Biodegradable Zn-2Cu-0.5Zr alloy promotes the bone repair of senile osteoporotic fractures via the immune-modulation of macrophages.

Delayed bone-healing of senile osteoporotic fractures remains a clinical challenge due to the alterations caused by aging in bone and immune systems. The novel biomaterials that address the deficiencies in both skeletal cells and immune systems are required to effectively treat the bone injuries of older patients. Zinc (Zn) has shown promise as a biodegradable material for use in orthopedic implants. To address the bone-healing deficiencies in elderly patients with bone injuries, we developed a biodegradable Zn-based alloy (Zn-2Cu-0.5Zr) with enhanced mechanical properties, including a yield strength of 198.7 MPa and ultimate tensile strength of 217.6 MPa, surpassing those of pure Zn and Zn-2Cu alloys. Cytotoxicity tests conducted on bone marrow mesenchymal stem cells (BMSCs) and MC3T3-E1 cells demonstrated that the extracts from Zn-2Cu-0.5Zr alloy exhibited no observable cytotoxic effects. Furthermore, the extracts of Zn-2Cu-0.5Zr alloy exhibited significant anti-inflammatory effects through regulation of inflammation-related cytokine production and modulation of macrophage polarization. The improved immune-osteo microenvironment subsequently contributed to osteogenic differentiation of BMSCs. The potential therapeutic application of Zn-2Cu-0.5Zr in senile osteoporotic fracture was tested using a rat model of age-related osteoporosis. The Zn-2Cu-0.5Zr alloy met the requirements for load-bearing applications and accelerated the healing process in a tibial fracture in aged rats. The imaging and histological analyses showed that it could accelerate the bone-repair process and promote the fracture healing in senile osteoporotic rats. These findings suggest that the novel Zn-2Cu-0.5Zr alloy holds potential for influencing the immunomodulatory function of macrophages and facilitating bone repair in elderly individuals with osteoporosis.

Programmed core-shell electrospun nanofibers to sequentially regulate osteogenesis-osteoclastogenesis balance for promoting immediate implant osseointegration.

The biology of immediate post-extraction implant osseointegration is mediated by a coordinated cascade of osteoblast-osteoclast interactions. The aim of this study was to develop a dual-delivery system that allowed sequential release of substance P (SP) to promote bone regeneration and alendronate (ALN) to reduce bone resorption, which will improve the implant osseointegration. We used coaxial electrospinning to fabricate the core-shell poly lactic-co-glycolic acid (PLGA)/gelatin nanofibers, which consists of SP in the shell and ALN in the core. This programmed delivery system was shown to release SP and ALN sequentially to match the spatio-temporal specificity of bone healing. The migration assay demonstrated that the SP-ALN dual-delivery system increased bone marrow mesenchymal stem cells (BMSCs) transmigration. Besides, the expression of osteogenic/osteoclastic markers, Alizarin Red staining, tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining and bone resorption experiment showed that the dual-delivery system can render a microenvironment favorable for osteogenic differentiation and adverse to osteoclastogenesis. Using a rat immediate implant model, we validated the promoted osteogenic property and osseointegration around the implants of SP-ALN dual-delivery system by micro-computed tomography (micro-CT) and histological analysis. These findings suggest that the dual-delivery system with time-controlled release of SP and ALN by core-shell nanofibers provides a promising strategy to facilitate immediate implant osseointegration through favorable osteogenesis. STATEMENT OF SIGNIFICANCE: Immediate implant placement is potentially challenged by the difficulties in achieving primary implant stability and early osteogenesis. Initial period of osteointegration is regulated by osteoblastic/osteoclastic cells resulting in a coordinated healing process. To have an efficient bone regeneration, the coaxial electrospinning was used to fabricate a programmed dual-delivery system. The SP released rapidly and favored for BMSCs migration and osteogenic differentiation, while the sustained release of ALN can reduce the bone resorption. The rat immediate implant model indicated that the SP-ALN dual-delivery system could present the promoted peri­implant osteogenic property and osseointegration through modulating the osteogenesis-osteoclastogenesis balance. This work highlights the sequential dual delivery of SP and ALN has a promising potential of achieving enhanced osseointegration for immediate implant placement.

