Asymmetric maxillary protraction for unilateral cleft lip and palate patients using finite element analysis.

OBJECTIVE: Unilateral cleft lip and palate (UCLP) patients frequently present with an asymmetry in the nasomaxillary complex and a maxillary hypoplasia. The aim of this study was to investigate biomechanic effects of asymmetric maxillary protraction in UCLP patients using finite element method. METHODS: A finite element model of a UCLP patient's skull was generated using data from spiral computed tomographic scans. On the basis of this finite element model, three groups of orthopedic forces were loaded. All forces were applied in a direction that was 30 degrees downward and forward to the occlusal plane on the region of the alveolar of the maxillary canine. The value of orthopedic force was 5 N in cleft side and 5 N in noncleft side (group A), 6 N in cleft side and 5 N in noncleft side (group B), and 7 N in cleft side and 5 N in noncleft side (group C), respectively. RESULTS: All 3 groups were effective in promoting maxilla forward. In group B, the displacement difference between the cleft side and the noncleft side was the smallest. The largest value difference between the cleft side and the noncleft side was found in group C. CONCLUSIONS: Maxillary protraction with a loading of 6 N in the cleft side and 5 N in the noncleft side produced the most favorable outcome. It can be suggested that it might be advantageous to perform asymmetric maxillary protraction on UCLP patients.

Biomechanical effects on maxillary protraction of the craniofacial skeleton with cleft lip and palate after alveolar bone graft.

OBJECTIVE: To explore the biomechanical effects of maxillary protraction on the craniofacial skeleton in patients with unilateral cleft lip and palate (UCLP) after alveolar bone graft (ABG) and resorption of ABG, thus to provide theoretical basis for the clinical application of maxillary protraction, which can improve the facial deformity of the UCLP patients. METHODS: A finite element model of a UCLP patient's skull was generated using data from spiral computed tomographic (CT) scans. Based on this finite element model, another 6 ABG finite element models were constructed to simulate ABG and resorption of ABG, respectively (nonresorption model, upper one-third resorption of the grafted bone model, upper two-thirds resorption of the grafted bone model, lower one-third resorption of the grafted bone model, lower two-thirds resorption of the grafted bone model, upper one-third and lower one-third resorption of the grafted bone model). Two additional models were developed to simulate maxillary protraction with expansion and maxillary protraction alone. All models were loaded with orthopedic force (30 degrees downward and forward to the occlusal plane, 500 g per side) on the region of alveolar of maxillary canine. RESULTS: Before ABG, the cleft side showed larger displacement than the noncleft side, when it came to the stress distribution in the craniofacial suture, it showed an asymmetric pattern as well. After ABG, the displacement difference between the cleft side and the noncleft side decreased, and the stress distribution in the craniofacial suture showed more symmetric than that before ABG. The pterygopalatine suture obtained the largest value, followed by zygomaticotemporal, zygomaticomaxillary, and zygomaticofrontal sutures among the observed sutures. Higher stresses and pronounced forward displacement were generated in the craniofacial sutures after maxillary protraction with expansion. CONCLUSIONS: Maxillary protraction after ABG performed a more favorable outcome. Among the ABG models, nonresorption model showed the best effect after loading maxillary protraction force, and resorption in the lower region of the grafted bone showed a better effect than resorption in the upper region of the grafted bone. Maxillary expansion could effectively facilitate the orthopedic of the maxillary protraction presumably.

'Invisible' orthodontics by polymeric 'clear' aligners molded on 3D-printed personalized dental models.

