The bone-forming effects of HIF-1?-transduced BMSCs promote osseointegration with dental implant in canine mandible.
ABSTRACT: The presence of insufficient bone volume remains a major clinical problem for dental implant placement to restore the oral function. Gene-transduced stem cells provide a promising approach for inducing bone regeneration and enhancing osseointegration in dental implants with tissue engineering technology. Our previous studies have demonstrated that the hypoxia-inducible factor-1? (HIF-1?) promotes osteogenesis in rat bone mesenchymal stem cells (BMSCs). In this study, the function of HIF-1? was validated for the first time in a preclinical large animal canine model in term of its ability to promote new bone formation in defects around implants as well as the osseointegration between tissue-engineered bone and dental implants. A lentiviral vector was constructed with the constitutively active form of HIF-1? (cHIF). The ectopic bone formation was evaluated in nude mice. The therapeutic potential of HIF-1?-overexpressing canine BMSCs in bone repair was evaluated in mesi-implant defects of immediate post-extraction implants in the canine mandible. HIF-1? mediated canine BMSCs significantly promoted new bone formation both subcutaneously and in mesi-implant defects, including increased bone volume, bone mineral density, trabecular thickness, and trabecular bone volume fraction. Furthermore, osseointegration was significantly enhanced by HIF-1?-overexpressing canine BMSCs. This study provides an important experimental evidence in a preclinical large animal model concerning to the potential applications of HIF-1? in promoting new bone formation as well as the osseointegration of immediate implantation for oral function restoration.
Project description:Cellular and molecular events in osseointegration at the dental implant surface remain largely unknown. We hypothesized that bone marrow stromal cells (BMSCs) participate in this process, and that osterix (Osx) promotes implant osseointegration. To prove this hypothesis, we tracked double-labeled BMSCs in implantation sites created in nude mice transplanted with these cells. We also inserted implants into the femurs of our established transgenic mice after local administration of viruses encoding Osx, to determine the osteogenic effects of Osx. Immunohistochemical results demonstrated that BMSCs can recruit from peripheral circulation and participate in wound healing and osseointegration after implantation. Microcomputed tomography (microCT) analysis revealed an increased bone density at the bone-to-implant interface in the Osx group, and histomorphometric analysis indicated an elevated level of bone-to-implant contact in the Osx group. We concluded that exogenous BMSCs participate in the osseointegration after implantation, and that Osx overexpression accelerates osseointegration.
Project description:Irradiated bone has a greater risk of implant failure than nonirradiated bone. The purpose of this study was to investigate the influence of cell sheets composed of co-cultured bone marrow mesenchymal stromal cells (BMSCs) and endothelial progenitor cells (EPCs) on implant osseointegration in irradiated bone. Cell sheets (EPCs, BMSCs or co-cultured EPCs and BMSCs) were wrapped around titanium implants to make cell sheet-implant complexes. The co-cultured group showed the highest osteogenic differentiation potential in vitro, as indicated by the extracellular matrix mineralization and the expression of osteogenesis related genes at both mRNA and protein levels. The co-cultured cells promoted ectopic bone formation as indicated by micro-computed tomography (Micro-CT) and histological analysis. In the irradiated tibias of rats, implants of the co-cultured group showed enhanced osseointegration by Micro-CT evaluation and histological observation. Co-cultured EPCs and BMSCs also up-regulated the expression of osteogenesis related genes in bone fragments in close contact with implants. In conclusion, cell sheets of co-cultured EPCs and BMSCs could promote osseous healing around implants and are potentially useful to improve osseointegration process for patients after radiotherapy.
Project description:Additive manufacturing can be used to create personalized orthopedic and dental implants with varying geometries and porosities meant to mimic morphological properties of bone. These qualities can alleviate stress shielding and increase osseointegration through bone ingrowth, but at the expense of reduced fatigue properties compared to machined implants, and potential for loose build particle erosion. Hot isostatic pressure (HIP) treatment is used to increase fatigue resistance; implant surface treatments like grit-blasting and acid-etching create microroughness and reduce the presence of loose particles. However, it is not known how HIP treatment affects surface treatments and osseointegration of the implant to bone. We manufactured two titanium-aluminum-vanadium constructs, one with simple through-and-through porosity and one possessing complex trabecular bone-like porosity. We observed HIP treatment varied in effect and was dependent on architecture. Micro/meso/nano surface properties generated by grit-blasting and acid-etching were altered on biomimetic HIP-treated constructs. Human mesenchymal stem cells (MSCs) were cultured on constructs fabricated +/- HIP and subsequently surface-treated. MSCs were sensitive to 3D-architecture, exhibiting greater osteogenic differentiation on constructs with complex trabecular bone-like porosity. HIP-treatment did not alter the osteogenic response of MSCs to these constructs. Thus, HIP may provide mechanical and biological advantages during implant osseointegration and function.