An adiponectin receptor agonist promote osteogenesis via regulating bone-fat balance.

OBJECTIVES: Adiponectin signalling has been considered to be a promising target to treat diabetes-related osteoporosis. However, contradictory results regarding bone formation were observed due to the various isoforms of adiponectin. Therefore, it would be necessary to investigate the effect of adiponectin receptor signals in regulating bone-fat balance. MATERIALS AND METHODS: We primarily applied a newly found specific activator for adiponectin receptor, AdipoRon, to treat bone metabolism-related cells to investigate the role of Adiponectin receptor signals on bone-fat balance. We then established femur defect mouse model and treated them with AdipoRon to see whether adiponectin receptor activation could promote bone regeneration. RESULTS: We found that AdipoRon could slightly inhibit the proliferation of pre-osteoblast and pre-osteoclast, but AdipoRon showed no effect on the viability of mesenchymal stromal cells. AdipoRon could remarkably promote cell migration of mesenchymal stromal cells. Additionally, AdipoRon promoted osteogenesis in both pre-osteoblasts and mesenchymal cells. Besides, AdipoRon significantly inhibited osteoclastogenesis via its direct impact on pre-osteoclast and its indirect inhibition of RANKL in osteoblast. Moreover, mesenchymal stromal stems cells showed obviously decreased adipogenesis when treated with AdipoRon. Consistently, AdipoRon-treated mice showed faster bone regeneration and repressed adipogenesis. CONCLUSIONS: Our study demonstrated a pro-osteogenic, anti-adipogenic and anti-osteoclastogenic effect of adiponectin receptor activation in young mice, which suggested adiponectin receptor signalling was involved in bone regeneration and bone-fat balance regulation.

Treatment of hemimandibular hyperplasia by computer-aided design and computer-aided manufacturing cutting and drilling guides accompanied with pre-bent titanium plates.

PURPOSE: The treatment of hemimandibular hyperplasia (HH) is difficult by performing condylectomy and orthognathic surgery in one stage. This study investigated the clinical feasibility of treating HH with computer-aided design and computer-aided manufacturing (CAD/CAM) cutting and drilling guides and the pre-bent titanium plates to improve the accuracy of operation to avoid condyle reconstruction. METHODS: 12 patients diagnosed with HH were included in this study from 2014 to 2018. Conservative condylectomy and bimaxillary orthognathic surgery were performed in all patients. The CAD/CAM cutting and drilling guides and the pre-bent titanium plates were used to guide surgeries. Follow-up and radiographic examinations were performed. The difference between virtually simulated and postoperative models was measured. RESULTS: All patients got satisfactory and stable results, without complications or obvious relapse during follow-up. Occlusion relationship, temporomandibular joint function and facial symmetry were improved obviously after surgery. Comparison between simulated plans and actual postoperative outcomes showed that the surgical plans were transferred accurately. CONCLUSIONS: CAD/CAM cutting and drilling guides and the pre-bent titanium plates described in this paper can help transferring the results from computer simulation to the operating room accurately. Conservative condylectomy can be operated exactly matching bimaxillary orthognathic surgery for treating HH, avoiding condyle reconstruction.

The Drilling Guiding Templates and Pre-Bent Titanium Plates Improves the Operation Accuracy of Orthognathic Surgery With Computer-Aided Design and Computer-Aided Manufacturing Occlusal Splints for Patients With Facial Asymmetry.

