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Chondrocyte hypertrophy is a significant factor in cartilage development, yet the molecular mechanism for cell volume expand during the process is remains unclear. In the present study, the relationship between Swell1, a cell volume regulated anion channel, and chondrocyte hypertrophy was explored. The results reveal that the spatiotemporal expression of Swell1 was similar with the development process of hypertrophic chondrocytes in condyles. Through Col10a1 mediated knock out of Swell1 in hypertrophy chondrocytes, we found that there are less obvious boundary between different condylar cartilage layers in which increased hypertrophic chondrocytes were scattered in all three cartilage layers. The cortical bone mass and bone mineral density in the subchondral bone significantly increased. Additionally, knock out of Swell1 could increase the expression of OCN in the femur condyle. Based on the aforementioned findings, a conclusion could be drawn that Swell1 is a significant factor in chondrocyte hypertrophy during the condylar osteochondral development process, and there was some difference between the mandibular and femur condyles, which will provide some new clues for understanding the development of cartilage and related diseases.

Aberrations in tissue-specific enhancers underlie many developmental defects. Disrupting a noncoding region distal from the human SOX9 gene causes the Pierre Robin sequence (PRS) characterized by the undersized lower jaw. Such a craniofacial-specific defect has been previously linked to enhancers transiently active in cranial neural crest cells (CNCCs). We demonstrate that the PRS region also strongly regulates Sox9 in CNCC-derived Meckel’s cartilage (MC), but not in limb cartilages, even after decommissioning of CNCC enhancers. Such an MC-specific regulatory effect correlates with the MC-specific chromatin contacts between the PRS region and Sox9 , highlighting the importance of lineage-dependent chromatin topology in instructing enhancer usage. By integrating the enhancer signatures and chromatin topology, we uncovered >10,000 enhancers that function differentially between MC and limb cartilages and demonstrated their association with human diseases. Our findings provide critical insights for understanding the choreography of gene regulation during development and interpreting the genetic basis of craniofacial pathologies.

The present study aimed to explore the efficacy and safety profile of liquid phase concentrated growth factor (LPCGF) in promoting autologous fat graft survival. LPCGF/PRP was mixed with human fat tissues at different proportions and transplanted into nude mice. Three months after transplantation, the implanted fat tissues were retrieved for analysis. H&E staining was used to quantify the neovascularization. Immunohistochemical staining was applied to quantify the CD34-positive stem cells and the fluorescence intensity of VEGF and TGF-β. Addition of LPCGF to autologous fat reduced the fat absorption by 5–15%, especially at the early stage, and no complications were observed. In addition, the effect was improved with increased CGF. Liquid phase concentrated growth factor improves autologous fat graft survival, and the most suitable ratio of LPCGF/fat is 1:8. LPCGF is rich in VEGF, TGF-β and CD34-positive stem cells, which can improve the fat transplantation effect, but the specific influence of a single component requires future evaluation. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

With this research, we aimed to evaluate the effect of condylar osteochondroma (OC) resection through an intraoral approach on the masticatory functions. Resection of condylar OC was carried out via an intraoral approach with the help of three-dimensional (3D) design, endoscope, and navigation system. The T-Scan III computerised occlusal analysis system was used to evaluate the occlusal force distribution, recorded at pre-treatment (T1) and post-treatment (T2) intervals. Records of the clinical examination of the temporomandibular joint (TMJ), including maximal interincisal opening, mandibular lateral and forward movements, were also collected. Ten patients with condylar OC were enrolled in this study. The difference of force distribution between bilateral occlusion was reduced in T2 compared with T1 (11.92% ± 4.41% vs 48.52 % ± 28.37%, p0.05), indicating better occlusal force distribution obtained after surgery. There was no significant difference in functions of the TMJ, such as maximal interincisal opening, and mandibular lateral and forward movements between T2 and T1 (p0.05). Accordingly, condylar OC resection through an intraoral approach would obtain a satisfactory occlusal balance with no impairment of the temporomandibular joint functions.

Purpose The aim of this study was to evaluate whether surgical treatment can distinctly improve temporomandibular joint (TMJ) function and morphology in adult patients with condylar head fractures (CHFs) when compared with conservative treatment. Patients and methods A retrospective study was performed to evaluate surgical and conservative outcomes in all patients who had suffered CHFs. In this study, all patients were divided into a surgical group and a conservative group. In the surgical group patients were treated by open reduction and internal fixation (ORIF) combined disc anchorage, while in the conservative group patients were treated by a removable splint combined with intermaxillary elastics. Clinical and radiological outcomes were evaluated and functional outcomes were assessed using the Helkimo index score. Paired t-tests, Wilcoxon signed rank tests, independent t-tests and χ2 tests were used to assess inter-group differences. Results 75 TMJs in 56 patients were included in this study and were divided into a surgical group (56 TMJs in 40 patients) and a conservative group (19 TMJs in 16 patients). The results showed that the Helkimo index score for TMJ in the surgical group was better than in the conservative group (pAi = 0.032, pDi = 0.001, respectively). Ramus height in the surgical group (61.08 ± 4.04 mm) recovered more than in the conservative group (54.82 ± 3.06 mm) (p = 0.012). Discs became shorter, moved further forward, and became severely distorted in the conservative group (disc length = 7.32 ± 1.35 mm). In contrast, discs became longer, retained a normal disc–condyle relationship, and formed a normal shape in the surgical group (disc length = 11.05 ± 2.07 mm) (p = 0.003). According to the MRI images, joint effusion, retrodiscal tear, and lateral capsular tear were better cured in the surgical group (p = 0.001, p Conclusion Based on these results, it seems that surgical treatment of condylar head fractures should be the preferred approach if there are no contraindications for general anesthesia.