Project description:The presence of nerve endings around implants is well-known, but the interaction between the peripheral nervous system and the osseointegration of implants has not been thoroughly elucidated to date. The purpose of this study was to test the effects of selective sensory denervation on early implant osseointegration. Forty male Sprague-Dawley rats were divided randomly into two groups, group A and group B, and they were treated with capsaicin and normal saline, respectively. One week later, titanium implants were placed in the bilateral femurs of the rats. Three and six weeks after implantation, histological examination, microcomputed tomography and biomechanical testing were performed to observe the effect of sensory denervation on implant osseointegration. At three weeks and six weeks, bone area, trabecular bone volume/total bone volume and bone density were significantly lower in group A than in group B. Similarly, the bone-implant contact rate, trabecular number and trabecular thickness were clearly lower in group A than in group B at three weeks. However, the trabecular separation spacing in group A was greater than that in group B at both time points. Biomechanical testing revealed that the implant-bone binding ability of group A was significantly lower than that in group B. The research demonstrated that sensory innervation played an important role in the formation of osseointegration. Selective-sensory denervation could reduce osseointegration and lower the binding force of the bone and the implant.
Project description:Animal studies and the scarce clinical trials available that have been conducted suggest that bioactive surfaces on dental implants could improve the osseointegration of such implants. The purpose of this systematic review was to compare the effectiveness of osseointegration of titanium (Ti) dental implants using bioactive surfaces with that of Ti implants using conventional surfaces such as sandblasted large-grit acid-etched (SLA) or similar surfaces. Applying the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the MEDLINE, PubMed Central and Web of Science databases were searched for scientific articles in April 2020. The keywords used were "dental implants", "bioactive surfaces", "biofunctionalized surfaces", and "osseointegration", according to the question: "Do bioactive dental implant surfaces have greater osseointegration capacity compared with conventional implant surfaces?" Risk of bias was assessed using the Cochrane Collaboration tool. 128 studies were identified, of which only 30 met the inclusion criteria: 3 clinical trials and 27 animal studies. The average STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) and ARRIVE (Animal Research: Reporting of In Vivo Experiments) scores were 15.13 ± 2.08 and 17.7±1.4, respectively. Implant stability quotient (ISQ) was reported in 3 studies; removal torque test (RTT)-in 1 study; intraoral periapical X-ray and microcomputed tomography radiological evaluation (RE)-in 4 studies; shear force (SF)-in 1 study; bone-to-implant contact (BIC)-in 12 studies; and BIC and bone area (BA) jointly-in 5 studies. All animal studies reported better bone-to-implant contact surface for bioactive surfaces as compared to control implants with a statistical significance of p < 0.05. Regarding the bioactive surfaces investigated, the best results were yielded by the one where mechanical and chemical treatment methods of the Ti surfaces were combined. Hydroxyapatite (HA) and calcium-phosphate (Ca-Ph) were the most frequently used bioactive surfaces. According to the results of this systematic review, certain bioactive surfaces have a positive effect on osseointegration, although certain coating biomolecules seem to influence early peri-implant bone formation. Further and more in-depth research in this field is required to reduce the time needed for osseointegration of dental implants.
Project description:Several factors affect dental implant osseointegration, including surgical issues, bone quality and quantity, and host-related factors, such as patients' nutritional status. Many micronutrients might play a key role in dental implant osseointegration by influencing some alveolar bone parameters, such as healing of the alveolus after tooth extraction. This scoping review aims to summarize the role of dietary supplements in optimizing osseointegration after implant insertion surgery. A technical expert panel (TEP) of 11 medical specialists with expertise in oral surgery, bone metabolism, nutrition, and orthopedic surgery performed the review following the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) model. The TEP identified micronutrients from the "European Union (EU) Register of nutrition and health claims made on foods" that have a relationship with bone and tooth health, and planned a PubMed search, selecting micronutrients previously identified as MeSH (Medical Subject Headings) terms and adding to each of them the words "dental implants" and "osseointegration". The TEP identified 19 studies concerning vitamin D, magnesium, resveratrol, vitamin C, a mixture of calcium, magnesium, zinc, and vitamin D, and synthetic bone mineral. However, several micronutrients are non-authorized by the "EU Register on nutrition and health claims" for improving bone and/or tooth health. Our scoping review suggests a limited role of nutraceuticals in promoting osseointegration of dental implants, although, in some cases, such as for vitamin D deficiency, there is a clear link among their deficit, reduced osseointegration, and early implant failure, thus requiring an adequate supplementation.