The malalignment of teeth is treated classically by metal braces with alloy wires, which has an unfavorable influence on the patients appearance during the treatment. With the development of digitization, computer simulation and three-dimensional (3D) printing technology, herein, a modern treatment was tried using clear polymeric aligners, which were fabricated by molding polyurethane films via thermoforming on the 3D-printed personalized dental models. The key parameters of photocurable 3D printing of dental models and the mechanical properties of the clear aligner film material were examined. The precision of a 3D-printed dental model mainly relied on characteristics of photocurable resin, the resolution of light source and the exposure condition, which determined the eventual shape of the molded clear aligner and thus the orthodontic treatment efficacy. The biocompatibility of the polyurethane film material was confirmed through cytotoxicity and hemolysis tests in vitro. Following a series of 3D-printed personalized dental models and finite element analysis to predict and plan the fabrication and orthodontic processes, corresponding clear aligners were fabricated and applied in animal experiments, which proved the efficacy and biocompatibility in vivo. Clinical treatments of 120 orthodontic cases were finally carried out with success, which highlights the advantage of the clear aligners as an esthetic, compatible and efficient appliance.

[Experimental study on the effect of tooth movement with thin and thick aligners in rabbits].

PURPOSE: To explore the effect of tooth movement on lower incisors of rabbits with thin and thick aligners. METHODS: A group of 6 male New Zealand rabbits were randomly divided into 2 groups, the experimental group(n=3) was designed to move the lower incisors distally by 3 steps with thin and thick aligners(0.625 and 0.75 mm)，0.33 mm each；the control group (n=3) was designed to move the teeth by 3 steps with aligner of conventional thickness (0.75 mm), 0.20 mm each. Polyvinyl siloxane impressions were taken before and after aligner placement. The data of tooth movement were measured. SPSS 19.0 software package was used for statistical analysis. RESULTS: The accuracy of tooth movement expression in both groups decreased gradually from the incisal part to the gingival part. The rate of tooth movement in the experimental group was significantly higher than that of the control group（P<0.001）. CONCLUSIONS: The tooth movement of rabbit mandibular central incisor was tipping with the clear aligner. The rate of tooth movement was increased by applying thin and thick aligners，but the accuracy of tooth movement was decreased.

MEF/KSF-conditioned culture medium: An effective method for in vitro culture of mouse dermal papilla cells with osteogenic differentiation potential.

Hair follicle stem cells are pluripotent and have a self-renewal capacity and multi-differentiation potential in vitro. As hair follicle stem cells can be easily sampled from the skin and hair of clinical patients at a considerable quantity, these cells have potential applications in wound repair and skin tissue engineering. Effective approaches for the in vitro culture and amplification of mouse hair follicle stem cells, as well as the in vitro osteogenic differentiation potential and cell source when obtaining mouse-separated cells were examined. Serial subculture was performed in different culture systems. Cell source was detected based on the relevant surface markers derived from mouse hair follicles at the gene and protein levels, and the differential potential was determined. The proliferative ability of hair follicle-derived stem cells obtained from mouse embryonic fibroblast (MEF)/keratinocyte serum-free medium (KSF)-conditioned medium was the highest among all culture systems. The induced group had a stronger osteogenic differentiation potential compared with the non-induced group, indicating that the cells obtained from MEF/KSF-conditioned medium were cells derived from the hair follicle dermal papilla. Therefore, the strong osteogenic differentiation potential of the hair follicle-derived mesenchymal stem cells was screened with MEF/KSF-conditioned culture medium following amplification, and biological characteristics similar to those of hair follicle dermal papilla cells were observed.

Biomechanical analysis of rapid maxillary expansion in the UCLP patient.

This study was designed to investigate the biomechanical effects of rapid maxillary expansion (RME) in the patient with unilateral cleft lip and palate (UCLP). A finite element model of a patient's craniofacial complex with UCLP was created using data from spiral computed tomographic (CT) scanning. A transversal displacement with a magnitude of 5mm was applied on the maxillary premolar and first permanent molar crown of the model simulating the clinical situation. The stress and deformation within the craniofacial complex were then calculated and analyzed during 0.25- and 5-mm expansions. The corresponding orthodontic forces on each loaded tooth were also calculated. Obtained results revealed the biomechanical performance of the craniofacial complex with UCLP undergoing RME, including the distribution pattern of the stress and displacement, the transmission and dissipation of the orthodontic force, the stress level and the magnitude of the orthodontic force. All these findings could help us better comprehend the biomechanical mechanism of RME in the UCLP patient and provided theoretic data for optimizing surgical assisted RME in clinic.

Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses.

Clinical trials have proven oncolytic virotherapy to be safe but not effective. We have shown that oncolytic viruses (OV) injected into intracranial gliomas established in rodents are rapidly cleared, and this is associated with up-regulation of markers (CD68 and CD163) of cells of monocytic lineage (monocytes/microglia/macrophages). However, it is unclear whether these cells directly impede intratumoral persistence of OV through phagocytosis and whether they infiltrate the tumor from the blood or the brain parenchyma. To investigate this, we depleted phagocytes with clodronate liposomes (CL) in vivo through systemic delivery and ex vivo in brain slice models with gliomas. Interestingly, systemic CL depleted over 80% of peripheral CD163+ macrophages in animal spleen and peripheral blood, thereby decreasing intratumoral infiltration of these cells, but CD68+ cells were unchanged. Intratumoral viral titers increased 5-fold. In contrast, ex vivo CL depleted only CD68+ cells from brain slices, and intratumoral viral titers increased 10-fold. These data indicate that phagocytosis by both peripheral CD163+ and brain-resident CD68+ cells infiltrating tumor directly affects viral clearance from tumor. Thus, improved therapeutic efficacy may require modulation of these innate immune cells. In support of this new therapeutic paradigm, we observed intratumoral up-regulation of CD68+ and CD163+ cells following treatment with OV in a patient with glioblastoma.

[Finite element analysis of clear aligners in extractive cases].

PURPOSE: This study analysed the mechanical features of the extraction space closure in clear aligners through mechanical research. METHODS: A patient with four first premolars extraction was chosen as sample, and four plans with clear aligners for space closure were designed, including anterior retraction entirely, anterior retraction dispersedly, posterior movement mesially and posterior movement dispersedly. Finite element analysis was performed separately. RESULTS: In anterior retraction, when there was no anterior space, the force acted on them more evenly, and the posteriors needed to provide more anchorage; when anterior space existed, the force acted on the central incisors first and largely, and the posteriors needed to provide less anchorage. In posterior anchorage, when the posteriors moved entirely with mesial movement, it might help to protect second premolar's anchorage while molars would receive more mesial force; when the posteriors moved separately without designed movement, the second premolar would undertake more anchorage and more tendency to incline mesially; when the posteriors moved entirely without designed movement, the anchorage would distribute more evenly. CONCLUSIONS: Selection of the way of retracting anteriors should be based on the difference of stress distribution in different ways in addition to individual discrepancy and clinical facts. Selection of the way of moving posteriors should be based on the distribution of anchorage as well as avoiding posterior open bite. Less amount of correction in each step has better axial control.

Cationic lipid-coated magnetic nanoparticles associated with transferrin for gene delivery.

Cationic lipid-coated magnetic nanoparticles (MPs) associated with transferrin were evaluated as gene transfer vectors in the presence of a static magnetic field. MPs were prepared by chemical precipitation and were surface-coated with cationic lipids, composed of DDAB/soy PC (60:40 mole/mole). These cationic MPs were then combined with polyethylenimine (PEI) condensed plasmid DNA, followed by transferrin. The resulting magnetic electrostatic complexes retained relatively compact particle size and showed complete DNA condensation. Their transfection activity in the presence of a static magnetic field was evaluated by luciferase and green fluorescent protein (GFP) reporter genes. The magnetic complexes exhibited up to 300-fold higher transfection activity compared to commonly used cationic liposomes or cationic polymer complexes, based on luciferase assay. The enhancement in transfection activity was maximized when the cells were exposed to the vectors for a relatively short period of time (15 min), or were treated in media containing 10% serum. Incorporation of transferrin further improved transfection efficiency of the cationic MPs. However, when cells were incubated for 4h in serum-free media, magnetic and non-magnetic vectors showed similar transfection efficiencies. In conclusion, transferrin-associated cationic MPs are excellent gene transfer vectors that can mediate very rapid and efficient gene transfer in vitro in the presence of a magnetic field.

Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil.

PURPOSE: Liposomes co-encapsulating doxorubicin (DOX) and verapamil (VER), and conjugated to transferrin (Tf-L-DOX/VER) were synthesized and evaluated in K562 leukemia cells. The design of this formulation was aimed at selective targeting of tumor cells, reducing cardiotoxicity of DOX and VER, as well as overcoming P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) phenotype. METHODS: The liposomes were prepared by polycarbonate membrane extrusion, followed by pH-gradient driven remote loading and Tf conjugation. Kinetics of in vitro release of DOX and VER from liposomes was determined by measuring changes in the concentration of encapsulated drugs. Uptake of Tf-conjugated liposomes by K562 cells was evaluated by fluorescence microscopy and by fluorometry. Cytotoxicities of various formulations of DOX were determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide (MTT) assay. RESULTS: Efficiencies for liposomal loading of DOX and VER were 95% and 70%, respectively. The mean particle diameter for the liposomes was approximately 110nm. Rates of release for DOX and VER were similar in singly-loaded and co-loaded liposomes. Tf-L-DOX/VER showed efficient uptake by the TfR+ K562 cells. In DOX-resistant K562 cells (K562/DOX), Tf-L-DOX/VER showed 5.2 and 2.8 times greater cytotoxicity (IC50 = 4.18 muM) than non-targeted liposomes (L-DOX/VER) (IC50 = 21.7 muM) and Tf-targeted liposomes loaded with DOX alone (Tf-L-DOX) (IC50 = 11.5 muM), respectively. CONCLUSIONS: The combination of TfR targeting and co-encapsulation of DOX and VER was highly effective in overcoming drug resistance in K562 leukemia cells.

Construction of anti-EGFR immunoliposomes via folate-folate binding protein affinity.

A novel method for synthesis of anti-EGFR immunoliposomes using folate-folate binding protein (FBP) affinity is described. An anti-EGFR antibody (cetuximab or C225) was covalently linked to FBP via a thioether bond. Liposomes incorporating a lipophilic folate derivative (folate-PEG-cholesterol) were prepared by polycarbonate membrane extrusion. Anti-EGFR immunoliposomes were then obtained by combining FBP-C225 and folate-liposomes and evaluated for uptake and cytotoxicity in EGFR-overexpressing U87 human glioblastoma cells. Anti-EGFR immunoliposomes constructed via folate-FBP affinity exhibited excellent stability under physiological pH, and quickly released the bound FBP-C225 upon low pH (pH 3.5) treatment. Flow cytometry and fluorescence microscopy showed similar receptor-specific binding and internalization for both folate-FBP affinity-coupled and covalently coupled C225-immunoliposomes, but not for the non-targeted IgG-immunoliposomes. C225-immunoliposomes loaded with anticancer drug doxorubicin were more cytotoxic than non-targeted immunoliposomes in EGFR-overexpressing U87 glioma cells. Folate-FBP affinity is a potential method for construction of immunoliposomes and may have applications in synthesis of targeted drug carriers in general.

The changing model of big pharma: impact of key trends.

Recent years have seen exciting breakthroughs in biomedical sciences that are producing truly novel therapeutics for unmet patient needs. However, the pharmaceutical industry is also facing significant barriers in the form of pricing and reimbursement, continued patent expirations and challenging market dynamics. In this article, we have analyzed data from the 1995-2015 period, on key aspects such as revenue distribution, research units, portfolio mix and emerging markets to identify four key trends that help to understand the change in strategic focus, realignment of R&D footprint, the shift from primary care toward specialty drugs and biologics and the growth of emerging markets as major revenue drivers for big pharma.

