Risk of thromboembolism after intraosseous implantation of metallic devices with extracellular vesicles derived from multipotent stromal cells: preliminary results

Cover Page

Cite item

Full Text

Abstract

Background. New implantation methods are of great importance due to the development of endoprostheses in traumatology and orthopedics, restorative medicine and dentistry. Equally important is the early detection and description of the implant-associated complications.

The aim of the study is to find and describe thrombi and emboli in the heart and lungs formed after experimental implantation of metallic devices in the peripheral part of limb using extracellular vesicles of mesenchymal stromal cells.

Methods. Outbred rabbits of both genders at the age from 4 to 6 months and of weight from 3 to 4 kg underwent experimental implantation. The study enrolled 57 species in total. They were divided into two groups: 30 animals underwent implantation of metallic devices using extracellular vesicles of mesenchymal stromal cells (EV MSCs), 27 — without their use. The rabbits’ hearts and lungs were studied by light microscopy methods at different stages after integration of screw titanium implants into the proximal condyle of the tibia using EV MSCs.

Results. After implantation of metallic devices into the proximal condyle of the tibia, we detected fibrin, detritus and even the red bone marrow structures (various blast forms of hematopoietic cells: megakaryocytes, cells of the erythroid and myeloid lineages) in the right cavities of the heart. In the pulmonary arteries, we also found thrombi and emboli, which either led to the obliteration of the involved vessel or to gradual lysis, not disappearing completely within 10 days of follow-up.

Conclusions. After intraosseous implantation of the metallic devices, there is an embolism risk in the right atria and ventricle of the heart and the pulmonary arteries and veins due to the debris migration with the bloodstream from the surgery site. At the same time, one cannot exclude a thrombotic risk in the heart and pulmonary arteries as a reaction to the presence of detritus. It is advisable to take measures aimed at preventing both debris releasing into the bloodstream and pulmonary embolism during any implantations into the bone tissues, even of relatively small devices. Using EV MSCs to affect the implant engraftment processes has no significant effect on the severity and frequency of thromboembolic complications.

About the authors

Igor V. Maiborodin

Institute of Chemical Biology and Fundamental Medicine Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: imai@mail.ru
ORCID iD: 0000-0002-8182-5084

Dr. Sci (Med.), Professor

Russian Federation, Novosibirsk

Maksim E. Ryaguzov

Institute of Chemical Biology and Fundamental Medicine Siberian Branch of the Russian Academy of Sciences

Email: rymax@mail.ru
ORCID iD: 0000-0002-5279-3650

Cand. Sci (Med.)

Russian Federation, Novosibirsk

Sergey A. Kuzkin

Federal Research Center for Fundamental and Translational Medicine

Email: acutus@mail.ru
ORCID iD: 0000-0002-9046-0099

Cand. Sci (Med.)

Russian Federation, Novosibirsk

Aleksandr A. Shevela

Institute of Chemical Biology and Fundamental Medicine Siberian Branch of the Russian Academy of Sciences

Email: mdshevela@gmail.com
ORCID iD: 0000-0001-9235-9384

Dr. Sci (Med.)

Russian Federation, Novosibirsk

Boris V. Sheplev

Institute of Chemical Biology and Fundamental Medicine Siberian Branch of the Russian Academy of Sciences

Email: shepa@icloud.com
ORCID iD: 0009-0008-4140-3531

Dr. Sci (Med.)

Russian Federation, Novosibirsk

Igor O. Marinkin

Institute of Chemical Biology and Fundamental Medicine Siberian Branch of the Russian Academy of Sciences

Email: rector@ngmu.ru
ORCID iD: 0000-0002-9409-4823

Dr. Sci (Med.), Professor

Russian Federation, Novosibirsk

Vitalina I. Maiborodina

Institute of Chemical Biology and Fundamental Medicine Siberian Branch of the Russian Academy of Sciences

Email: mai_@mail.ru
ORCID iD: 0000-0002-5169-6373

Dr. Sci (Med.)

