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Osseointegration and foreign body reaction: Titanium implants activate the immune system and suppress bone resorption during the first 4 weeks after implantation. Trindade Ricardo,Albrektsson Tomas,Galli Silvia,Prgomet Zdenka,Tengvall Pentti,Wennerberg Ann Clinical implant dentistry and related research BACKGROUND:Osseointegration mechanisms are still not entirely understood. PURPOSE:The present pilot study aims at demonstrating the involvement of the immune system in the process of osseointegration around titanium implants, comparing bone healing in the presence and absence of a titanium implant. MATERIALS AND METHODS:Fifteen New Zealand White rabbits had one osteotomy performed at each of the distal femurs; on one side, no implant was placed (sham) and on the other side a titanium implant was introduced. Subjects were sacrificed at 10 and 28 days for gene expression analysis (three subjects each time point) and for decalcified qualitative histology (six subjects each time point). At 10 days, the three subjects for gene expression analysis were part of the six subjects for histology. RESULTS:Gene expression analysis: at 10 days, ARG1 was significantly up-regulated around titanium, indicating an activation of M2-macrophages. At 28 days CD11b, ARG1, NCF-1, and C5aR1 were significantly up-regulated, indicating activation of the innate immune system, respectively M1-macrophages, M2-macrophages and group 2-innate lymphoid cells, neutrophils, and the complement system; on the other hand, the bone resorption markers RANKL, OPG, cathepsin K, and TRAP were significantly down-regulated around titanium. HISTOLOGY:at 10 days new bone formation is seen around both sham and titanium sites, separating bone marrow from the osteotomy/implant site; at 28 days no bone trabeculae is seen on the sham site, which is healing at the original cortical level, whereas around titanium implants, bone continues into organization of more mature cortical-like bone, forming a layer between the implant and the bone marrow. CONCLUSIONS:The presence of a titanium implant during bone healing activates the immune system and displays type 2 inflammation, which is likely to guide the host-biomaterial relationship. At the same time, bone resorption is suppressed around titanium sites compared to sham sites after 4 weeks of implantation, suggesting a shift to a more pronounced bone forming environment. This suggests two important steps in osseointegration: identification of the titanium foreign body by the immune system and the development of a bone forming environment, that at tissue level translates into bone build-up on the titanium surface and can be perceived as an attempt to isolate the foreign body from the bone marrow space. 10.1111/cid.12578
Sinus augmentation using a mini-pig model: Effect of ceramic and allogeneic bone biomaterials. Susin Cristiano,Fiorini Tiago,Lee Jaebum,de Freitas Rubens Moreno,Chiu Hsien-Chung,Prasad Hari S,Buxton Amanda N,Wikesjö Ulf M E Journal of clinical periodontology BACKGROUND:Present clinical practice broadly relies on off-the-shelf allogeneic, xenogeneic or synthetic bone biomaterials in support of sinus augmentation. Also, recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge carrier (rhBMP-2/ACS) has been shown to support clinically relevant bone formation when used to augment the maxillary sinus. OBJECTIVES:To evaluate local bone formation/dental implant osseointegration following implantation of two particulate bone biomaterials using the mini-pig sinus augmentation model. METHODS:Nine adult Göttingen mini-pigs were used for evaluation of a biphasic ceramic (15%/85% HA/ß-TCP) and an allogeneic mineralized bone biomaterial. Treatments randomized to contralateral sinus sites included sham-surgery (control) and biomaterials. Two threaded dental implants (ø4.0 × 11.5 mm) were placed at each sinus site. The animals were euthanized at 8 weeks for histologic analysis. RESULTS:Execution of the surgical protocol and healing was unremarkable. Limited infraorbital swelling was observed until suture removal. The biphasic ceramic and allogeneic bone biomaterials produced significantly increased bone formation (5.2 ± 1.9 mm and 4.9 ± 1.6 mm vs. 2.6 ± 0.5 mm, p < 0.05) and osseointegration (18.0 ± 6.0% and 25.1 ± 18.2% vs. 10.1 ± 8.0%, p < 0.05) over the sham-surgery control. No significant differences were observed between biomaterials. CONCLUSIONS:Implantation of biphasic ceramic or allogeneic bone biomaterials enhances bone formation in the mini-pig maxillary sinus, however, dental implant bone support is incomplete resulting in overall limited osseointegration. 10.1111/jcpe.12766