Facial asymmetry is a common maxillofacial deformity which requires surgery to recover the 3-dimensional relationship of bones. The computer-aided design and computer-aided manufacturing (CAD/CAM) has been developed and applied to improve orthognathic analysis and surgery design. How to accurately realize the preoperative design of orthognathic surgery with CAD/CAM occlusal splints during operation remains a big problem. In this study, 24 consecutive patients with facial asymmetry were recruited and assigned to 2 groups. For Group A, CAD/CAM was applied to designing and producing not only the occlusal splints, but also the drilling guiding templates and pre-bent titanium plates, and for Group B CAD/CAM was applied for occlusal splints only. Postoperative clinical examinations, symmetry evaluation through 3D cephalometric analysis, accuracy comparison using color distance maps and quantitative accuracy analysis were performed. Symmetry evaluation showed that patients of both groups achieved improved facial symmetry after surgery. The color distance maps and quantitative accuracy analysis together demonstrated significantly less difference found between virtual simulated surgery and postoperative CT scan data in Group A than in Group B. In conclusion, by navigation with the drilling guiding templates and pre-bent titanium plates, the facial symmetry for patients with facial asymmetry was successfully restored after orthognathic surgery, same as applying CAD/CAM occlusal splints only. However, the drilling guiding templates and pre-bent titanium plates would provide a more accurate performance according to preoperative simulation, especially for proximal mandibular segments.

Fluorine-contained hydroxyapatite suppresses bone resorption through inhibiting osteoclasts differentiation and function in vitro and in vivo.

OBJECTIVES: Fluorine, an organic trace element, has been shown to unfavourably effect osteoclasts function at a low dose. Use of hydroxyapatite (HA) has been effective in exploring its roles in promoting bone repair. In this study, we used HA modified with fluorine to investigate whether it could influence osteoclastic activity in vitro and ovariectomy-induced osteoclasts hyperfunction in vivo. MATERIALS AND METHODS: Fluorohydroxyapatite (FHA) was obtained and characterized by scanning electron microscope (SEM). Osteoclasts proliferation and apoptosis treated with FHA were assessed by MTT and TUNEL assay. SEM, F-actin, TRAP activity and bone resorption experiment were performed to determine the influence of FHA on osteoclasts differentiation and function. Moreover, HA and FHA were implanted into ovariectomized osteoporotic and sham surgery rats. Histology and Micro-CT were examined for further verification. RESULTS: Fluorine released from FHA slowly and sustainably. FHA hampered osteoclasts proliferation, promoted osteoclasts apoptosis, suppressed osteoclasts differentiation and function. Experiments in vivo validated that FHA participation brought about an inhibitory effect on osteoclasts hyperfunction and less bone absorption. CONCLUSION: The results indicated that FHA served as an efficient regulator to attenuate osteoclasts formation and function and was proposed as a candidature for bone tissue engineering applications.

Management of condylar resorption before or after orthognathic surgery: A systematic review.

BACKGROUND: Orthognathic surgery is a surgical procedure for the correction of maxillofacial deformities. The existence of condylar resorption before orthognathic surgery affects the selection of surgery time and plan. Besides, condylar resorption after orthognathic surgery often leads to the recurrence of deformities and affects the long-term effect of surgery. The purpose of this study was to perform a systematic review of the management of condylar resorption before or after orthognathic surgery. METHODS: A systematic review of the scientific literature listed on PubMed, Embase, and Cochrane Controlled Trials Register was performed, up to October 2018. The outcome of the search was reviewed with a chart. RESULTS: Ten articles with 180 patients were included in this study based on inclusion and exclusion criteria. We compared these studies to examine the effectiveness of the management of condylar resorption. CONCLUSION: The occurrence of condylar resorption can be influenced by complex factors. The management of condylar resorption before or after orthognathic surgery should base on the severity of condylar resorption. As the eligible studies with small sample sizes, heterogeneity in management method and outcome, high-quality clinical study concerning condylar resorption treatment is needed.

