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

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.

Multipotent Stromal Cell Extracellular Vesicle Distribution in Distant Organs after Introduction into a Bone Tissue Defect of a Limb.

When administered intravenously, extracellular vesicles derived from multipotent stromal cells (MSC EVs) immediately pass through the lungs along with the blood and regularly spread to all organs. When administered intraperitoneally, they are absorbed either into the blood or into the lymph and are quickly disseminated throughout the body. The possibility of generalized spread of MSC EVs to distant organs in case of local intratissular administration remains unexplored. However, it is impossible to exclude MSC EV influence on tissues distant from the injection site due to the active or passive migration of these injected nanoparticles through the vessels. The research is based on findings obtained when studying the samples of lungs, heart, spleen, and liver of outbred rabbits of both sexes weighing 3-4 kg at various times after the injection of EVs derived from MSCs of bone marrow origin and labeled by PKH26 into an artificially created defect of the proximal condyle of the tibia. MSC EVs were isolated by serial ultracentrifugation and characterized by transmission electron microscopy and flow cytometry. After the introduction of MSC EVs into the damaged proximal condyle of the tibia of rabbits, these MSC EVs can be found most frequently in the lungs, myocardium, liver, and spleen. MSC EVs enter all of these organs with the blood flow. The lungs contained the maximum number of labeled MSC EVs; moreover, they were often associated with detritus and were located in the lumen of the alveoli. In the capillary network of various organs except the myocardium, MSC EVs are adsorbed by paravasal phagocytes; in some cases, specifically labeled small dust-like objects can be detected throughout the entire experiment-up to ten days of observation. Therefore, we can conclude that the entire body, including distant organs, is effected both by antigenic detritus, which appeared in the bloodstream after extensive surgery, and MSC EVs introduced from the outside.