Reflections on: distraction osteogenesis. Distraction osteogenesis--the future?
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Humans↗
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Reflections on: distraction osteogenesis. Distraction osteogenesis.
Explore the source record for details and available documents.
Humans↗
The molecular biology of distraction osteogenesis.
Distraction osteogenesis has become a mainstay in bone tissue engineering and has significantly improved our armamentarium for reconstructive craniomaxillofacial procedures. However, although the biomechanical, histological, and ultrastructural changes associated with distraction osteogenesis have been widely described, the molecular mechanisms governing the formation of new bone in the interfragmental gap of gradually distracted bone segments remain largely unclear. Recently, a rat model of mandibular distraction was described that provides an excellent environment for deciphering the molecular mechanisms that mediate distraction osteogenesis. This article presents the hypotheses and current research that have furthered knowledge of the molecular mechanisms that govern distraction osteogenesis. Recent studies have implicated a growing number of cytokines that are intimately involved in the regulation of bone synthesis and turnover. The gene regulation of numerous cytokines (transforming growth factor-beta1, -beta2, -beta3, bone morphogenetic proteins, insulin-like growth factor-1, fibroblast growth factor-2) and extracellular matrix proteins (osteonectin, osteopontin) during distraction osteogenesis have been best characterized and are discussed in this article. It is believed that understanding the biomolecular mechanisms that mediate membranous distraction osteogenesis may guide the development of targeted strategies designed to improve distraction osteogenesis and accelerate bone healing.
Animals↗
[The molecular biology of distraction osteogenesis].
Distraction osteogenesis has become a mainstay in bone engineering and the recent application of this technique to the membranous craniofacial skeleton has significantly improved our armamentarium for reconstructive craniomaxillofacial procedures. However, if the biomechanical, histological and ultrastructural changes associated with distraction osteogenesis have been widely described, the molecular mechanisms governing the formation of new bone in the interfragmental gap of gradually distracted bone segments remain largely unclear. Recently, our laboratory has described a rat mandibular distraction model that provides an excellent environment for deciphering the molecular mechanisms that mediate distraction osteogenesis. In this Article, we present the hypotheses and current research that have furthered our knowledge of the molecular mechanisms that govern distraction osteogenesis. Recent studies have implicated a growing number of cytokines that are intimately involved in the regulation of bone synthesis and turnover. The gene regulation of numerous cytokines (Transforming Growth Factor-B, Bone Morphogenetic Proteins, Insulin-like Growth Factor-1, Fibroblast Growth Factor-2) during distraction osteogenesis have been best characterized and will be discussed in this text. We believe that novel systems like the rat model will facilitate our understanding of the biomolecular mechanisms that mediate membranous distraction osteogenesis and will ultimately guide the development of targeted-strategies designed to accelerate bone healing.
Animals↗
Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis.
Distraction osteogenesis is widely used in treating deformities, defects, and fractures of both long bones and craniofacial bones. Demands for acceleration of bone consolidation are increased in distraction osteogenesis. Nerve growth factor (NGF) can enhance innervation and bone regeneration in a fracture model and stimulate differentiation of osteoblastic cells. In this study, we tested the ability of locally applied NGF to enhance bone regeneration in a rabbit model of mandibular distraction osteogenesis. Twenty rabbits underwent bilateral distraction osteogenesis with a rate of 0.5 mm per 12 h. Two times 0.04 mg human NGFbeta (hNGFbeta) in buffer was injected into the callus after distraction. The contralateral side received placebo injections. Rabbits were euthanized at consolidation times of 14 and 28 days. Specimens were subjected to radiography, callus dimensions measurement, mechanical testing, and bone histological and histomorphometric analysis. The maximum load, bone volume/total volume, mineral apposition rate of the 1st to 11th day, and mineralized bone percentage were significantly higher in the hNGFbeta side at 14 and 28 days (p<0.05). The data indicate that locally applied hNGFbeta can accelerate callus maturation and may be an option to shorten the consolidation period in distraction osteogenesis.
Administration, Topical↗
The role of angiogenesis in a murine tibial model of distraction osteogenesis.