Tumour-selective drug delivery via folate receptor-targeted liposomes.

Tumour cell-targeted liposomal delivery has the potential to enhance the therapeutic efficacy and reduce the toxicity of anticancer agents. Folate receptor (FR) expression is frequently amplified among human malignancies. FR is, therefore, potentially useful as a tumour marker for targeted drug delivery. FR-mediated liposomal delivery has been shown to enhance the antitumour efficacy of doxorubicin both in vitro and in vivo, and to overcome P-glycoprotein-mediated multi-drug resistance. In addition, FR-targeted liposomes have shown utility as effective delivery vehicles of genes and antisense oligodeoxyribonucleotides to FR(+) tumour cells. Both solid tumours and leukaemias can potentially benefit from FR-targeted drug delivery. Multiple mechanisms might contribute to greater therapeutic efficacy for FR-targeted liposomes, such as FR-dependent cytotoxicity and antiangiogenic activity. Further investigation of this promising drug delivery strategy is clearly warranted.

[Maxillary protraction with and without maxillary expansion on unilateral cleft lip and palate model: a finite element analysis].

PURPOSE: The aim of this finite element study was to investigate biomechanical effects of maxillary protraction with and without maxillary expansion on unilateral cleft lip and palate(UCLP)model before and after alveolar bone graft (ABG). METHODS: Orthopedic force (30° downward and forward to the occlusal plane, 5N/side) with expansion and without expansion were loaded on models before ABG, and after ABG respectively. Initial displacement and sutural stress were analyzed by using ANSYS12.0 software. RESULTS: The amount of displacement at the cleft side was larger than that at the non-cleft side before ABG, a more symmetrical pattern was obtained after ABG. Regardless of ABG, maxillary protraction with maxillary expansion exhibited more evident forward displacement of maxilla. The sutural stress values after maxillary protraction with maxillary expansion were significantly higher than without expansion. CONCLUSIONS: Analysis of these results showed that maxillary protraction with expansion could presumably promote the orthopedic effects of the facemask on UCLP patients, and more uniform force would obtain after ABG.

Impact of rapid maxillary expansion in unilateral cleft lip and palate patients after secondary alveolar bone grafting: review and case report.

The purpose of this article was to analyze the effects and short-term stability of rapid maxillary expansion performed after secondary alveolar bone grafting in unilateral cleft lip and palate (UCLP) patients. Two UCLP patients with severe maxillary constriction who had previous bone grafting were involved in this study. A hyrax rapid expansion appliance was placed on 4 abutment teeth and activated twice daily. An opening of the midpalatal suture was found on the posttreatment occlusal radiographs, which was clinically confirmed by the diastema. Posteroanterior cephalometric tracing analysis demonstrated significant increases in maxillary and dental arch width. No obvious radiographic alteration was observed in the grafted areas.

[The reliability and accuracy of the digital models reconstructed by cone-beam computed tomography].

PURPOSE: To evaluate the reliability of the digital models scanned by cone-beam computed tomography (CBCT). METHODS: Forty plaster models of patients with orthodontic treatment were selected. These plaster models were scanned and measured by 3DX cone beam CT, compared with manual measurement via concordance correlation coefficient (CCC) and mean difference (MD). RESULTS: The CCC of all the measurement was from 0.847 to 0.993. The value of MD of all the measurement was below 0.25mm except CFF6, PWF5 and PWF6, which was 0.34mm, 0.63mm and 1.49mm, respectively. CONCLUSIONS: The reliability and accuracy of the digital models scanned by cone-beam CT is very high. The accuracy of measurement of the dental cusp is the highest, the dental fossa is the second, and the lowest point of palatal gingival is the third.

[The effectiveness of asymmetric extraction in treatment of Class II division 1 malocclusions].