Micrognathia is a common craniofacial deformity which represents hypoplastic development of the mandible, accompanied by retrognathia and consequent airway problems. Usually, micrognathia is accompanied by multiple systematic defects, known as syndromic micrognathia, and is in close association with genetic factors. Now, large quantities of pathogenic genes of syndromic micrognathia have been revealed. However, how these different pathogenic genes could lead to similar phenotypes, and whether there are some common characteristics among these pathogenic genes are still unknown. In this study, we proposed a genetic-phenotypic classification of syndromic micrognathia based on pathogenic genes information obtained from Phenolyzer, DAVID, OMIM, and PubMed database. Pathogenic genes of syndromic micrognathia could be divided into four groups based on gene function, including cellular processes and structures, cell metabolism, cartilage and bone development, and neuromuscular function. In addition, these four groups exhibited various clinical characteristics, and the affected systems, such as central nervous system, skeletal system, cardiovascular system, oral and dental system, respiratory system and muscle, were different in these four groups. This classification could provide meaningful insights into the pathogenesis of syndromic micrognathia, and offer some clues for understanding the molecular mechanism, as well as guiding precise clinical diagnosis and treatment for syndromic micrognathia.

Purpose The exact development process underlying traumatic heterotopic ossification of the temporomandibular joint (THO-TMJ) is largely unclear. In this study, we try to explore the histological development process of THO-TMJ. Materials and methods Condylar cartilage of one-month-old male mice was partially removed from the left joint with small scissors to induce THO-TMJ. The phenotypes were observed using gross observation, microcomputed tomography (micro-CT) scans and histological examination from one month to six months after surgery. Results The micro-CT examination results showed that the injured condyle integrated with ectopic bone tissue to form an osteophyte and that the volume and density of the osteophyte grew exponentially with time. Hematoxylin and eosin (H&E), safranin O and fast green staining of the THO-TMJ specimens revealed that the ectopic bone tissue was mainly nonmineralized fibrous tissue 1 month after surgery. This tissue gradually transformed into cartilage 3 months after surgery. Finally, the tissues transformed into mature bone tissue 6 months after surgery. Immunofluorescence staining showed VEGF-α expression in the heterotopic tissue 1 month after surgery, and the expression of Sox9 in the heterotopic tissue was obvious 3 months after surgery. Furthermore, OCN expression was evident in most of the heterotopic tissue 6 months after surgery. The results also showed clear hypoxia-inducible factor 1-alpha (Hif-1α) expression in the injured chondrocytes of the condyle, especially in the articular proliferative zone and fibrocartilaginous zone. Conclusions The THO-TMJ imaging characteristics indicated an exponential change with time. Histologically, the development process of THO-TMJ is an endochondral ossification process and includes three stages, fibroproliferative, chondrogenic and osteogenic stage. In addition, Hif-1α, which was expressed in some of the injured chondrocytes, may play an essential role in the initial THO-TMJ.

Purpose Arytenoid dislocation is a rare complication after tracheal intubation, and there are no published studies reporting on arytenoid dislocation during orthognathic surgery. The frequency of this phenomenon and the results of therapy were evaluated in this study. Materials and Methods Three of 5,032 patients who underwent orthognathic surgery during an 11-year period had a postoperative arytenoid dislocation. Closed reduction was used in these 3 patients. To check the therapeutic effect, arytenoid dislocation symptoms were recorded and acoustic analysis was performed before reduction, immediately after reduction, and 1, 2, and 4 weeks after reduction. Results The incidence of arytenoid dislocation in orthognathic surgery was 0.0596%. The symptoms of 2 patients showed marked improvement 2 weeks after reduction with voice recovery and resolution of odynophagia. The symptoms of the other patient showed marked improvement 4 weeks after reduction. The treatment effects for all 3 patients were satisfactory. Conclusion Arytenoid dislocation must be considered in cases of prolonged hoarseness after orthognathic surgery. Examination should be carried out as soon as possible, which can hasten the treatment of arytenoid dislocation and achieve a good outcome.

Genetic studies have revealed a critical role of Distal-homeobox (Dlx) genes in bone formation, and our previous study showed that Dlx2 overexpressing in neural crest cells leads to profound abnormalities of the craniofacial tissues. The aim of this study was to investigate the role and the underlying molecular mechanisms of Dlx2 in osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) and pre-osteoblast MC3T3-E1 cells. Initially, we observed upregulation of Dlx2 during the early osteogenesis in BMSCs and MC3T3-E1 cells. Moreover, Dlx2 overexpression enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization in BMSCs and MC3T3-E1 cell line. In addition, micro-CT of implanted tissues in nude mice confirmed that Dlx2 overexpression in BMSCs promoted bone formation in vivo. Unexpectedly, Dlx2 overexpression had little impact on the expression level of the pivotal osteogenic transcription factors Runx2, Dlx5, Msx2, and Osterix, but led to upregulation of Alp and Osteocalcin (OCN), both of which play critical roles in promoting osteoblast maturation. Importantly, luciferase analysis showed that Dlx2 overexpression stimulated both OCN and Alp promoter activity. Through chromatin-immunoprecipitation assay and site-directed mutagenesis analysis, we provide molecular evidence that Dlx2 transactivates OCN and Alp expression by directly binding to the Dlx2-response cis-acting elements in the promoter of the two genes. Based on these findings, we demonstrate that Dlx2 overexpression enhances osteogenic differentiation in vitro and accelerates bone formation in vivo via direct upregulation of the OCN and Alp gene, suggesting that Dlx2 plays a crucial role in osteogenic differentiation and bone formation., Osteogenesis: Dlx2 gene plays key role in bone development The distal-less homeobox (Dlx) gene family is related to various features of bone development, and the Dlx2 member of that family has been found to play a crucial role in bone formation. A team headed by Steve Guofang Shen at the Shanghai Jiao Tong University School of Medicine in China investigated the function of Dlx2 in osteogenic (bone development) differentiation of mouse bone marrow stromal cells (BMSCs) and MC3T3-E1 cells (precursors of osteoblasts, the major cellular component of bone). The team found that overexpression of Dlx2 promotes osteogenic differentiation in vitro and accelerates bone formation in vivo by enhancing Osteocalcin and Alp genes (both of which play critical roles in promoting osteoblast maturation). The authors conclude that their results suggest a promising future strategy for treating bone defects where BMSCs overexpress Dlx2.