Distraction osteogenesis (DO) is one of the most dramatic in vivo applications of mechanical stimulation as a means of inducing bone regeneration. A simple and reproducible murine model of tibia distraction osteogenesis was developed using a monolateral fixator. Bone formation was assessed histologically over a 35-day time course. The steady state expression of a broad family of angiogenesis-associated genes was assessed by microarray hybridization analyses over the same time course, while the immediate gene response that was induced during each cycle of distraction was assessed at 30 min and 8 h after the first and last rounds of activation of the fixator. Distraction osteogenesis promoted new bone formation primarily through an intramembranous process with maximal osteogenesis during the active distraction period. Histological analysis also showed that dense cortical bone continued to be formed, during the consolidation phase, for 2 weeks after distraction ended. The analysis of steady state mRNA expression levels over the time course of DO showed that VEGF-A and neuropilin, an alternate receptor for VEGF-A, both angiopoietin (Ang) 1 and 2 factors, and the Ang receptor Tie2 were the critical angiogenic factors during DO. A key transcriptional regulator of many of the angiogenic factors, hypoxia-induced factor1alpha (Hif-1a), the FGF binding protein pleiotropin/OSF1, and multiple MMP(s), were also induced during the active distraction period. Examination of the expression of angiogenic factors that were induced after each cycle of activation, demonstrated that Hif-1a, Nrp1, and VEGF-A were all cyclically induced after each increment of distraction. These results suggest that these factors are early mediators that are produced by distraction and contribute toward the processes that promote bone formation. These experiments represent the first step in defining the molecular mechanisms that regulate skeletal regeneration and the functional relationship between angiogenesis and osteogenesis during distraction osteogenesis.
Animals↗
A CT scan technique for quantitative volumetric assessment of the mandible after distraction osteogenesis.
Distraction osteogenesis has become an accepted method of treatment for patients requiring reconstruction of hypoplastic mandibles. We present a quantitative analysis of volumetric changes after distraction osteogenesis in a series of 10 patients. Group I (n = 5 patients, 3 unilateral craniofacial microsomia, 1 Goldenhaar syndrome, and 1 bilateral craniofacial microsomia) underwent unilateral distraction of the mandible. Group II (n = 5 patients, 1 Nager syndrome, 1 bilateral craniofacial microsomia, 1 developmental micrognathia, and 2 Treacher Collins syndrome) underwent bilateral distraction of the mandible. Predistraction and postdistraction axial and three-dimensional computed tomographic (CT) scans were digitized and transferred to a computer for analysis with image-processing software to determine the changes in volume of the mandible and bony regenerate. The CT-derived volume method was validated by scanning three dry cadaver mandible specimens and comparing the volume data with those derived from a water-displacement method. The difference between the two methods was less than 5 percent. The mean distracted length, as recorded from the calibrated device, was 22.6 mm in the 10 patients. In the unilateral distraction group, the mean increase in hemimandibular bone volume was 2.8 cc, with a mean percentage increase of 27 percent in the distracted hemimandible. In the bilaterally distracted patients, the mean increase in total mandibular volume was 7.9 cc, with a mean percentage increase in bone volume of 25 percent. This study represents the first attempt to quantify the increase in bone volume resulting from distraction osteogenesis. Quantitative volumetric analysis of CT scans is an accurate method to measure the amount of bone regenerate in patients undergoing distraction osteogenesis of the mandible or the extremities. The concept and utility of quantifying the volumetric changes in bone following distraction osteogenesis may become more important as multiplanar devices are developed and used in other areas of the craniofacial skeleton.
Adolescent↗
Expression of angiogenic factors during distraction osteogenesis.