The Ultrastructural Relationship Between Osteocytes and Dental Implants Following Osseointegration. Du Zhibin,Ivanovski Saso,Hamlet Stephen M,Feng Jian Q,Xiao Yin Clinical implant dentistry and related research BACKGROUND:Osteocytes, the most abundant cells in bone, have multiple functions, including acting as mechanosensors and regulating mineralization. It is clear that osteocytes influence bone remodeling by controlling the differentiation and activity of osteoblasts and osteoclasts. Determining the relationship between titanium implants and osteocytes may therefore benefit our understanding of the process of osseointegration. PURPOSE:The aim of this study was to visualize the ultrastructural relationship between osteocytes and the titanium implant surface following osseointegration in vivo. MATERIALS AND METHODS:Titanium implants were placed in the maxillary molar regions of eight female Sprague Dawley rats, 3 months old. The animals were sacrificed 8 weeks after implantation, and undecalcified tissue sections were prepared. Resin-cast samples were subsequently acid-etched with 37% phosphoric acid prior to examination using scanning electron microscopy. RESULTS:Compared with mature bone, where the osteocytes were arranged in an ordered fashion, the osteocytes appeared less organized in the newly formed bone around the titanium implant. Further, a layer of mineralization with few organic components was observed on the implant surface. This study shows for the first time that osteocytes and their dendrites are directly connected with the implant surface. CONCLUSIONS:This study shows the direct anchorage of osteocytes via dendritic processes to a titanium implant surface in vivo. This suggests an important regulatory role for osteocytes and their lacunar-canalicular network in maintaining long-term osseointegration. 10.1111/cid.12257
Relationships among Bone Quality, Implant Osseointegration, and Wnt Signaling. Li J,Yin X,Huang L,Mouraret S,Brunski J B,Cordova L,Salmon B,Helms J A Journal of dental research A variety of clinical classification schemes have been proposed as a means to identify sites in the oral cavity where implant osseointegration is likely to be successful. Most schemes are based on structural characteristics of the bone, for example, the relative proportion of densely compact, homogenous (type I) bone versus more trabeculated, cancellous (type III) bone. None of these schemes, however, consider potential biological characteristics of the bone. Here, we employed multiscale analyses to identify and characterize type I and type III bones in murine jaws. We then combined these analytical tools with in vivo models of osteotomy healing and implant osseointegration to determine if one type of bone healed faster and supported osseointegration better than another. Collectively, these studies revealed a strong positive correlation between bone remodeling rates, mitotic activity, and osteotomy site healing in type III bone and high endogenous Wnt signaling. This positive correlation was strengthened by observations showing that the osteoid matrix that is responsible for implant osseointegration originates from Wnt-responsive cells and their progeny. The potential application of this knowledge to clinical practice is discussed, along with a theory unifying the role that biology and mechanics play in implant osseointegration. 10.1177/0022034517700131
Promoting Osseointegration of Dental Implants in Dog Maxillary Sinus Floor Augmentation Using Dentin Matrix Protein 1-Transduced Bone Marrow Stem Cells. Ma Dong,Wang Yuanyin,Chen Yongxiang,Yang Gang,Liu Xin Tissue engineering and regenerative medicine BACKGROUND:Beta-tricalcium phosphate (β-TCP) has been employed successfully as a synthetic graft material in maxillary sinus floor augmentation (MSFA) for placing dental implants. However, the lack of osteogenic and osteoinductive properties of this substitute invariably results in bone regeneration of low quality and quantity. The purpose of this study was to determine whether loading dentin matrix protein-1 (DMP1) gene-modified bone marrow mesenchymal stem cells (BMSCs) onto β-TCP promoted bone regeneration and osteointegration of dental implants in MSFA of dogs. METHODS:BMSCs were transduced with a lentiviral vector overexpressing the DMP1 gene (Lenti-DMP1) and with a lentiviral vector overexpressing enhanced green fluorescent protein (Lenti-EGFP) in vitro and were loaded into β-TCP scaffolds for autologous sinus grafting. Beagles received bilateral MSFA with four biomaterials (① Lenti-DMP1-transduced BMSCs/β-TCP, ② Lenti-EGFP-transduced BMSCs/β-TCP, ③ BMSCs/β-TCP, ④ β-TCP) and simultaneous implant placement at each sinus. Twelve weeks post operation, the maxillae were explanted, and every sinus was evaluated by radiographic observation, micro-CT and histological analysis. The osteogenic outcomes of bone regeneration and osseointegration were compared between the four groups. RESULTS:The sinuses grafted with Lenti-DMP1-transduced BMSCs/β-TCP constructs presented a significantly higher increase in compact radiopaque area, higher local bone mineral densities, greater bone-implant contact and greater bone density when compared to other three groups. CONCLUSION:These results demonstrated that combinations of β-TCP and DMP1 gene-modified BMSCs could be used to construct tissue-engineered bone to enhance mineralization of the regenerated bone and osseointegration of dental implants in MSFA. 10.1007/s13770-020-00277-1