Purpose Views on treatment procedures for condylar head fractures (CHFs) are far from reaching a consensus. The aim of this study was to evaluate the changes in disc status for anteromedial disc displacement with anchorage (AMDDwA) and without anchorage (AMDDwoA — just suturing to the adjacent TMJ soft tissue) in adult CHFs, to get a better understanding of this very complex process and to show that rigid disc anchorage is an essential technique for the treatment of CHF during the open reduction and internal fixation (ORIF). Patients and methods 144 temporomandibular joints (TMJ) in 95 patients were included in this retrospective study, and were divided into an AMDDwA group (50 TMJs in 38 patients) and an AMDDwoA group (94 TMJs in 57 patients) based on the different surgical procedures. The joints were quantitatively and qualitatively assessed for disc length and disc morphology preoperatively and at follow-up visits. Other variables, such as disc position, joint effusion, retrodiscal tear and lateral capsular tear, were also evaluated. Paired t-tests, Wilcoxon signed rank tests, independent t-tests and χ2 tests were used to assess intragroup and intergroup differences. Results The results showed that discs became shorter, moved further forward and distorted more seriously in the AMDDwoA group. In contrast, discs became longer, maintained a normal disc–condyle relationship in the AMDDwA group. Joint effusion, retrodiscal tear, and lateral capsular tear healed well in both groups. Conclusion Taking these findings together suggests that the rigid disc anchorage is an alternative technique for the treatment of CHF.

Comprehensive characterization of spatial and temporal gene expression patterns in humans is critical for uncovering regulatory codes of the human genome and understanding molecular mechanisms of human diseases. The ubiquitously expressed genes (UEGs) refer to those genes expressed across a majority, if not all, phenotypic and physiological conditions of an organism. It is known that many human genes are broadly expressed across tissues. However, most previous UEG studies have only focused on providing a list of UEGs without capturing their global expression patterns, thus limiting the potential use of UEG information. In this article, we propose a novel data-driven framework to leverage the extensive collection of ∼40,000 human transcriptomes to derive a list of UEGs and their corresponding global expression patterns, which offers a valuable resource to further validate and characterize human UEGs. Our results suggest that about half (12,234; 49.01%) of the human genes are expressed in at least 80% of human transcriptomes and the median size of the human transcriptome is 16,342 (65.44%). This suggests that the average difference in gene content between human transcriptomes is only 16.43%. Through gene clustering, we identified a set of UEGs, named LoVarUEGs, that have stable expression across human transcriptomes and can be used as internal reference genes for expression measurement. To further demonstrate the usefulness of this resource, we evaluated the uniqueness of repression for 16 previously predicted disallowed genes in islets beta cells and found that seven of these genes showed relatively more varied expression patterns, suggesting that the repression of these genes may not be unique to islets beta cells. We have made our resource publicly available at https://github.com/macroant/HumanUEGs.

Hemifacial microsomia (HM) is a craniofacial congenital defect involving the first and second branchial arch, mainly characterized by ocular, ear, maxilla-zygoma complex, mandible, and facial nerve malformation. HM follows autosomal dominant inheritance. Whole-exome sequencing of a family revealed a missense mutation in a highly conserved domain ofITPR1. ITPR1 is a calcium ion channel. By studyingITPR1’s expression pattern, we found that ITPR1 participated in craniofacial development, especially the organs that corresponded to the phenotype of HM. In zebrafish,itpr1b, which is homologous to humanITPR1, is closely related to craniofacial bone formation. The knocking down ofitpr1bin zebrafish could lead to a remarkable decrease in craniofacial skeleton formation. qRT-PCR suggested that knockdown ofitpr1bcould increase the expression ofplcb4while decreasing the mRNA level of Dlx5/6. Our findings highlighted ITPR1’s role in craniofacial formation for the first time and suggested thatITPR1mutation contributes to human HM.

The contributing factors and the origins of precursor cells in traumatic heterotopic ossification around the temporomandibular joint (THO-TMJ), which causes obvious restriction of mouth opening and maxillofacial malformation, remain unclear. In this study, our findings demonstrated that injured chondrocytes in the condylar cartilage, but not osteoblasts in the injured subchondral bone, played definite roles in the development of THO-TMJ in mice. Injured condylar chondrocytes without articular disc reserves might secrete growth factors, such as IGF1 and TGFβ2, that stimulate precursor cells, such as endothelial cells and muscle-derived cells, to differentiate into chondrocytes or osteoblasts and induce THO-TMJ. Preserved articular discs can alleviate the pressure on the injured cartilage and inhibit the development of THO-TMJ by inhibiting the secretion of these growth factors from injured chondrocytes. However, the exact molecular relationships among trauma, the injured condylar cartilage, growth factors such as TGFβ2, and pressure need to be explored in detail in the future.