Russian Federation, Novosibirsk

Elena L. Lushnikova

Federal Research Center for Fundamental and Translational Medicine

Email: pathol@inbox.ru
ORCID iD: 0000-0002-3269-2465

Dr. Sci (Biol.), Professor

Russian Federation, Novosibirsk

References

  1. Li T., Wang Q., Wang W., Yang J., Dong S. One filter may be enough for duplicate inferior vena cava filter implantation in patients with deep venous thrombosis: Two cases report. Medicine (Baltimore). 2022;101(52): e32480. doi: 10.1097/MD.0000000000032480.
  2. Shah K.J., Roy T.L. Catheter-Directed Interventions for the Treatment of Lower Extremity Deep Vein Thrombosis. Life (Basel). 2022;12(12):1984. doi: 10.3390/life12121984.
  3. Marques M.A., Fiorelli S.K.A., Barros B.C.S., Ribeiro A.J.A., Ristow A.V., Fiorelli R.K.A. Protocol for prophylaxis of venous thromboembolism in varicose vein surgery of the lower limbs. Rev Col Bras Cir. 2022;49:e20223326. doi: 10.1590/0100-6991e-20223326-en.
  4. Bharti N., Mahajan S. Massive pulmonary embolism leading to cardiac arrest after tourniquet deflation following lower limb surgery. Anaesth Intensive Care. 2009;37(5):867-868.
  5. Drouin L., Pistorius MA., Lafforgue A., N’Gohou C., Richard A., Connault J. et al. Upper-extremity venous thrombosis: A retrospective study about 160 cases. Rev Med Interne. 2019;40(1):9-15. (In French). doi: 10.1016/j.revmed.2018.07.012.
  6. Khan O., Marmaro A., Cohen D.A. A review of upper extremity deep vein thrombosis. Postgrad Med. 2021;133(sup1):3-10. doi: 10.1080/00325481.2021.1892390.
  7. Duan Y., Wang G.L., Guo X., Yang LL., Tian F.G. Acute pulmonary embolism originating from upper limb venous thrombosis following breast cancer surgery: Two case reports. World J Clin Cases. 2022;10(21):7445-7450. doi: 10.12998/wjcc.v10.i21.7445.
  8. Major K.M., Bulic S., Rowe V.L., Patel K., Weaver F.A. Internal jugular, subclavian, and axillary deep venous thrombosis and the risk of pulmonary embolism. Vascular. 2008;16(2):73-79. doi: 10.2310/6670.2008.00019.
  9. Kim S., Ahn H., Shin S.A., Park J.H., Won C.W. Trends of thromboprophylaxis and complications after major lower limb orthopaedic surgeries in Korea: National Health Insurance Claim Data. Thromb Res. 2017;155:48-52. doi: 10.1016/j.thromres.2017.04.023.
  10. Heijboer R.R.O., Lubberts B., Guss D., Johnson A.H., DiGiovanni C.W. Incidence and Risk Factors Associated with Venous Thromboembolism After Orthopaedic Below-knee Surgery. J Am Acad Orthop Surg. 2019;27(10):e482-e490. doi: 10.5435/JAAOS-D-17-00787.
  11. Gurunathan U., Barras M., McDougall C., Nandurkar H., Eley V. Obesity and the Risk of Venous Thromboembolism after Major Lower Limb Orthopaedic Surgery: A Literature Review. Thromb Haemost. 2022; 122(12):1969-1979. doi: 10.1055/s-0042-1757200.
  12. Grandi G., Antonini E., Bianchi C. Pulmonary bone-marrow embolism. Analysis of 53 cases. Minerva Med. 1978;69(8):491-494. (In Italian).
  13. Orlowski J.P., Julius C.J., Petras R.E., Porembka D.T., Gallagher J.M. The safety of intraosseous infusions: risks of fat and bone marrow emboli to the lungs. Ann Emerg Med. 1989;18(10):1062-1067. doi: 10.1016/s0196-0644(89)80932-1.
  14. Kemona A., Nowak H.F., Dziecioł J., Sulik M., Sulkowski S. Pulmonary bone marrow embolism in nonselected autopsy material. Patol Pol. 1989;40(2): 197-204. (In Polish).
  15. Koessler M.J., Pitto R.P. Fat and bone marrow embolism in total hip arthroplasty. Acta Orthop Belg. 2001;67(2):97-109.
  16. Issack P.S., Lauerman M.H., Helfet D.L., Sculco T.P., Lane J.M. Fat embolism and respiratory distress associated with cemented femoral arthroplasty. Am J Orthop (Belle Mead NJ). 2009;38(2):72-76.
  17. Sharma P., Gautam A., Kumar P., Malhotra P., Nada R., Ahluwalia J. Bone marrow emboli following bone marrow procedure: A possible complication. Indian J Pathol Microbiol. 2022;65(4):946-947. doi: 10.4103/ijpm.ijpm_442_21.