PURPOSE: To analyze hard and soft tissue profile changes before and after asymmetric extraction treatment of Angle Class II division 1 malocclusion. METHODS: Thirty patients of Angle Class II division 1 malocclusions (11 males, 19 females, average age 13.6 years) were divided into two groups according to their extraction approach. In asymmetric extraction group, 2 first maxillary premolars and 1 first mandibular premolar were extracted. In the control group, all 4 first premolars were extracted. Lateral cephalometric radiographs were taken before and after treatment to compare hard and soft-tissue changes between the two groups, and the cephalometric measurements were analysed by SAS6.12 software package for independent sample t test. RESULTS: In comparison of the changes between the two groups, significant differences in dentoskeletal measurements were observed with NAPog, SNA, ANB, MP-SN and with the inclinations of the upper and lower incisors (P<0.01). Significant differences in soft-tissue changes were also observed in the thickness of upper lip, the Z angle (P<0.01) and the nasolabial angle (P<0.05). Compared to the profile before treatment,only inclination of lower incisors changed significantly after treatment (P<0.01). CONCLUSIONS: Asymmetric extractions is feasible in treatment of Class II division 1 malocclusions evidenced by retractions of both upper and lower incisors and improves sagittal soft-tissue profile. Supported by Research Fund of Science and Technology Commission of Shanghai Municipality (Grant No.08DZ2271100).

[Sagital position of glenoid fossa in Angle Class II malocclusion with mandibular retrusion].

PURPOSE: To evaluate and compare the morphology and position of the glenoid fossa in patients with Class II malocclusion associated with mandibular retrusion and Class I malocclusion in the permanent dentition. METHODS: A sample of 26 subjects(12 males, 14 females, average age 13.4 years) with skeletal and dental Class II malocclusion associated with mandibular retrusion, was compared with a matched group of 31 subjects(12 males, 19 females, aged 12.9 years) with skeletal and dental Class I relationships. The lateral cephalograms were traced and the cephalometric analysis was taken by Nemotec Dental Studio 2006 software before orthodontic treatment. The comparisons between the two groups on the cephalometric measures for the assessment of glenoid fossa were performed by means of an independent samples t test using SPSS 15.0 software package. The correlation and regression analysis was also performed within the measures in the Class II group. RESULTS: The results showed there was significant difference of Wits, GF/Ptm-FH and GF-FMN between the two groups (P<0.01). There was a significant correlation between the GF-FMN vs. AOBO, GF-FMN vs. GF/S-FH, GF/S-FH vs.GF/Ptm-FH, S/Ptm-FH vs. GF/Ptm-FH in the Class II group. The regression equations of the GF-FMN vs. AOBO and GF-FMN vs. GF/S-FH were also obtained (P<0.05). CONCLUSIONS: The Class II malocclusion associated with mandibular retrusion patients have a posteriorly displaced glenoid fossa compared with Class I patients. Cephalometric measurement is a useful tool to evaluate the glenoid fossa morphology and position.

The association between lower incisal inclination and morphology of the supporting alveolar bone--a cone-beam CT study.

AIM: To investigate the relationship between the positioning of the lower central incisor and physical morphology of the surrounding alveolar bone. METHODOLOGY: Thirty-eight patients (18 males, 20 females), with mean age of 13.4 years, were included in this study. As part of orthodontic treatment planning the patients were required to take dental Cone-beam CT (CBCT) covering the region of lower incisors, the surrounding alveolar bone and the mandibular symphysis. The cephalometric parameters were designed and measured to indicate the inclination of lower central incisor and physical morphology of the adjacent alveolar bone. Computer-aided descriptive statistical analysis was performed using SPSS 15.0 software package for Windows. A correlation analysis and a linear regression analysis between the incisor inclination and the alveolar bone morphology were performed. RESULTS: Significant positive correlations were found between the lower central incisor inclination and the morphological contour of the alveolar bone (P < 0.05). The lower central incisor root apex was closer to the lingual alveolar crest when it was buccally inclined. CONCLUSION: The morphology of the alveolar bone may be affected by incisal inclination.