Distraction osteogenesis is a unique and effective way to treat limb length inequality resulting from congenital and posttraumatic skeletal defects. However, despite its widespread clinical use, the cellular and molecular mechanisms by which this surgical treatment promotes new bone formation are not well understood. Previous studies in distraction osteogenesis have noted increased blood flow and vessel formation within the zone of distraction. These observations suggest that distraction osteogenesis may be driven in part by an angiogenic process. Using immunohistological analysis, the expression of two different angiogenic factors (VEGF and bFGF) was shown to localize at the leading edge of the distraction gap, where nascent osteogenesis was occurring. These cells were spatially adjacent to new vessels that were identified by staining for factor VIII. Microarray analysis detected maximal mRNA expression for a wide variety of angiogenic factors including angiopoietin 1 and 2, both Tie receptors, VEGF-A and -D, VEGFR2, and neuropilin 1. Expression of these factors was found to be maximal during the phase of active distraction. Expression of mRNA for extracellular matrix proteins and BMPs was also maximal during this period. A comparison between the patterns of gene expression in fracture healing and distraction osteogenesis revealed similarities; however, the expression of a number of genes showed selective expression in these two types of bone healing. These data suggest that bone formation during distraction osteogenesis is accompanied by the robust induction of factors associated with angiogenesis and support further investigations to elucidate the mechanisms by which angiogenic events promote bone repair and regeneration.
Angiogenesis Inducing Agents↗
Three-dimensional finite element analysis of the mandible and temporomandibular joint on simulated occlusal forces before and after vertical ramus elongation by distraction osteogenesis.
Distraction osteogenesis has recently become a mainstay for treatment of mandibular hypoplasia. Thorough knowledge about changes in the temporomandibular joint (TMJ) and the surrounding parts of the mandible and the skull after mandibular distraction is still lacking. The purpose of the current study was to investigate the stress distribution in the mandible and the TMJ before and after skeletal correction by intraoral unilateral vertical mandibular ramus distraction, using a finite element (FE) model. The FE models were based on computed tomography scans and magnetic resonance imaging scans of a patient with unilateral hypoplasia of the right mandibular ramus caused by juvenile idiopathic arthritis. The character of stress distribution in the mandible and TMJ before and after skeletal correction by 15 mm of vertical distraction of the mandibular ramus was analyzed quantitatively and compared during centric occlusion. Before the distraction osteogenesis treatment, the condyles, articular discs, and glenoid fossa regions are loaded with a different stress pattern. The affected right condyle, disc, and fossa are loaded diffusely and externally in comparison with the anterior and with centralized loading on the normal left side. After unilateral mandibular distraction osteogenesis, the load became more centric and symmetrical. The results suggest that correction of the mandibular deformity by distraction osteogenesis tends to normalize the stress patterns in the TMJ.
Arthritis, Juvenile↗
An immunohistochemical analysis of the temporal and spatial expression of growth factors FGF 1, 2 and 18, IGF 1 and 2, and TGFbeta1 during distraction osteogenesis.
Distraction osteogenesis (DO) is a well established surgical technique that generates new bone by gradual distraction of two bony segments. In this study, we investigated the temporal and spatial profile of FGF 1, 2 and 18, IGF 1 and 2, and TGFbeta1 during distraction osteogenesis using immunohistochemistry. An osteotomy was performed on the right tibia of 13 white male New Zealand rabbits. After a delay of 7 days, distraction was started at a rate of 0.25 mm/12 hrs for 3 weeks which was followed by a 3 week period of consolidation. Immunohistochemical analysis was performed on a weekly interval to determine the expression of the growth factors. Staining of all growth factors was apparent at various levels in the centre and callus region in fibroblasts and chondrocyte cells. FGF2 however, showed continued high expression in osteoblasts. Within two weeks after the end of distraction all growth factors showed a reduction in expression except for FGF18 which maintained high levels of expression (up to 100% staining) throughout the distraction and consolidation phases. The study suggests that in comparison to the other investigated growth factors, FGF18 may play in important role throughout the entire process of distraction osteogenesis.
Animals↗
In vitro analysis of distraction osteogenesis.
Distraction osteogenesis has been widely used for lengthening craniomaxillofacial bone. The healing process of distracted bone has been studied mainly by histological observation in vivo. To analyze the cellular response to the mechanical stress of distraction, we have established and evaluated an in vitro model of distraction osteogenesis using an organ culture technique. Five-week-old male Wistar rats were used for the experiments. The tibial bone was fractured by hand and fixed for 1 week by acrylic resin. After the initial healing period, the tibial bone was harvested and used for this study. A distraction instrument was devised to control the strain on the cultured bone using a micrometer. After distraction, the samples were histologically evaluated for ossification by hematoxylin and eosin stain and Alcian blue stain. As a result, the histological finding for the bone region at a slow rate of distraction (0.5 mm/day) was different from that at a rapid rate of distraction (1.0 mm/day). The proliferation of cartilage was inhibited at the rapid distraction rate. Thus, we hypothesized that mechanical stress regulated cartilaginous growth in tissue cultivation. Judging from this experiment, the model was useful for investigation of the mechanism of bone formation in distraction osteogenesis, because it was simple and served to isolate many factors.