Mandibular condylar osteochondroma (OC) can result in facial asymmetry, malocclusion, and temporomandibular joint dysfunction. The authors have previously demonstrated a novel method for conservative condylectomy and simultaneous orthognathic surgery for treatment of mandibular condylar OC. The purpose of this study was to evaluate the immediate improvement and long-term stability of mandibular symmetry in the treatment of condylar OC. Fifty-six patients with unilateral mandibular condylar OC combined with secondary facial asymmetry and malocclusion were enrolled in this retrospective study. The computerized tomography (CT) scans were acquired with the mandible in centric relation (CR) before surgery, 1 week and 12 to 18 months after surgery. The images were reconstructed and processed for the analysis with ProPlan CMF 2.1 software. After defining the skeletal landmarks and the reference planes, the chin deviation, chin rotation and mandibular asymmetry index were calculated. The operations and healing were uneventful and the patients showed no signs of recurrence or temporomandibular joint ankylosis during the follow-up. Facial symmetry was greatly improved right after the surgery in the chin deviation (from 9.2 to 1.7 mm, P < 0.01), chin rotation (from 11.2 to 2.3, P < 0.01) and the asymmetry index of three mandibular landmarks (Go, MF and Sg, all P < 0.01). It also showed a stable result after 12 to 18 months follow-up. We also established a novel measurement method, which showed that the combination of conservative condylectomy via the intraoral approach based on intraoperative navigation and simultaneous orthognathic surgery is effective for improving the facial symmetry when treat the mandibular condylar OC.

Purpose To systematically evaluate the effects of surgically assisted rapid maxillary expansion (SARME) on nasal cavity and its associated respiratory function changes. Material and methods Multiple electronic databases were searched, authors were contacted as required, and reference lists of potentially relevant studies were screened. Articles that included patients older than 16 who had received SARME were considered. Data extraction and quality assessment were performed independently and in duplicate. Results Eight articles, including 161 patients, were finally selected and analyzed. Nasal cavity significantly augmentation after SARME has been recognized by 7 studies with moderate-quality evidence. Among them, the nasal cavity volume increased 40% in 2 studies. Totally, the range of increasing in nasal cavity volume was 7.6% to 99%. One study had recorded the nasal expiratory and inspiratory flow significantly increased 18.5% and 21.7%, respectively. Conclusion SARME was found to produce meaningful volume augmentation in nasal cavity with adult patients. However, the improvement of nasal respiratory function has not been well elucidated; thus, SARME is not yet recommended for the purpose of improving nasal respiratory.

TBX22 is a gene which contribute to cleft lip/palate, and many mutation sites of TBX22 have been reported. However, the exact role of TBX22 mutation in Chinese nonsyndromic cleft lip/palate (NSCL/P) family was not clearly explored. In this study, we tried to investigate the profiles and effects of TBX22 mutation in Chinese NSCL/P family. Members of two Chinese NSCL/P families and 200 normal controls were enrolled in this study. Further, DNA sequence and bioinformatic analysis for TBX22 were performed. The results showed that a novel and essential splicing site mutation, IVS6-1G>C , was detected in a family with cleft palate. The bioinformatic analysis results showed that this mutation would lead to abnormal transcription or translation, followed by a loss of function of TBX22. In addition, a hemizygous missense mutation, c.874G>A (p.D292N), was first reported in another Chinese family, which may exhibit aggravated effects on the phenotypes of CL/P. Taking these findings together, this study provides a profile of TBX22 mutation in Chinese NSCL/P families, and further confirmed the important role of TBX22 in familial cases with X-linked cleft palate.

Objectives In this study, we tried to explore the effects of a single condylar neck fracture without condylar cartilage injury during the pathogenesis process of traumatic heterotopic ossification around the temporomandibular joint (THO-TMJ). Study Design One-month-old C57 BL/6 J male mice were divided into 2 groups. In group 1, condylar cartilage was partially removed in the right joint to induce THO. In group 2, a single fracture on the condylar neck was created using small scissors. The condylar head was repositioned to its original place if any displacement occurred. The phenotypes were observed using gross observation, micro–computed tomography, and histologic examination. Results The results showed obvious hyperplasia in the right condyle in group 1, with ectopic bones and cartilage in the periarticular region. In group 2, the surface of condyle was smooth, but the size of the right condylar head became smaller. Conclusions Taking these findings together, we concluded that it is condylar cartilage injury, and not a single condylar neck fracture without condylar cartilage injury, that contributes to the development of THO-TMJ.

Because of the obscure etiology of osteoarthritis (OA) and unsatisfactory treatment outcomes, new effective and minimally invasive therapies are urgently needed. Oxidative stress elicited by excessive reactive oxygen species (ROS) accumulation has historically been considered a potential trigger of OA. Polydopamine (PDA), an emerging versatile biopolymer produced by self-polymerization of dopamine, has attracted considerable attention in biomedical applications by virtue of its excellent biocompatibility and intriguing ROS-scavenging capacity. Herein, an antioxidative/anti-inflammatory dual-task nanoplatform based on PDA nanoparticles (NPs) is introduced for the treatment of temporomandibular joint osteoarthritis (TMJ-OA). In addition to directly reacting with ROS as a reducing agent, PDA NPs also regulate ROS generation in mitochondria which are considered cellular powerhouses. Specifically, the efficiency of mitochondrial oxidative phosphorylation (OXPHOS) is significantly increased in the presence of PDA NPs, indicating that PDA NPs may increase the efficiency of mitochondrial respiration, hence reducing ROS production. This intriguing dual-antioxidative mechanism may account for the remarkable antioxidative capacity of PDA NPs. Moreover, the anti-inflammatory capacity of PDA NPs is revealed both in vitro and in vivo. This work not only opens a new avenue for OA treatment but also provides valuable insights into the design of biomaterials with multiple biomedical applications via regulation of cellular energy metabolism.