Project description:Surface modification of titanium (Ti) implants promotes bone formation and shortens the osseointegration period. The aim of this study was to promote bone regeneration and stability around implants using atmospheric pressure plasma (APP) pretreatment. This was followed by immobilization of stem cells from human exfoliated deciduous teeth-conditioned medium (SHED-CM) on the Ti implant surface.Ti samples (implants, discs, powder) were treated with APP for 30 seconds. Subsequently, these were immobilized on the treated Ti surface, soaked and agitated in phosphate-buffered saline or SHED-CM for 24 hours at 37 °C. The surface topography of the Ti implants was observed using scanning electron microscopy with energy dispersive X-ray spectroscopy. In vivo experiments using Ti implants placed on canine femur bone were then conducted to permit histological analysis at the bone-implant boundary. For the in vitro experiments, protein assays (SDS-PAGE, Bradford assay, liquid chromatography-ion trap mass spectrometry) and canine bone marrow stromal cell (cBMSC) attachment assays were performed using Ti discs or powder.In the in vitro study, treatment of Ti implant surfaces with SHED-CM led to calcium phosphate and extracellular matrix protein immobilization. APP pretreatment increased the amount of SHED-CM immobilized on Ti powder, and contributed to increased cBMSC attachment on Ti discs. In the in vivo study, histological analysis revealed that the Ti implants treated with APP and SHED-CM stimulated new bone formation around implants.Implant device APP pretreatment followed by SHED-CM immobilization may be an effective application to facilitate bone regeneration around dental implants.
Project description:While contemporary prosthetic devices restore some function to individuals who have lost a limb, there are efforts to develop bio-integrated prostheses to improve functionality. A critical step in advancing this technology will be to securely attach the device to remnant bone. To investigate mechanisms for establishing robust implant fixation in bone while undergoing loading, we previously used a topology optimization scheme to develop optimized orthopedic implants and then fabricated selected designs from titanium (Ti)-alloy with selective laser sintering (SLS) technology. In the present study, we examined how implant architecture and mechanical stimulation influence osseointegration within an in vivo environment. To do this, we evaluated three implant designs (two optimized and one non-optimized) using a unique in vivo model that applied cyclic, tension/compression loads to the implants. Eighteen (six per implant design) adult male canines had implants surgically placed in their proximal, tibial metaphyses. Experimental duration was 12 weeks; daily loading (peak load of ±22 N for 1000 cycles) was applied to one of each animal's bilateral implants for the latter six weeks. Following harvest, osseointegration was assessed by non-destructive mechanical testing, micro-computed tomography (microCT) and back-scatter scanning electron microscopy (SEM). Data revealed that implant loading enhanced osseointegration by significantly increasing construct stiffness, peri-implant trabecular morphology, and percentages of interface connectivity and bone ingrowth. While this experiment did not demonstrate a clear advantage associated with the optimized implant designs, osseointegration was found to be significantly influenced by aspects of implant architecture.
Project description:Osseointegration is the key to implant stability and occlusal support. Biomechanical response and remodeling of peri-implant bone occurs under impact loading. Sclerostin participates in bone formation and resorption through Wnt and RANKL pathways. However the mechanism of microdamage and expression of sclerostin in peri-implant bone under impact load is still unclear. In present study, specific impact forces were applied to the implants with favorable osseointegration in rabbits. The microdamage of peri-implant bone and the expression of sclerostin, ?-catenin and RANKL during the process of bone damage and remodeling were investigated by micro-CT, histology, immunofluorescence and RT-qPCR analysis. Interface separation and trabecular fracture were found histologically, which were consistent with micro-CT analyses. Throughout remodeling, bone resorption was observed during the first 14 days after impact, and osseointegration and normal trabecular structure were found by 28?d. The expression of sclerostin and RANKL increased after impact and reached a maximum by 14?d, then decreased gradually to normal levels by 28?d. And ?-catenin expression was opposite. Results indicated that sclerostin may involve in the peri-implant bone damage caused by impact and remodeling through Wnt/?-catenin and RANKL/RANK pathways. It will provide a new insight in the diagnosis and treatment for patients suffering impact.
Project description:Of all geometric shapes, a tri-oval one may be the strongest because of its capacity to bear large loads with neither rotation nor deformation. Here, we modified the external shape of a dental implant from circular to tri-oval, aiming to create a combination of high strain and low strain peri-implant environment that would ensure both primary implant stability and rapid osseointegration, respectively. Using in vivo mouse models, we tested the effects of this geometric alteration on implant survival and osseointegration over time. The maxima regions of tri-oval implants provided superior primary stability without increasing insertion torque. The minima regions of tri-oval implants presented low compressive strain and significantly less osteocyte apoptosis, which led to minimal bone resorption compared to the round implants. The rate of new bone accrual was also faster around the tri-oval implants. We further subjected both round and tri-oval implants to occlusal loading immediately after placement. In contrast to the round implants that exhibited a significant dip in stability that eventually led to their failure, the tri-oval implants maintained their stability throughout the osseointegration period. Collectively, these multiscale biomechanical analyses demonstrated the superior in vivo performance of the tri-oval implant design.