Role of Hippo-YAP Signaling in Osseointegration by Regulating Osteogenesis, Angiogenesis, and Osteoimmunology. Zhou Anqi,Yu Hui,Liu Jiayi,Zheng Jianan,Jia Yinan,Wu Bingfeng,Xiang Lin Frontiers in cell and developmental biology The social demand for dental implantation is growing at a rapid rate, while dentists are faced with the dilemma of implantation failures associated with unfavorable osseointegration. Clinical-friendly osteogenesis, angiogenesis and osteoimmunology around dental implants play a pivotal role in a desirable osseointegration and it's increasingly appreciated that Hippo-YAP signaling pathway is implicated in those biological processes both and in a variety of study. In this article we review the multiple effects of Hippo-YAP signaling in osseointegration of dental implants by regulating osteogenesis, angiogenesis and osteoimmunology in peri-implant tissue, as well as highlight prospective future directions of relevant investigation. 10.3389/fcell.2020.00780
A pre-clinical murine model of oral implant osseointegration. Mouraret S,Hunter D J,Bardet C,Brunski J B,Bouchard P,Helms J A Bone Many of our assumptions concerning oral implant osseointegration are extrapolated from experimental models studying skeletal tissue repair in long bones. This disconnect between clinical practice and experimental research hampers our understanding of bone formation around oral implants and how this process can be improved. We postulated that oral implant osseointegration would be fundamentally equivalent to implant osseointegration elsewhere in the body. Mice underwent implant placement in the edentulous ridge anterior to the first molar and peri-implant tissues were evaluated at various timepoints after surgery. Our hypothesis was disproven; oral implant osseointegration is substantially different from osseointegration in long bones. For example, in the maxilla peri-implant pre-osteoblasts are derived from cranial neural crest whereas in the tibia peri-implant osteoblasts are derived from mesoderm. In the maxilla, new osteoid arises from periostea of the maxillary bone but in the tibia the new osteoid arises from the marrow space. Cellular and molecular analyses indicate that osteoblast activity and mineralization proceeds from the surfaces of the native bone and osteoclastic activity is responsible for extensive remodeling of the new peri-implant bone. In addition to histologic features of implant osseointegration, molecular and cellular assays conducted in a murine model provide new insights into the sequelae of implant placement and the process by which bone is generated around implants. 10.1016/j.bone.2013.07.021
Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis. Mediero Aránzazu,Ramkhelawon Bhama,Wilder Tuere,Purdue P Edward,Goldring Steven R,Dewan M Zahidunnabi,Loomis Cynthia,Moore Kathryn J,Cronstein Bruce N Annals of the rheumatic diseases OBJECTIVE:Netrin-1 is a chemorepulsant and matrix protein expressed during and required for osteoclast differentiation, which also plays a role in inflammation by preventing macrophage egress. Because wear particle-induced osteolysis requires osteoclast-mediated destruction of bone, we hypothesised that blockade of Netrin-1 or Unc5b, a receptor for Netrin-1, may diminish this pathological condition. METHODS:C57BL/6 mice, 6-8 weeks old, had 3 mg of ultrahigh-molecular-weight polyethylene particles implanted over the calvaria and then received 10 µg of monoclonal antibodies for Netrin-1 or its receptors, Unc5b and deleted in colon cancer (DCC), injected intraperitoneally on a weekly basis. After 2 weeks, micro-computed tomography and histology analysis were performed. Netrin-1 expression was analysed in human tissue obtained following primary prosthesis implantation or after prosthesis revision for peri-implant osteolysis and aseptic implant loosening. RESULTS:Weekly injection of anti-Netrin-1 or anti-Unc5b-antibodies significantly reduced particle-induced bone pitting in calvaria exposed to wear particles (46±4% and 49±3% of control bone pitting, respectively, p<0.001) but anti-DCC antibody did not affect inflammatory osteolysis (80±7% of control bone pitting, p=ns). Anti-Netrin-1 or anti-Unc5b, but not anti-DCC, antibody treatment markedly reduced the inflammatory infiltrate and the number of tartrate resistance acid phosphatase (TRAP)-positive osteoclasts (7±1, 4±1 and 14±1 cells/high power field (hpf), respectively, vs 12±1 cells/hpf for control, p<0.001), with no significant changes in alkaline phosphatase-positive osteoblasts on bone-forming surfaces in any antibody-treated group. Netrin-1 immunostaining colocalised with CD68 staining for macrophages. The peri-implant tissues of patients undergoing prosthesis revision surgery showed an increase in Netrin-1 expression, whereas there was little Netrin-1 expression in soft tissues removed at the time of primary joint replacement. CONCLUSIONS:These results demonstrate a unique role for Netrin-1 in osteoclast biology and inflammation and may be a novel target for prevention/treatment of inflammatory osteolysis. 10.1136/annrheumdis-2015-207593