Distal-less homeobox 2 (Dlx2) is a member of the homeodomain family of transcription factors and is important for the development of cranial neural crest cells (CNCCs)‑derived craniofacial tissues. Previous studies revealed that Dlx2 was expressed in the cementum and a targeted null mutation disrupted tooth development in mice. However, whether Dlx2 overexpression may impair in vivo tooth morphogenesis remains to be elucidated. The present study used a transgenic mouse model to specifically overexpress Dlx2 in neural crest cells in order to identify the dental phenotypes in mice by observation, micro‑computed tomography and histological examination. The Dlx2‑overexpressed mice exhibited tooth abnormalities including incisor cross‑bite, shortened tooth roots, increased cementum deposition, periodontal ligament disorganization and osteoporotic alveolar bone. Therefore, Dlx2 overexpression may alter the alveolar bone, cementum and periodontal ligament (PDL) phenotypes in mice.

Summary Objective In this study, the role of inflammation in traumatic heterotopic ossification around temporomandibular joint (THO-TMJ), as well as the preventive and treatment effect of celecoxib in THO-TMJ both in vivo and in vitro were explored. Design A surgically-induced THO-TMJ mouse model and a co-culture model of ATDC-5 or MC3T3-E1 and RAW-264.7 cells were used in this study for in vivo and in vitro research. Results A series of inflammatory factors, such as CD3, CD68, CD20, IL-10, IL-6 and TNF-α, were activated 48 h after trauma in a THO-TMJ model. Local trauma initiated systemic inflammatory responses as well as T cell- and macrophage-mediated local inflammatory responses around TMJ. In addition, expression of COX-2 was significantly elevated. The findings also showed that local injection of celecoxib could effectively alleviate the inflammatory response around TMJ at the early stage of trauma and inhibit the formation of THO-TMJ in vivo. Meanwhile, celecoxib could inhibit chondrogenic differentiation of ATDC-5 and osteogenic differentiation of MC3T3-E1 under inflammatory condition in vitro. Furthermore, celecoxib could inhibit the expression of Bmpr1b in the injured condylar cartilage at the initiation stage of THO-TMJ, which implied that Bmpr1b expressed by the residual condylar cartilage might be related to the pathogenesis of THO-TMJ. Conclusions Inflammation played a crucial role in the pathogenesis of THO-TMJ, and anti-inflammation might be a possible choice to inhibit THO-TMJ, which provided scientific clues for the mechanisms, pharmacotherapy and molecular intervention of THO-TMJ.

The effect of thalidomide on mandibular development is unclear. In this study, thalidomide was delivered to pregnant rabbits from the 8th to 14th day of gestation. Then, embryos were harvested for examination on the 16th day (GD16), 20th day (GD20) and 24th day (GD24) of gestation. The results showed obvious hemorrhage and hematoma on one side of the craniofacial region in 50 % of the thalidomide-treated embryos and obvious hemorrhage and hematoma on both sides of the craniofacial region in 50 % of the thalidomide-treated embryos at GD16. Histological examination showed soft tissues and mandible defects on the affected side of the maxillofacial region. The expression of Vegf-α, Ki67 and Sox9 on the affected side was significantly down-regulated in comparison to their expression on the unaffected side at GD20. There was also an obvious defect in the affected mandible, and the density of the skull and mandible was decreased compared to the unaffected side or the control group at GD24. These findings demonstrated that thalidomide may lead to hemorrhage and hematoma in the craniofacial region by inhibiting angiogenesis, resulting in the abnormal development of cranial neural crest cells that are involved in the normal development of the mandible in rabbits.

Diagnosis and treatment of velocardiofacial syndrome (VCFS) with variable genotypes and phenotypes are considered to be very complicated. Establishing an exact correlation between the phenotypes and genotypes of VCFS is still a challenging. In this paper, 88 Chinese VCFS patients were divided into five groups based on palatal anomalies and one or two of other four common phenotypes, and copy number variations (CNVs) were detected using multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH) and quantitative polymerase chain reaction. The findings showed that palatal anomalies and characteristic malformation of face were important indicators for 22q11.2 microdeletion, and there was difference inthe phenotypic spectrum between the duplication and deletion of 22q11.2. MLPA was a highly cost-effective, sensitive and preferred method for patients with 22q11.2 deletion or duplication. Our results also firstly reported that all three patients who simultaneously exhibited palatal anomalies and cognitive disorder, without other phenotypes, have Top3b duplication, which strongly suggested that Top3b may be a pathogenic gene for these patients. Further, the findings showed that patients with palatal anomalies and congenital heart disease or immune deficiency, with or without other uncommon phenotypes, exhibited heterogeneity in CNVs, including 4q34.1-qter, 6q25.3, 4q23, Xp11.4, 13q21.1, 17q23.2, 7p21.3, 2p11.2, 11q24.3 and 16q23.3, and some possible pathogenic genes, including BCOR, PRR20A, TBX2, SMYD1, KLKB1 and TULP4 have been suggested. For these patients, aCGH, whole genomic sequencing,combined with references and phenomics database to find pathogenic gene,may be choices of priority. Taking these findings together, we offered an alternative method for diagnosis of Chinese VCFS patients based on this phenotypic strategy.

