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First Experimental Study of the Influence of Extracellular Vesicles Derived from Multipotent Stromal Cells on Osseointegration of Dental Implants.

ABSTRACT: Herein, the aim was to study the state of the bone tissue adjacent to dental implants after the use of extracellular vesicles derived from multipotent stromal cells (MSC EVs) of bone marrow origin in the experiment. In compliance with the rules of asepsis and antiseptics under general intravenous anesthesia with propofol, the screw dental implants were installed in the proximal condyles of the tibia of outbred rabbits without and with preliminary introduction of 19.2 μg MSC EVs into each bone tissue defect. In 3, 7, and 10 days after the operation, the density of bone tissue adjacent to different parts of the implant using an X-ray unit with densitometer was measured. In addition, the histological examinations of the bone site with the hole from the removed device and the soft tissues from the surface of the proximal tibial condyle in the area of intra-bone implants were made. It was found out that 3 days after implantation with the use of MSC EVs, the bone density was statistically significantly higher by 47.2% than after the same implantation, but without the injection of MSC EVs. It is possible that as a result of the immunomodulatory action of MSC EVs, the activity of inflammation decreases, and, respectively, the degree of vasodilation in bones and leukocyte infiltration of the soft tissues are lower, in comparison with the surgery performed in the control group. The bone fragments formed during implantation are mainly consolidated with each other and with the regenerating bone. Day 10 demonstrated that all animals with the use of MSC EVs had almost complete fusion of the screw device with the bone tissue, whereas after the operation without the application of MSC EVs, the heterogeneous histologic pattern was observed: From almost complete osseointegration of the implant to the absolute absence of contact between the foreign body and the new formed bone. Therefore, the use of MSC EVs during the introduction of dental implants into the proximal condyle of the tibia of rabbits contributes to an increase of the bone tissue density near the device after 3 days and to the achievement of consistently successful osseointegration of implants 10 days after the surgery.

SUBMITTER: Maiborodin I

PROVIDER: S-EPMC8395855 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Spatiotemporal implant-bone biomechanics and mechanoadaptive strains in peri-implant tissue are poorly understood. Physical and chemical characteristics of an implant-bone complex (IBC) were correlated in three-dimensional space (along the length and around a dental implant) to gather insights into time related integration of the implant with the cortical portion of a jaw bone in a rat. Rats (N = 9) were divided into three experimental groups with three rats per time point; 3-, 11-, and 24-day. All rats were fed crumbled hard pellets mixed with water (soft-food diet) for the first 3 days followed by a hard-food diet with intact hard-food pellets (groups of 11- and 24-day only). Biomechanics of the IBCs harvested from rats at each time point was evaluated by performing mechanical testing in situ in tandem with X-ray imaging. The effect of physical association (contact area) of a loaded implant with adapting peri-implant tissue, and resulting strain within was mapped by using digital volume correlation (DVC) technique. The IBC stiffness at respective time points was correlated with mechanical strain in peri-implant tissue. Results illustrated that IBC stiffness at 11-day was lower than that observed at 3-day. However, at 24-day, IBC stiffness recovered to that which was observed at 3-day. Correlative microscopy and spectroscopy illustrated that the lower IBC stiffness was constituted by softer and less mineralized peri-implant tissue that contained varying expressions of osteoconductive elements. Lower IBC stiffness observed at 11-day was constituted by less mineralized peri-implant tissue with osteoconductive elements that included phosphorus (P) which was co-localized with higher expression of zinc (Zn), and lower expression of calcium (Ca). Higher IBC stiffness at 24-day was constituted by mineralized peri-implant tissue with higher expressions of osteoconductive elements including Ca and P, and lower expressions of Zn. These spatiotemporal correlative maps of peri-implant tissue architecture, heterogeneous distribution of mineral density, and elemental colocalization underscore mechanoadaptive physicochemical properties of peri-implant tissue that facilitate functional osseointegration of an implant. These results provided insights into 1) plausible "prescription" of mechanical loads as an osteoinductive "therapeutic dose" to encourage osteoconductive elements in the peri-implant tissue that would facilitate functional osseointegration of the implant; 2) a "critical temporal window" between 3 and 11 days, and perhaps it is this acute phase during which key candidate regenerative molecules can be harnessed to accelerate osseointegration of an implant under load.