  18. Maiborodin I., Shevela A., Matveeva V., Morozov V., Toder M., Krasil’nikov S. et al. First Experimental Study of the Influence of Extracellular Vesicles Derived from Multipotent Stromal Cells on Osseointegration of Dental Implants. Int J Mol Sci. 2021;22(16):8774. doi: 10.3390/ijms22168774.
  19. Maiborodin I., Shevela A., Toder M., Marchukov S., Tursunova N., Klinnikova M. et al. Multipotent Stromal Cell Extracellular Vesicle Distribution in Distant Organs after Introduction into a Bone Tissue Defect of a Limb. Life (Basel). 2021;11(4):306. doi: 10.3390/life11040306.
  20. Maiborodin I., Klinnikova M., Kuzkin S., Maiborodina V., Krasil’nikov S., Pichigina A. et al. Morphology of the Myocardium after Experimental Bone Tissue Trauma and the Use of Extracellular Vesicles Derived from Mesenchymal Multipotent Stromal Cells. J Pers Med. 2021;11(11):1206. doi: 10.3390/jpm11111206.
  21. Coipeau P., Rosset P., Langonne A., Gaillard J., Delorme B., Rico A. et al. Impaired differentiation potential of human trabecular bone mesenchymal stromal cells from elderly patients. Cytotherapy. 2009;11(5):584-594. doi: 10.1080/14653240903079385.
  22. Martins A.A., Paiva A., Morgado J.M., Gomes A., Pais M.L. Quantification and immunophenotypic characterization of bone marrow and umbilical cord blood mesenchymal stem cells by multicolor flow cytometry. Transplant Proc. 2009;41(3):943-946. doi: 10.1016/j.transproceed.2009.01.059.
  23. Berner A., Siebenlist S., Reichert J.C., Hendrich C., Nöth U. Reconstruction of osteochondral defects with a stem cell-based cartilage-polymer construct in a small animal model. Z Orthop Unfall. 2010;148(1):31-38. (In German). doi: 10.1055/s-0029-1240753.
  24. Zhao J., Xu J.J. Experimental study on application of polypropylene hernia of fat stem cells in rats. Eur Rev Med Pharmacol Sci. 2018;22(18):6156-6161. doi: 10.26355/eurrev_201809_15957.
  25. Blazquez R., Sanchez-Margallo F.M., de la Rosa O., Dalemans W., Alvarez V., Tarazona R. et al. Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Front Immunol. 2014;5:556. doi: 10.3389/fimmu.2014.00556.
  26. Oshchepkova A., Neumestova A., Matveeva V., Artemyeva L., Morozova K., Kiseleva E. et al. Cytochalasin-B-inducible nanovesicle mimics of natural extracellular vesicles that are capable of nucleic acid transfer. Micromachines (Basel). 2019;10(11):750. doi: 10.3390/mi10110750.
  27. Lin Y., Zhang F., Lian X.F., Peng W.Q., Yin C.Y. Mesenchymal stem cell-derived exosomes improve diabetes mellitus-induced myocardial injury and fibrosis via inhibition of TGF-β1/Smad2 signaling pathway. Cell Mol Biol (Noisy-le-grand). 2019;65(7):123-126.
  28. Liang P., Ye F., Hou C.C., Pi L., Chen F. Mesenchymal stem cell therapy for patients with ischemic heart failure – past, present, and future. Curr Stem Cell Res Ther. 2021;16(5):608-621. doi: 10.2174/1574888X15666200309144906.
  29. Sadallah S., Eken C., Schifferli J.A. Ectosomes as modulators of inflammation and immunity. Clin Exp Immunol. 2011;163(1):26-32. doi: 10.1111/j.1365-2249.2010.04271.x.
  30. Silachev D.N., Goryunov K.V., Shpilyuk M.A., Beznoschenko O.S., Morozova N.Y., Kraevaya E.E. et al. Effect of MSCs and MSC-derived extracellular vesicles on human blood coagulation. Cells. 2019;8(3):258. doi: 10.3390/cells8030258.
  31. Tang X.D., Shi L., Monsel A., Li X.Y., Zhu H.L., Zhu Y.G. et al. Mesenchymal stem cell microvesicles attenuate acute lung injury in mice partly mediated by Ang-1 mRNA. Stem Cells. 2017;35(7):1849-1859. doi: 10.1002/stem.2619.
  32. Haga H., Yan I.K., Borrelli D.A., Matsuda A., Parasramka M., Shukla N. et al. Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury. Liver Transpl. 2017;23(6):791-803. doi: 10.1002/lt.24770.
  33. Toh W.S., Lai R.C., Hui J.H.P., Lim S.K. MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin. Cell Dev Biol. 2017;67:56-64. doi: 10.1016/j.semcdb.2016.11.008.