Reconstruction of bone defects is still a challenge. In this study, we developed and systematically evaluated a novel injectable strontium-containing hydroxyapatite (Sr-HA) bone cement in which Sr-HA powder included 5% Sr and was mixed with a setting liquid that included 5% potassium citrate. This Sr-HA cement was mainly composed of HA and α-tricalcium phosphate (TCP) and exhibited favorable injectability (100%), setting times (the initial setting time was 240 s and the final setting time was 420 s), compressive strength (73.4 MPa), maximal load and maximum bending stress, and excellent radiopacity. In addition, the Sr-HA cement also had excellent biocompatibility that exhibited low cytotoxicity for cell proliferation and no obvious disturbing effect on the osteogenic differentiation of periodontal ligament stem cells (DLSCs) and dental pulp stem cells (DPSCs). However, the Sr-HA cement could slightly promote the osteogenic differentiation of MC3T3 cells, which also implied that it would promote osseointegration between the cement and surrounding bone but would not obviously disturb the biological behavior of DLSCs and DPSCs. An in vivo study further confirmed that Sr-HA cement exhibited favorable osseointegration with the maxilla and tibia. All these findings implied that the novel Sr-HA cement was a suitable bone substitution for bone defects.

Treacher Collins syndrome (TCS) is a rare, autosomal-dominant disorder characterized by craniofacial deformities, and is primarily caused by mutations in the Tcof1 gene. This article was aimed to perform a comprehensive literature review and systematic bioinformatic analysis of Tcof1-related molecular networks in TCS. First, the up- and down-regulated genes in Tcof1 heterozygous haploinsufficient mutant mice embryos and Tcof1 knockdown and Tcof1 over-expressed neuroblastoma N1E-115 cells were obtained from the Gene Expression Omnibus database. The GeneDecks database was used to calculate the 500 genes most closely related to Tcof1. Then, the relationships between 4 gene sets (a predicted set and sets comparing the wildtype with the 3 Gene Expression Omnibus datasets) were analyzed using the DAVID, GeneMANIA and STRING databases. The analysis results showed that the Tcof1-related genes were enriched in various biological processes, including cell proliferation, apoptosis, cell cycle, differentiation, and migration. They were also enriched in several signaling pathways, such as the ribosome, p53, cell cycle, and WNT signaling pathways. Additionally, these genes clearly had direct or indirect interactions with Tcof1 and between each other. Literature review and bioinformatic analysis finds imply that special attention should be given to these pathways, as they may offer target points for TCS therapies.

Distal-less homeobox 2 (Dlx2), a member of the Dlx family of transcription factors, is important for the development of craniofacial tissues. Previous studies based on knock‑out mutant mice revealed that Dlx2 primarily disturbed the development of tissues from maxillary arch. The present study used a transgenic mouse model to specifically overexpress Dlx2 in neural crest cells in order to investigate the role of Dlx2 overexpression in post‑natal condyle in mice. The model was constructed and the phenotype observed using gross observation, micro‑CT scan and histological examination. The model determined that overexpression of Dlx2 may lead to postnatal condyle malformation, subchondral bone degradation and irregular histological structure of the condylar cartilage. In addition, the expression of osteocalcin in the condyle region was markedly downregulated, whereas expression of msh homeobox 2 was upregulated. The results of the present study suggest that Dlx2 overexpression in cranial neural crest cells would disrupt the development of post‑natal condyle, which demonstrates that the expression level and the spatiotemporal expression patterns of Dlx2 may be important in regulating the development of post-natal condyle in mice, and also offered a possible temporal‑mandibular joint osteoarthritis model animal for future studies.

PURPOSE The depression of alar base in affected side in patients with unilateral complete cleft lip/palate (CL/P) is one of common clinical features. In this study, the authors try to explore the effect of subcutaneous C shape muscular flap for correcting the depression of alar base in affected side in patients with unilateral complete CL/P during primary surgery. METHODS A total of 30 patients with unilateral complete CL/P who received primary correction of the lip nose deformity were included in this study. The C flap was used to drop and lengthen the height of upper lip in unaffected side, and the subcutaneous muscular flap was dissected from the C flap and positioned at the alar base in the affected side of upper lip to correct the depression. Then the surgical effect was evaluated based on clinical examination during follow-up. RESULTS Alar base symmetry was obtained in 26 patients of this case series, and 4 patients showed slight improvement in alar base symmetry. No major complications such as flap necrosis, infection, or hypertrophic scars were observed during surgery and follow-up. No additional incisions and operative time were necessary. CONCLUSION The subcutaneous C shape muscular flap described in this article could offer enough muscular support and markedly correct the depression of nostril and alar base in affected side in primary lip nose repair with no additional incisions and operative time for patients with unilateral complete CL/P.

Hemifacial microsomia (HFM) is a common congenital malformation of the craniofacial region. There are 3 possible pathogenic models of HFM—vascular abnormality and hemorrhage in the craniofacial region, damage to Meckel’s cartilage, and the abnormal development of cranial neural crest cells—and the most plausible hypothesis is the vascular abnormality and hemorrhage model. These 3 models are interrelated, and none of them is completely concordant with all the variable manifestations of HFM. External environmental factors (e.g., thalidomide, triazene, retinoic acid, and vasoactive medications), maternal intrinsic factors (e.g., maternal diabetes), and genetic factors (e.g., the recently reported mutations in OTX2, PLCD3, and MYT1) may lead to HFM through ≥1 of these pathogenic processes. Whole genome sequencing to identify additional pathogenic variants, biological functional studies to understand the exact molecular mechanisms, and additional animal model and clinical studies with large stratified samples to elucidate the pathogenesis of HFM will be necessary. Small-molecule drugs, as well as CRISPR/CAS9-based genetic interventions, for the prevention and treatment of HFM may also be a future research hotspot.