Synergetic effect of topological cue and periodic mechanical tension-stress on osteogenic differentiation of rat bone mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are able to self-renew and differentiate into tissues of mesenchymal origin, making them to be significant for cell-based therapies, such as metabolic bone diseases and bone repair. Regulating the differentiation of MSCs is significant for bone regeneration. Electrospun fibers mimicking natural extracellular matrix (ECM), is an effective artificial ECM to regulate the behaviors and fates of MSCs. The aligned electrospun fibers can modulate polar cell pattern of bone mesenchymal stem cells, which leads to more obvious osteogenic differentiation. Apart from the topographic effect of electrospun fibers, mechanical cues can also intervene the cell behaviors. In this study, the osteogenic differentiation of rat bone mesenchymal stem cells was evaluated, which were cultured on aligned/random electrospun fiber mats materials under mechanical tension intervention. Scanning electron microscope and immune-fluorescent staining were used to directly observe the polarity changing of cellular morphology and cytoskeleton. The results proved that aligned electrospun fibers could be more conducive to promote osteogenic differentiation of rat bone mesenchymal stem cells and this promotion of osteogenic differentiation was enhanced by tension intervention. These results were correlated to the quantitative real-time PCR assay. In general, culturing rat bone mesenchymal stem cells on electrospun fibers under the intervention of mechanical tension is an effective way to mimic a more real cellular microenvironment.

Cone-beam computed tomography evaluation of the maxillofacial features of patients with unilateral temporomandibular joint ankylosis undergoing condylar reconstruction with an autogenous coronoid process graft.

OBJECTIVE: To evaluate the changes in the jaws and the upper airways of unilateral temporomandibular joint ankylosis patients who underwent condylar reconstruction via autogenous coronoid process grafts using cone-beam computed tomography (CBCT). STUDY DESIGN: The 27 included patients underwent CBCT examinations at three stages: T0 (within two weeks before surgery), T1 (two weeks after surgery), and T2 (an average of 13 months after surgery). Forty items related to the maxillofacial hard tissues and the upper airway collected at the three times and the coronoid process graft volumes after surgery were compared. RESULTS: Some integral items related to the mandibular hard tissues exhibited statistical difference shortly after surgery. Some integral items related to maxillofacial hard tissues changing obviously long period after surgery may result from graft remodeling. Asymmetry-related item regarding local neo-condyle and some airway items were significantly different between T0 and T1. Due to variations in graft remodeling, some related local asymmetry items and airway items differed significantly between T0 and T2. CONCLUSIONS: Anteriorly and inferiorly located neo-condyles and a trend toward the pronation of the mandible were observed and the narrowness of the upper airway was improved shortly after surgery. The grafts remodeled differently and some integral and asymmetry items related to neo-condyle changed. The improvements in the upper airway were slightly reduced.

Histopathologic comparison of condylar hyperplasia and condylar osteochondroma by using different staining methods.

OBJECTIVE: The objectives of this study were to investigate the application and differential diagnostic value of safranin O staining, safranin-fast green staining, and Runt-related transcription factor 2 (Runx2) immunohistochemistry with regard to condylar hyperplasia and condylar osteochondroma. STUDY DESIGN: Histopathologic presence was evaluated by using hematoxylin and eosin staining, safranin O staining, safranin-fast green staining, and immunohistochemistry of Runx2 in postoperative specimens of normal condyle (control), condylar hyperplasia, and condylar osteochondroma. RESULTS: Safranin O staining clearly highlighted the tissue structure of the condylar cartilage, especially the hypertrophic layer. The safranin-fast green method showed a contrast in staining between cartilage and subchondral cancellous bone in the condyle specimens. Both methods were better than hematoxylin and eosin staining for morphologically distinguishing condylar hyperplasia and condylar osteochondroma. The expression of Runx2 in condylar hyperplasia was significantly greater than that in condylar osteochondroma. CONCLUSIONS: This study indicated that safranin O staining and safranin-fast green staining are effective staining methods to differentiate between condylar hyperplasia and condylar osteochondroma. Immunohistochemistry findings suggested that Runx2 is valuable in the differential diagnosis of these two diseases.