Acrylic Resins↗
Expression of basic fibroblast growth factor during distraction osteogenesis.
Distraction osteogenesis is a process of tissue regeneration under an external mechanical stimulation. In the study, the spatial and temporal expression patterns of basic fibroblast growth factor in the newly formed osseous tissue during distraction osteogenesis in goats were studied using immunohistochemistry. During the distraction period, the expression of basic fibroblast growth factor was observed in the osteoblasts on the newly formed trabecular bone and the bone formation front. The cells of osteoblastic lineage and the mesenchymal cells in the distraction callus also expressed basic fibroblast growth factor. The expression of basic fibroblast growth factor in the distraction period was stronger than that during the latency and consolidation periods. However, some osteoblasts still were expressing basic fibroblast growth factor in the consolidation periods. According to these results, basic fibroblast growth factor may have a local regulatory role during distraction osteogenesis. The tensile force may stimulate the expression of basic fibroblast growth factor in osteoblasts and other cell types.
Animals↗
Limb salvage using distraction osteogenesis.
Distraction osteogenesis is a novel technique for the biological restoration of segmental bone defects. Definitive treatment of musculoskeletal tumors often requires large bony resections that can leave patients with significant osseous defects. Limb salvage using distraction osteogenesis is an attractive reconstructive alternative that may, in fact, offer advantages over other conventional techniques. We present our initial experience with the use of distraction osteogenesis in limb salvage.
Adolescent↗
Expression of bone morphogenetic proteins during mandibular distraction osteogenesis.
Distraction osteogenesis is a form of in vivo tissue engineering in which the gradual separation of cut bone edges results in the generation of new bone. In this study, the temporal and spatial expression of bone morphogenetic proteins (BMPs) 2, 4, and 7 was examined in a rabbit model of mandibular distraction osteogenesis. Fourteen skeletally mature male rabbits were studied. After osteotomy, a distractor was applied to one side of the mandible. After 1 week of latency, distraction was initiated at 0.25 mm every 12 hours for 3 weeks (distraction period), followed by a 3-week consolidation period. Two animals were killed each week after surgery. The generate bone was analyzed for the expression of BMP-2, -4, and -7 by using standard bone histological and immunohistochemical techniques. BMP-2 and -4 were highly expressed in osteoblastic cells during the distraction period and in chondrocytes during the consolidation period. BMP-7 demonstrated relatively minor expression in osteoblastic cells during the distraction period. All BMPs were strongly expressed in vascularized connective tissue during the distraction period. These data indicate that BMPs participate in the translation of mechanical stimuli into a biological response during mandibular distraction osteogenesis.
Animals↗
Moulding of the generate to control open bite during mandibular distraction osteogenesis.
Distraction osteogenesis of the craniofacial skeleton has become a widely accepted, safe, and effective means of craniofacial reconstructive surgery. Despite excellent results in general, there are still some uncertainties related to the procedure, such as development of an anterior open bite (AOB) during mandibular distraction. The aim of this study was to examine whether 'moulding of the generate', i.e. use of intermaxillary elastics during the active distraction phase is possible to close the mandibular plane angle and open bite. Three subjects, 13- and 15-year-old males and a 7-year-old female, underwent mandibular linear and angular bilateral distraction osteogenesis with moulding of the generate. Lateral cephalograms were obtained before the introduction of elastics and following distraction, once the activation was stopped and the patients were ready for the consolidation phase. Conventional cephalometric measurements were used to assess possible changes in the mandibular plane angle and incisor position. Three different anchorage systems (dental, orthopaedic, and skeletal) were used for placement of the intermaxillary elastics. Cephalometric examination showed that the mandibular plane angle was decreased during active distraction osteogenesis with the introduction of elastics and angulation of the distraction device. Depending on the type of elastic anchorage system, smaller or greater amounts of extrusion of the incisors were noted. Moulding of the generate during active distraction can be performed to reduce the mandibular plane angle and open bite. To prevent unwanted dentoalveolar changes from occurring during elastic traction, skeletal rather than dental fixation of the elastics is recommended. Intrusive mechanics may be incorporated into the orthodontic appliances to balance extrusive force by the moulding elastics.