Temporomandibular joint (TMJ) ankylosis can restrict the mandibular movement, followed by resulting in numerous problems. To understand the mechanism of TMJ ankylosis (TMJA) and prevent the generation of TMJA is urgent necessary. Although many factors contribute to it, trauma is the most common cause of TMJA. The mechanisms of TMJA are still unclear, and the distraction osteogenesis of the lateral pterygoid muscle (LPM) may play an important role. Injection of very small amounts of botulinum toxin type A (BTA) can temporarily block the muscle’s impulse and has been revealed to be an effective treatment method for many temporomandibular disorders. In this article, we make a hypothesis that LPM injection of BTA as a novel method for immobilization of mandible, followed by preventing the traumatic TMJA. Furthermore, the side effects of local injection of BTA also are minimal, temporary, reversible and self-limiting. If this strategy is validated, LPM injection of BTA will be a cost effective way to be administrated to prevent the traumatic TMJA.

The abnormal cartilage/bone metabolism in unilateral condyle may be a direct factor that contributes to developmental mandibular laterognathism. However, although many molecules have been demonstrated to play crucial roles in the development of temporomandibular joints, the exact molecular mechanisms that lead to the disrupted condylar cartilage/bone development were greatly unknown. In this retrospective study, our findings revealed that serum alkaline phosphatase (ALP) level in adult patients with developmental mandibular laterognathism was lower than that in control subjects, and the serum ALP levels continue to reduce in adult patients (>20 years old). Although the exact relationship between the lower serum ALP level and developmental mandibular laterognathism is unclear, the findings further support the opinion that the condylar growth may sustain for a long time in the affected condyle in patients with developmental mandibular laterognathism and offer an alternative choice to use total serum ALP activity as a possible biomarker to assess condylar growth activity in patients with developmental mandibular laterognathism.

Emerging evidence suggests amniotic epithelial cells (AECs) as a promising source of progenitor cells in regenerative medicine and bone tissue engineering. However, investigations comparing the regenerative properties of AECs with other sources of stem cells are particularly needed before the feasibility of AECs in bone tissue engineering can be determined. This study aimed to compare human amniotic epithelial cells (hAECs), human bone marrow mesenchymal stem cells (hBMSCs), and human amniotic fluid derived mesenchymal stem cells (hAFMSCs) in terms of their morphology, proliferation, immunophenotype profile, and osteogenic capacityin vitroandin vivo. Not only greatly distinguished by cell morphology and proliferation, hAECs, hAFMSCs, and hBMSCs exhibited remarkably different signature regarding immunophenotypical profile. Microarray analysis revealed a different expression profile of genes involved in ossification along the three cell sources, highlighting the impact of different anatomical origin and molecular response to osteogenic induction on the final tissue-forming potential. Furthermore, our data indicated a potential role of FOXC2 in early osteogenic commitment.

The spheno-occipital synchondrosis (SOS) in cranial base is an important growth center for the craniofacial skeleton, and also is a guide rail for development of the maxilla, midface, and mandible. Previous studies showed that SOS may be a treatment target for youngsters with midfacial hypoplasia and small cranial vault secondary to craniosynostosis. However, most of studies about the SOS are based on imaging data. In this study, we try to explore the characteristics of postnatal development of the mouse SOS based on histological analysis. Our findings showed that the width of the SOS in mice were gradually decreased from newborn mice to adult mice, and the SOS cartilage was gradually became small, then almost completely ossificated in adult mice. The resting and proliferative layers in SOS cartilage were gradually decreased, and almost only hypertrophic chondrocytes while no resting and proliferative layer chondrocytes in adult mice. The proliferative ability of SOS chondrocytes also gradually decreased. These findings will be of benefit for the further clinical treatment for patients with midfacial hypoplasia or small cranial vault secondary to craniosynostosis. Further evidence-based research about the clinical implication is necessary in future.

Objective The aim of this study was to explore the cause of type B condylar head fracture after parasymphyseal impact, and evaluate the biomechanics of osteosynthesis using two positional screws for the repair of this type of fractures. Methods A finite element model of the mandible was created, and a parasymphyseal impact was simulated using Mimics 10.01 and Abaqus 6.10 software. The type B condylar head fracture was simulated in the right condyle using a mimics simulation cut with polyplane module according to the analyzed results together with clinical experience, and the left condyle was used as a control. Two positional screws were used for rigid internal fixation of the fracture. von Mises stress distributions in the condyles and screws were analyzed. Results The von Mises stress generated in parasymphyseal trauma simulation showed a significant concentration in the sagittal direction of the condyle. In two-positional-screw osteosynthesis of the condylar head fractures, stress concentration appeared within the screws in the gap area between the two fractured segments and the area around the screw head. A small amount of stress was distributed in the screw holes and on the posterior surfaces of both segments. The von Mises stress was negligible in the fractured sagittal surfaces. Conclusion It is reasonable to attribute the cause of type B condylar head fracture to the anatomical features of the condyle. The biomechanics of two-positional-screw osteosynthesis revealed that the stress can transmit through the screws to the medial fragments, and the stresses on both sagittal fractured surfaces are minimal.