Project description:BackgroundThe paracrine effects of multipotent mesenchymal stromal cells (MSCs) are mediated by their secretome composed by soluble factors (i.e., cytokines, growth factors, hormones) and extracellular vesicles (EVs). EVs promote intercellular communication, and the EV cargoes [e.g., proteins, soluble factors, microRNAs (miRNAs), messenger RNA (mRNA), DNA] reflect the molecular and functional characteristics of their parental cells. MSC-derived EVs (MSC-EVs) are currently evaluated as subcellular therapeutics. A key function of the MSC secretome is its ability to promote immune tolerance (i.e., immunopotency), a property that is enhanced by priming approaches (e.g., cytokines, hypoxia, chemicals) and inversely correlates with the age of the MSC donors. We evaluated mechanisms underlying MSC vesiculation and the effects of inflammation and aging on this process.MethodsWe evaluated the effects of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) on human adipose-derived MSC: (a) vesiculation (custom RT2 Profiler PCR Array), (b) EV profiles (Nanoparticle Tracking Analysis and Nanoparticle Flow Cytometry), (c) EV cargo (proteomic analysis and Western blot analysis), and (d) immunopotency (standard MSC:CD4 T cell proliferation inhibition assay). We confirmed the role of RAB27B on MSC vesiculation (RAB27B siRNA) and assessed its differential contribution to vesiculation in adult and pediatric MSCs (qPCR).ResultsCytokine priming upregulated RAB27B in adipose-derived MSCs increasing their secretion of exosome-like small EVs (sEVs; < 200 nm) containing two key mediators of immunopotency: A20 and TSG-6. These EVs inhibited T cell proliferation in a dose-dependent manner. RAB27B siRNA inhibited MSC vesiculation. Adipose-derived MSCs isolated from pediatric donors exhibited higher RAB27B expression and secreted more sEVs than adult MSCs.ConclusionsCytokine priming is a useful strategy to harvest anti-inflammatory MSC-sEVs for clinical applications. Of relevance, donor age should be considered in the selection of MSC-sEVs for clinical applications.

Project description:BackgroundTitanium (Ti) is now widely used as implant material due to its excellent mechanical properties and superior biocompatibilities, while its inert bioactivities might lead to insufficient osseointegration, and limit its performance in dental applications.MethodsWe introduced a robust and simple approach of modifying titanium surfaces with polysaccharide complexes. Titanium samples were subjected to hydrothermal treatment to create a uniform porous structure on the surface, followed by coating with a bioinspired and self-assembly polydopamine layer. Strontium Eucommia Ulmoides Polysaccharide (EUP-Sr) complexes are then introduced to the polydopamine-coated porous titanium. Multiple morphological and physiochemical characterizations are employed for material evaluation, while cell proliferation and gene expression tests using macrophages, primary alveolar bone osteoblasts, and vascular endothelial cells are used to provide an overall insight into the functions of the product. The significances of statistical differences were analyzed using student's t-test.ResultsMicroscopic and spectrometric characterizations confirmed that the Ti surface formed a porous structure with an adequate amount of EUP-Sr loading. The attachment was attributed to hydrogen bonding between the ubiquitous glycosidic linkage of the polysaccharide complex and the ring structure of polydopamine, yet the loaded EUP-Sr complex can be gradually released, consequently benefiting the neighboring microenvironment. Cell experiments showed no cytotoxicity of the material, and the product showed promising anti-inflammation, osseointegration, and angiogenesis properties, which were further confirmed by in vivo evaluations.ConclusionWe believe the EUP-Sr modified titanium implant is a promising candidate to be used in dental applications with notable osteoimmunomodulation and angiogenesis functions. And the novel technique proposed in this study would benefit the modification of metal/inorganic surfaces with polysaccharides for future research.

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First Experimental Study of the Influence of Extracellular Vesicles Derived from Multipotent Stromal Cells on Osseointegration of Dental Implants.

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