Adolescent↗
Computer planning for distraction osteogenesis.
Distraction osteogenesis of the mandible has found an application in the treatment of patients with a variety of different mandibular deformities. Compared with the relatively simple unidirectional distraction of long bones as described by Ilizarov, the three-dimensional distraction of the mandible is extremely complex. Whereas experience with orthognathic surgery clearly demonstrates that careful presurgical planning is necessary to achieve predictable outcomes, there are few reported methods for the planning of mandibular distraction. The authors have developed a method for planning distraction osteogenesis of the mandible that involves the use of three-dimensional modeling and animation to simulate distraction osteogenesis in virtual reality. The first step in the authors' treatment planning process is to obtain a three-dimensional computerized scan of the facial skeleton. From this scan, a three-dimensional wire-mesh model is built using animation software. With the same software, a virtual distractor is built and installed on the wire-mesh model. The osteotomies and the distraction process are then simulated. Finally, a recipe for sequencing the linear and angular changes of the distractor is calculated. The authors have used this planning process in seven patients (age range, 4 to 10 years): four with unilateral mandibular deformities and three with bilateral. The planning process has yielded predictable and reproducible results.
Child↗
Application of locked intramedullary nails in the treatment of complications after distraction osteogenesis.
Distraction osteogenesis (callotasis) has been widely used in patients with limb-length inequality or massive bone defects. This procedure, however, may be associated with a high incidence of physical and psychosocial complications. Callotasis telescoping on a locked intramedullary nail has been used to shorten the period of external fixation. Little attention has been given to the use of locked intramedullary nails in the treatment of complications after callotasis. Between 1990 and 1999, we used locked intramedullary nailing in 27 patients for the treatment of complications after distraction osteogenesis. There were 17 men and ten women with a mean age of 33.2 years (16 to 66). The nail was inserted at a mean of 3.4 weeks (0 to 15) after removal of the external fixator. Simultaneous autogenous bone grafting and soft-tissue reconstruction were also undertaken in seven and two patients, respectively. There was consolidation of the callus or docking site in all patients at a mean of 6.4 months (2 to 14) after surgery. The mean shortening of the callus was 0.7 cm (0 to 2.5). Two patients had infection at the site of a distal screw which resolved after removal of the nail. In 17 patients the nail was removed at a mean of 26 months after its insertion. Locked intramedullary nails are useful in treating complications after distraction osteogenesis in skeletally mature patients. The risk of infection should be borne in mind.
Adolescent↗
Sustained expression of transforming growth factor-beta1 by distraction during distraction osteogenesis.
Distraction osteogenesis is a well-established clinical treatment for limb length discrepancy and skeletal deformities. In our previous studies, we have shown that the tension at the distraction gap correlated with the plasma bone specific alkaline phosphatase activity during distraction. Transforming growth factor-beta1 (TGF-beta1) has been shown to have a regulatory role in alkaline phosphatase activity during fracture healing. This study is to investigate the expression of TGF-beta1 during distraction as a biological response to mechanically stimulated osteoblastic activity by immunohistochemistry. The expression of TGF-beta1 in the distraction callus was compared with that in the fracture callus. During the distraction phase, the osteoblasts and osteocytes expressed a high level of TGF-beta1. Moderate expression of TGF-beta1 was observed in fibroblast-like cells in the fibrous zone of the distraction callus. After the distraction stopped, the expression of TGF-beta1 in different cell types decreased. In fracture healing, the strong expression of TGF-beta1 declined after the first week. Our results showed that the mechanical force induced and sustained TGF-beta1 expression in osteoblasts and fibroblasts-like cells of the distraction callus. Transforming growth factor-beta1 may play a role in transducing mechanical stimulation to biological tissue during in distraction osteogenesis.
Animals↗