Patients with nasomaxillary hypoplasia have severe facial concavity and compromised skeletal class III malocclusion. Its treatment is still a challenge to surgeons. Our aim was to evaluate the combination of midfacial distraction and orthognathic surgery in the treatment of nasomaxillary hypoplasia. Four patients with nasomaxillary hypoplasia were enrolled in this study. After Le Fort II osteotomy, the rotational distraction of nasomaxillary complex was performed to rehabilitate facial convexity. Then bilateral sagittal split ramus osteotomy with or without Le Fort I osteotomy was used to correct malocclusion. All patients healed uneventfully, and the maxillae moved forward conspicuously. No obvious pain and severe discomfort were complained during distraction. A significant advancement and downward movement of the maxilla were shown by cephalometric analysis. The combination of midfacial distraction and orthognathic surgery provides us an ideal alternative in the treatment of nasomaxillary hypoplasia.

In traditional virtual 3D orthognathic surgery, after repositioning the maxillary segment to the desired position, surgeons usually roughly rotate or adjust the mandibular segment to obtain a relatively good relationship with maxillary dentition to calculate the virtual terminal occlusion splint. However, surgeons are not easy to avoid penetrability, overlap, or an overly large space existing between the maxillary and mandibular dentitions during this process. The present report offered a new method to obtain a suitable virtual terminal occlusal splint that could avoid penetrability, overlap, or an overly large space between the maxillary and mandibular dentitions, and simultaneously accurately moving the maxillary or mandibular segment to the desired position utilizing the planned terminal occlusion plaster models in virtual orthognathic surgery. For double jaw surgery, after aligning the planned plaster models to the 3D maxilla and mandible, we could simultaneously move the maxillary and mandibular segment as a whole that maintain the planned terminal occlusion to the desired position. This present method may enhance the accuracy of 3D virtual orthognathic surgery and save plenty of time spend on virtual surgery simulation, which also offers a useful educational method for training junior surgeons and students.

As dental precursor cells, stem cells from the apical papilla (SCAP) are capable of forming roots and undergoing apexogenesis, which are impaired upon exposure to bacterial infection. Porphyromonas gingivalis is a common Gram-negative bacterium that is involved in pulpal and periapical infection. The purpose of this study was to investigate the effects of P. gingivalis lipopolysaccharide (LPS) on the Wnt/β-catenin and p38 mitogen-activated protein kinase (MAPK) signalling pathways in SCAP. As indicated by the IL-1β and TNF-α mRNA levels, P. gingivalis LPS induced the expression of pro-inflammatory cytokines in a dose-dependent manner. In addition, activation of the p38 MAPK and Wnt/β-catenin pathways was confirmed by the augmentation of phospho-p38 and β-catenin protein expression and increased expression of c-myc and cyclin D1 mRNA. Despite no significant increase in β-catenin mRNA expression, increased phosphorylation of glycogen synthase kinase (GSK)-3β suggested that GSK-3β was responsible for the accumulation of β-catenin in the cytoplasm and translocation to the nucleus. Previous studies have shown that GSK-3β plays a critical role in crosstalk between the Wnt/β-catenin and p38 MAPK pathways. In the present study, we showed that the level of p38 phosphorylation decreased upon pretreatment with a p38 MAPK inhibitor for 1 h before stimulating SCAP with 10 μg/ml P. gingivalis LPS. However, the levels of GSK-3β and β-catenin phosphorylation in the cytoplasm and nucleus were not significantly altered. Our results suggest that the p38 MAPK and canonical Wnt/β-catenin signalling pathways are activated by P. gingivalis LPS in SCAP, but we have no evidence that p38 MAPK is upstream of GSK-3β in the Wnt/β-catenin signalling pathway.

Stem cells isolated from the amniotic fluid have been shown as a promising candidate for cell therapy and tissue engineering. However, the experimental and preclinical applications of amniotic fluid-derived stem cells (AFSCs) in the very field of maxillofacial bone tissue engineering are still limited. In this study, rat AFSCs were successfully harvested and characterized in vitro. The rat AFSCs showed typical fibroblastoid morphology, stable proliferation activity and multi-differentiation potential. Flow-cytometry analysis demonstrated that these cells were positive for CD29, CD44, and CD90, while negative for hematopoietic markers such as CD34 and CD45. The regenerative performance of AFSCs-premixed with platelet rich plasma (PRP) gel in restoration of alveolar bone defect was further investigated using a modified rat maxillary alveolar defect model. Micro-computer tomography and histological examination showed a superior regenerative capacity of AFSCs-premixed with PRP gel at both 4 and 8 weeks after operation comparing with control groups. Moreover, the implanted AFSCs can survive in the defect site and directly participate in the bone tissue regeneration. Taken together, these results indicated the feasibility of an AFSCs-based alveolar bone tissue engineering strategy for alveolar defect restoration.

Numerous problems regarding craniomaxillofacial navigation surgery are not well understood. In this study, we performed a double-center clinical study to quantitatively evaluate the characteristics of our navigation system and experience in craniomaxillofacial navigation surgery. Fifty-six patients with craniomaxillofacial disease were included and randomly divided into experimental (using our AccuNavi-A system) and control (using Strker system) groups to compare the surgical effects. The results revealed that the average pre-operative planning time was 32.32 mins vs 29.74 mins between the experimental and control group, respectively (p > 0.05). The average operative time was 295.61 mins vs 233.56 mins (p > 0.05). The point registration orientation accuracy was 0.83 mm vs 0.92 mm. The maximal average preoperative navigation orientation accuracy was 1.03 mm vs 1.17 mm. The maximal average persistent navigation orientation accuracy was 1.15 mm vs 0.09 mm. The maximal average navigation orientation accuracy after registration recovery was 1.15 mm vs 1.39 mm between the experimental and control group. All patients healed and their function and profile improved. These findings demonstrate that although surgeons should consider the patients’ time and monetary costs, our qualified navigation surgery system and experience could offer an accurate guide during a variety of craniomaxillofacial surgeries.