Supplementary files

Supplementary Files
Action
1. JATS XML
2. Fig. 1. Structures of red bone marrow (a, b — without the use of EV MSCs) and blood clots (c, d — with the using EV MSCs) in the right cavities of the rabbit’s hearts 3 days after implantation of a metallic devices into the PTC: a — the right atrium and ventricle contain a large volume of blood clots; b — fragment “a”, a significant number of cells with segmented nuclei located in the cavity of the right heart ventricle, megakaryocytes are present (arrows); c — thrombus at the beginning of the coronary artery; d — old thrombus diffusely infiltrated with leukocytes, including neutrophils, with a “tail” along the blood flow. Hematoxylin and eosin staining

Download (188KB)
3. Fig. 2. Thrombi and emboli in the lung vessels of rabbits at various times after implantation of a metallic devices into the PTC: a, b — after 3 days in a thrombosed artery, fibrin, infiltrated by cells with segmented nuclei and eosinophilic cytoplasm, alternates with densely packed erythrocytes; c — on day 7, a heterogeneous structureless substance, infiltrated with segmented cells, is contained in the large artery with hypertrophied wall; d — after 7 days, structures of adipose tissue with hematopoietic cells between them are located in a vessel with a stretched wall; e — after 10 days, the artery with hypertrophied walls contains cellular structures with dense fibrous connective tissue, infiltrated with leukocytes and erythrocytes, between them; f — leukocyte infiltrate with a diameter of more than 200 microns in the parenchyma on 10 days. Hematoxylin and eosin staining

Download (267KB)
4. Fig. 3. Thromboembolism with fibrin and bone marrow structures of the lung vessels of rabbits on different dates after the introduction of an implant into the PTC with the preliminary EV MSCs administration: a — on the 3rd day, the vessel is densely filled by a heterogeneous structureless eosinophilic substance, infiltrated by cells with segmented nuclei, the cytoplasm of which has an intense eosinophilic color; b — after 3 days, the capillary, expanded to a spherical shape (arrow), of the alveolar septum, contains a structureless substance with macrophages; c — after 7 days, the artery contains adipose tissue with hematopoietic cells and a weakly eosinophilic structureless substance with leukocytes located along the edge; d — by day 7, there is appear vessels with significantly hypertrophied wall and a strongly stenosed clear with a red thrombus inside; e — after 10 days, the artery contains large cells with cellular fibrous structures between them; f — After 10 days, a red thrombus, infiltrated with segmented cells with an optically transparent substance next to them (arrows), is located in the capillary. Hematoxylin and eosin staining

Download (200KB)

Copyright (c) 2024 Eco-Vector

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

1. Я (далее – «Пользователь» или «Субъект персональных данных»), осуществляя использование сайта https://journals.rcsi.science/ (далее – «Сайт»), подтверждая свою полную дееспособность даю согласие на обработку персональных данных с использованием средств автоматизации Оператору - федеральному государственному бюджетному учреждению «Российский центр научной информации» (РЦНИ), далее – «Оператор», расположенному по адресу: 119991, г. Москва, Ленинский просп., д.32А, со следующими условиями.

2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».