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Denervation during mandibular distraction osteogenesis results in impaired bone formation.

ABSTRACT: Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy ("DO Den") and DO with IAN intact ("DO Inn"). DO Den demonstrated significantly reduced histological and radiological osteogenesis relative to DO Inn. Denervation preceding DO results in reduced SSC amplification and osteogenic potential in mice. Single cell RNA sequencing analysis revealed that there was a predominance of innervated SSCs in clusters dominated by pathways related to bone formation. A rare human patient specimen was also analyzed and suggested that histological, radiological, and transcriptional alterations seen in mouse DO may be conserved in the setting of denervated human mandible distraction. Fibromodulin (FMOD) transcriptional and protein expression were reduced in denervated relative to innervated mouse and human mandible regenerate. Finally, when exogenous FMOD was added to DO-Den and DO-Inn SSCs undergoing in vitro osteogenic differentiation, the osteogenic potential of DO-Den SSCs was increased in comparison to control untreated DO-Den SSCs, modeling the superior osteogenic potential of DO-Inn SSCs.

SUBMITTER: Tevlin R

PROVIDER: S-EPMC9902545 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Denervation during mandibular distraction osteogenesis results in impaired bone formation.

Tevlin Ruth R Griffin Michelle M Chen Kellen K Januszyk Michael M Guardino Nick N Spielman Amanda A Walters Shannon S Gold Garry Evan GE Chan Charles K F CKF Gurtner Geoffrey C GC Wan Derrick C DC Longaker Michael T MT

Scientific reports 20230206 1

Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy ("DO Den") and DO with IAN intact ("DO Inn"). DO ...[more]

PMID: 36747028

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Project description:Background: Interfragmentary movements have benefits in the improvement of bone formation during distraction osteogenesis (DO). Although several clinical studies reported positive outcomes regarding the application of the cyclic distraction-compression (CDC) dynamization technique in cases with poor bone formation during DO, they are mostly anecdotal without a detailed description. The purpose of this study was to investigate the effectiveness and potential mechanism of different amplitudes and rates of the CDC technique on bone regeneration in a rat femur DO model. Methods: A total of 60 adult male Sprague-Dawley rats underwent right femoral mid-diaphysis transverse osteotomy and were randomly and evenly divided into Control (no manipulation), Group1 (CDC therapy), Group2 (CDC therapy with larger amplitude), and Group3 (CDC therapy with a slower rate) after distraction. The CDC technique was performed during the middle phase of the consolidation period according to different protocols. Animals were sacrificed after 4 and 6 weeks of consolidation. The process of bone formation was monitored by digital radiographs, and the regenerate bone was evaluated by micro-computed tomography (micro-CT), biomechanical test, and histological analysis. The serum contents of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assay (ELISA). Results: Bone regeneration after the CDC technique was improved significantly during DO. The digital radiograph, micro-CT, histomorphological analysis, and biomechanical evaluation showed better effects regarding volume, continuity, and mechanical properties of the regenerate bone in Group2 and Group3 when compared to Group1. The angiogenic and osteogenic markers were more highly expressed in Group2 and Group3 than in Group1 according to the immunohistochemical analysis. As for ELISA, the serum contents of HIF-1α and VEGF were also increased after the CDC technique, especially in Group2 and Group3. Conclusion: The CDC dynamization technique has benefits on the improvement of bone formation during DO, and the mechanism may be due to tissue hypoxia activating the HIF pathway followed by the augmentation of osteogenic-angiogenic coupling. Better outcomes may be achieved by moderately increasing the amplitude and slowing down the rate of the CDC technique.

Project description:ObjectiveThe aim of the study was to report our experience with placed allogenic acellular bone matrix and mandibular distraction osteogenesis in Pierre Robin sequence (PRS), and explore the role of distraction in the osteogenesis of acellular bone.Materials and methodsA total of 428 neonates with severe PRS managed with placing allogenic acellular bone and bilateral mandibular distraction osteogenesis were included in the study. The procedure included using oblique-shaped osteotomy, fixing bilateral mandibular distractor, instantly extending a 4-6 mm gap, and placing allogenic acellular bone into the gap. The length of allogenic acellular bone was 4-5 mm. Although the surgical techniques, distraction, and consolidation periods were similar, the allogenic acellular bone matrix we placed was quite different from the traditional distraction. With the technology we used, tracheal intubation could be immediately removed, thus quickly improving breathing conditions compared to traditional methods after the surgery. The jaw extending and oral feeding could begin on the 5th day. The jaw was extended 0.6 mm twice a day until the mandible was overcorrected by 20%.ResultsAll 428 cases included in this study were successfully extubated after the operation, and the difficulty in breathing was instantly relieved. Total mandibular distraction was 15-20 mm. Oral feeding was started at 6 h to 6 days postoperatively, while hospital stay ranged from 18 to 20 days postoperatively. No major complications were reported. Medium to long-term results was good. Mandibular distractors were removed after 3 months.ConclusionsBilateral mandibular distraction osteogenesis combined with placing allogenic acellular bone in the neonate are safe and accurate procedures, which are the primary treatment options for cases of severe PRS. It can be considered that the tension of distraction can promote osteogenesis in acellular bone and thus improve distractive effect of the mandible.