Atomically resolved tissue integration. Karlsson Johan,Sundell Gustav,Thuvander Mattias,Andersson Martin Nano letters In the field of biomedical technology, a critical aspect is the ability to control and understand the integration of an implantable device in living tissue. Despite the technical advances in the development of biomaterials, the elaborate interplay encompassing materials science and biology on the atomic level is not very well understood. Within implantology, anchoring a biomaterial device into bone tissue is termed osseointegration. In the most accepted theory, osseointegration is defined as an interfacial bonding between implant and bone; however, there is lack of experimental evidence to confirm this. Here we show that atom probe tomography can be used to study the implant-tissue interaction, allowing for three-dimensional atomic mapping of the interface region. Interestingly, our analyses demonstrated that direct contact between Ca atoms and the implanted titanium oxide surface is formed without the presence of a protein interlayer, which means that a pure inorganic interface is created, hence giving experimental support to the current theory of osseointegration. We foresee that this result will be of importance in the development of future biomaterials as well as in the design of in vitro evaluation techniques. 10.1021/nl501564f
Osseointegration and current interpretations of the bone-implant interface. Shah Furqan A,Thomsen Peter,Palmquist Anders Acta biomaterialia Complex physical and chemical interactions take place in the interface between the implant surface and bone. Various descriptions of the ultrastructural arrangement to various implant design features, ranging from solid and macroporous geometries to surface modifications on the micron-, submicron-, and nano- levels, have been put forward. Here, the current knowledge regarding structural organisation of the bone-implant interface is reviewed with a focus on solid devices, mainly metal (or alloy) intended for permanent anchorage in bone. Certain biomaterials that undergo surface and bulk degradation are also considered. The bone-implant interface is a heterogeneous zone consisting of mineralised, partially mineralised, and unmineralised areas. Within the meso-micro-nano-continuum, mineralised collagen fibrils form the structural basis of the bone-implant interface, in addition to accumulation of non-collagenous macromolecules such as osteopontin, bone sialoprotein, and osteocalcin. In the published literature, as many as eight distinct arrangements of the bone-implant interface ultrastructure have been described. The interpretation is influenced by the in vivo model and species-specific characteristics, healing time point(s), physico-chemical properties of the implant surface, implant geometry, sample preparation route(s) and associated artefacts, analytical technique(s) and their limitations, and non-compromised vs compromised local tissue conditions. The understanding of the ultrastructure of the interface under experimental conditions is rapidly evolving due to the introduction of novel techniques for sample preparation and analysis. Nevertheless, the current understanding of the interface zone in humans in relation to clinical implant performance is still hampered by the shortcomings of clinical methods for resolving the finer details of the bone-implant interface. STATEMENT OF SIGNIFICANCE: Being a hierarchical material by design, the overall strength of bone is governed by composition and structure. Understanding the structure of the bone-implant interface is essential in the development of novel bone repair materials and strategies, and their long-term success. Here, the current knowledge regarding the eventual structural organisation of the bone-implant interface is reviewed, with a focus on solid devices intended for permanent anchorage in bone, and certain biomaterials that undergo surface and bulk degradation. The bone-implant interface is a heterogeneous zone consisting of mineralised, partially mineralised, and unmineralised areas. Within the meso-micro-nano-continuum, mineralised collagen fibrils form the structural basis of the bone-implant interface, in addition to accumulation of non-collagenous macromolecules such as osteopontin, bone sialoprotein, and osteocalcin. 10.1016/j.actbio.2018.11.018