movement into a distracted area appears to accelerate ossification and vascularization of regenerated bone in the that area.

Case report of de novo dup(18p)/del(18q) and r(18) mosaicism.

This is a report of a 27-year-old woman with an unusual de novo chromosomal abnormality. Mosaicism was identified in peripheral blood cells examined by standard G-bands by trypsin using Giemsa (GTG) analysis and fluorescence in situ hybridization (FISH) analysis with chromosome-18 region-specific probes, 46,XX,del(18)(pter --> q21.33:)[41], 46,XX,r(18)(::p11.21 --> q21.33::)[8], and 46,XX,der(18)(pter --> q21.33::p11.21 --> pter)[1]. On the other hand, the karyotype of periodontal ligament fibroblasts was nonmosaic, 46,XX, der(18)(pter --> q21.33::p11.21 --> pter)[50]. All cell lines appeared to be missing a portion of 18q (q21.33 --> qter). The pattern of the dup(18p)/del(18q) in the rod configuration raises the possibility of an inversion in chromosome 18 in one of the parents. However, no chromosomal anomaly was detected in either parent. The most probable explanation is that de novo rod and ring configurations arose simultaneously from an intrachromosomal exchange. The unique phenotype of this patient, which included primary hypothyroidism and primary hypogonadism, is discussed in relation to her karyotype.

Genetic variation of the MHC DQB locus in the finless porpoise (Neophocaena phocaenoides).

The Major Histocompatibility Complex (MHC) is a large multigene coding for glycoproteins that play a key role in the initiation of immune responses in vertebrates. The exon 2 region of the MHC DQB locus was analyzed using 160 finless porpoises from 5 populations in Japanese waters. The 5 populations were based on a previous mitochondrial DNA control region analysis, which showed distinct geographical separation. Eight DQB alleles were detected, and the geographical distribution of the alleles indicated that most of them are shared among the populations. Heterozygosity of the DQB alleles in each population ranged from 0.55 to 0.78, and for all 5 populations was 0.78. Low MHC variability is not a common feature in marine mammals, but the finless porpoise populations inhabiting coastal waters had a relatively high MHC heterozygosity. Balancing selection in the MHC DQB alleles of the finless porpoise was indicated by the higher rate of nonsynonymous than synonymous substitutions for PBR; however, an excess of hetrozygotes compared to expectation was not observed. This suggests that the MHC DQB locus in the finless porpoise may have been under balancing selection for a long evolutionary time period, and is influenced by genetic drift beyond the effect of balancing selection for short time periods in small local populations.

Simultaneous maxillary distraction osteogenesis using a twin-track distraction device combined with alveolar bone grafting in cleft patients: preliminary report of a technique.

The simultaneous use of cleft reduction and maxillary advancement by distraction osteogenesis has not been applied routinely because of the difficulty in three-dimensional control and stabilization of the transported segments. This report describes a new approach of simultaneous bilateral alveolar cleft reduction and maxillary advancement by distraction osteogenesis combined with autogenous bone grafting. A custom-made Twin-Track device was used to allow bilateral alveolar cleft closure combined with simultaneous maxillary advancement, using distraction osteogenesis and a rigid external distraction system in a bilateral cleft lip and palate patient. After a maxillary Le Fort I osteotomy, autogenous iliac bone graft was placed in the cleft spaces before suturing. A latency period of six days was observed before activation. The rate of activation was one mm/d for the maxillary advancement and 0.5 mm/d for the segmental transport. Accordingly, the concave facial appearance was improved with acceptable occlusion, and complete bilateral cleft closure was attained. No adjustments were necessary to the vector of the transported segments during the activation and no complications were observed. The proposed Twin-Track device, based on the concept of track-guided bone transport, permitted three-dimensional control over the distraction processes allowing simultaneous cleft closure, maxillary distraction, and autogenous bone grafting. The combined simultaneous approach is extremely advantageous in correcting severe deformities, reducing the number of surgical interventions and, consequently, the total treatment time.

Attitude of the canine in secondary bone-grafted and nongrafted patients with cleft lip and palate.

OBJECTIVE: To investigate the eruption pattern of the cleft-side canine regarding its pre-eruption position relative to the cleft in bone-grafted (BG) and nongrafted (NonBG) patients with cleft lip and palate. METHODS: Fifty-three patients with cleft lip and palate (21 BG, 32 NonBG) were examined by panoramic radiography and posteroanterior cephalography taken before and after canine eruption. Subjects were categorized into BG, NonBG, and control groups. Canines at the pre-eruption stage were categorized as close to (group 1) or distant from (group 2) the cleft area. The canine angle and its change between the two stages were evaluated. RESULTS: No significant differences were noted between the initial canine angle of the BG and NonBG groups. Although canines in the BG group erupted without a significant change in angle, the canine angle increased significantly (p < .0001) in the NonBG and control groups. In group 1, a greater change in canine angle was noted in the NonBG (p < .05) and control (p < .01) groups than in the BG group. In group 2, no significant difference was noted among the three groups. CONCLUSIONS: In BG patients, a canine located near the cleft appears to erupt at the same angle as it had before grafting. However, in NonBG patients, it erupts more vertically, guided by cortical bone. For canines distant from the cleft area, there is no significant difference in the change in angulation between NonBG and BG patients.

Experimental tooth movement into bone induced by recombinant human bone morphogenetic protein-2.

OBJECTIVE: The development of biomaterials for secondary bone grafting to the alveolar cleft, recombinant human morphogenetic protein-2 (rhBMP-2) may have great potential to promote osseous regeneration. The purpose of this study was to investigate the osteoinductive activity of low-dose rhBMP-2 (10 microg/100 microL) and the biological response of newly generated bone to orthodontic stimulation, compared with previous results using high-dose rhBMP-2 (40 microg/100 microL). METHOD: After extraction of the maxillary first premolars, bone defects were surgically created in eight adult beagle dogs using a 5-mm-diameter trepan bar. The rhBMP-2 with a PLGA/gelatin sponge complex (PGS) made of gelatin and polylactic acid polyglycolic acid copolymer was immediately implanted. The osteoinductive activity of rhBMP-2 and tooth movement into the newly generated bone was evaluated based on histological and morphometric examination. RESULTS: Dramatic histological and morphometric differences were found in the time course of bone remodeling between low- and high-dose rhBMP-2. The onset of bone remodeling occurred significantly earlier in low-dose rhBMP-2. During experimental tooth movement, in contrast to high-dose rhBMP-2, with which root resorption occurred, only partial cementum resorption occurred on the pressure side with low-dose rhBMP-2. CONCLUSION: These results indicated that the proper dosage of rhBMP-2 should be determined for successful clinical application.