Project description:BackgroundHypoxia is the critical driving force for angiogenesis and can trigger the osteogenic-angiogenic coupling followed by the enhancement of bone regeneration. While lots of studies showed that hypoxia administration can accelerate bone formation during distraction osteogenesis (DO), the therapeutic timing for the osteogenic purpose was concentrated on the distraction phase. The outcomes of hypoxia administration in the consolidation phase stay uncertain. The purpose of this study was to determine the osteogenic effectiveness of hypoxia therapy during the consolidation phase, if any, to enhance bone regeneration in a rat femoral DO model.MethodsA total of 42 adult male Sprague-Dawley rats underwent right femoral mid-diaphysis transverse osteotomy and were randomly divided into Control (NS administration, n = 21) and Group1 (deferoxamine therapy, n = 21) after distraction. During the consolidation phase, Group1 was treated with local deferoxamine (DFO) injection into the distraction zone, while the Control underwent the same dosage of NS. Animals were sacrificed after 2, 4, and 6 weeks of consolidation. The process of bone formation and remodeling was monitored by digital radiographs, and the regenerated bone was evaluated by micro-computed tomography (micro-CT), biomechanical test, and histological analysis. The serum content of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by enzyme linked immunosorbent assay (ELISA) for further analysis.ResultsBone regeneration was significantly enhanced after hypoxia therapy during the consolidation phase. The digital radiograph, micro-CT, and biomechanical evaluation showed better effects regarding volume, continuity, and mechanical properties of the regenerated bone in Group1. The histomorphological evaluation also revealed the hypoxia treatment contributed to accelerate bone formation and remodeling during DO. The higher positive expression of angiogenic and osteogenic markers were observed in Group1 after hypoxia administration according to the immunohistochemical analysis. The serum content of HIF-1α and VEGF was also increased after hypoxia therapy as evidenced from ELISA.ConclusionHypoxia administration during the consolidation phase of distraction osteogenesis has benefits in enhancing bone regeneration, including accelerates the bone formation and remodeling.

Project description:BackgroundThe clinical characteristics of bone nonunion during distraction osteogenesis (DO) were rarely discussed. This study was employed to specify the difference between bone union and nonunion during DO.MethodsThe patients with bone lengthening were recruited in our study. The bone union cases indicated the ones that remove the external fixator successfully, whereas the bone nonunion represented the bridging callus did not appear even after 9 months (an absence of bridging callus for at least three out of four cortices on plain radiographs) that needs autogenous bone transplantation. The differences in the pixel value ratio (PVR) growth of regenerated callus, lengthening index (LI), healing index (HI), external fixation index (EFI) and blood biochemical indexes between bone union and nonunion were analyzed.ResultsA total of 8 bone nonunion and 27 bone union subjects were included in this study. The PVR growth in bone nonunion was significantly lower than that in bone union (0.19 ± 0.06 vs. 0.32 ± 0.16, P = 0.048). Interestingly, the HI and EFI in bone nonunion was significantly higher than that in bone union (62.0 ± 31.4 vs. 37.0 ± 27.4, P = 0.036; 75.0 ± 30.9 vs. 49.9 ± 16.1, P = 0.006). However, no significant difference with regard to LI was identified (0.76 ± 0.52 vs. 0.77 ± 0.32, P = 0.976). Moreover, the circulating level of urea and lymphocyte count in bone union was significantly lower than that in bone nonunion (4.31 ± 1.05 vs. 5.17 ± 1.06, P = 0.049; 2.08 ± 0.67 vs. 2.73 ± 0.54, P = 0.018). On the contrary, the circulating level of magnesium in bone union was significantly higher than that in bone nonunion (0.87 ± 0.07 vs. 0.80 ± 0.07, P = 0.014).ConclusionCompared to the bone union, the PVR growth was significantly lower, whereas the HI and EFI was significantly higher in the bone nonunion. Moreover, the circulating level of urea, magnesium and lymphocyte count was also different between these two. Therefore, the PVR, HI and EFI seems to be reliable and sensitive indicators to reflect the bone nonunion during DO, which might be considered in bone lengthening. Further prospective studies are still needed to elaborate the concerned issues.

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Denervation during mandibular distraction osteogenesis results in impaired bone formation.

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Denervation during mandibular distraction osteogenesis results in impaired bone formation.

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