DOI: 10.25881/20728255_2023_18_2_21


Kokorin V.V.1, 2, Kraynyukov P.E.2, 3

1 Pirogov National Medical and Surgical Center, Moscow

2 P.V. Mandryka Central Military Clinical Hospital, Moscow

3 RUDN University, Moscow


The results of an experimental study of chronic surgical pathology of connective tissue on the example of periarticular structures are presented. The changes occurring in connective tissue during chronic inflammation and accompanied by its prolonged ischemia were modeled and studied in vivo. Neoangiogenesis was stimulated by activating proangiogenic factors using local integration of labeled mesenchymal multipotent stem cells (MMSCs).

Purpose. To study the effect of integrated mesenchymal multipotent stem cells in chronic surgical pathology of ischemic genesis on the process of connective tissue regeneration in vivo.

Materials and methods. The experiment was performed on 30 male Wistar stock rats weighing 200–300 g, distributed in 15 individuals into 2 study groups: the main (n = 15) and control (n = 15). All individuals underwent operative modeling of acute mechanical calcaneal enthesitis, as an analogue of changes occurring in tissues under conditions of ischemia. Labeled multipotent mesenchymal stem cells were implanted in the main group, and the healing process proceeded naturally in the control group.

Multipotent mesenchymal stem cells were isolated on the basis of intraabdominal visceral fat from the stromal-vascular fraction. The transplanted cell culture was labeled by transfection of a construct with a green fluorescent protein (GFP) in a lentiviral vector.

Withdrawal of animals from the experiment and morphological examination of tissues (morphometric, histological, immunohistochemical) were performed on the 1st, 15th, 30th and 60th days.

Results. Morphologically significant changes were noted by 30 days. In the control group, areas of excessive growth of granulation tissue rich in blood vessels, resorbable bone structures, and areas of formation of reactive osteogenesis were preserved.

In the experimental group, these manifestations regressed, the integration of the labeled cell culture of mesenchymal stem cells into the defect zone was successful, which was marked by more active signs of regeneration of the injury area; a stable network of blood vessels formed in a much larger volume in the thickness of the connective tissue structures of the regenerate; powerful strictly ordered bundles of collagen tendon fibers, without signs of edema.

Complete restoration of structures in both groups was observed by 60 days.

At the same time, in the experimental group, a distinctive feature were multiple groups of newly formed full-blooded blood vessels of different calibers penetrating the fibrous regenerate in close proximity to the “tide” zone - the terminal zone of mineralized and non-mineralized sections of fibrous cartilage tissue, without signs of an inflammatory reaction.

Conclusion. The angiogenic effect in ischemic tissues with the use of gene-cell constructs is realized through mechanisms that have not yet been fully studied. However, the effectiveness of this approach has been proven in the course of research and allows us to consider it as a safe tool in the complex treatment of surgical diseases, one of the pathogenesis factors of which is ischemia.

The conducted study gives the right to assert that the direct participation of integrated labeled MMSCs with fibro- and chondrogenic potential plays an exceptional role in the differentiation of fibrocytes (tendinocytes) and chondrocytes, has a powerful effect on the regeneration process in vivo and is accompanied by a neoangiogenic effect not only in artificial cultivation.

The problem of controlling cell differentiation, their mechanical, physical, and chemical triggers in programming a complex regulatory mechanism remains unresolved.

The correct choice of the source of cells and the method of their implantation plays an important role in the processes of angiogenesis and repair.

Keywords: enthesis, enthesopathy, neoangiogenesis, regeneration, experiment, periarticular, connective tissue, bioengineering, omics, cellular technologies.


1. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005 Dec 15; 438(7070): 932-6. doi: 10.1038/nature04478. PMID: 16355210.

2. Carmeliet P. Angiogenesis in health and disease. Nat. Med. 2003; 9: 653-660.

3. Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. Med. 1971; 285: 1182-1186.

4. Matai I, Kaur G, Seyedsalehi A, McClinton A, Laurencin CT. Progress in 3D bioprinting Technology for tissue/organ regenerative engineering. Biomaterials. 2020; 226: 119536. doi: 10.1016/j.biomaterials.2019.119536.

5. Shokrani H, Shokrani A, Sajadi SM, Seidi F, Mashhadzadeh AH, Rabiee N, Saeb MR, Aminabhavi T, Webster TJ. Cell-Seeded Biomaterial Scaffolds: The Urgent Need for Unanswered Accelerated Angiogenesis. Int J.

6. SHevchenko YUL, Matveev SA, Pinaev GP, et al. Eksperimental’noe obosnovanie vozmozhnosti implantacii embrional’nyh kardiomiocitov v kompleksnoj terapii miokardial’noj slabosti. Fiziologiya cheloveka. 1999; 25(4): 109-117. (In Russ.)

7. SHevchenko YUL. Mediko-biologicheskie i fiziologicheskie osnovy kletochnyh tekhnologij v serdechno-sosudistoj hirurgii. SPb. Nauka, 2006. 263 p. (In Russ.)

8. Nanomedicine. 2022; 17: 1035-1068. doi: 10.2147/IJN.S353062.

9. Gilpin SE, Wagner DE. Acellular human lung scaffolds to model lung disease and tissue regeneration . Eur Respir Rev. 2018; 27: 180021.

10. Iravani S, Varma RS. Green synthesis, biomedical and biotechnological applications of carbon and graphene quantum dots. Environ Chem Lett. 2020;1-25. doi: 10.1007 / s10311-020-00984-0.

For citation

Kokorin V.V., Kraynyukov P.E. Angiogenesis role in the regulation structural changes of connective tissue in chronic surgical pathology ischemic genesis. Bulletin of Pirogov National Medical & Surgical Center. 2023;18(2):21-28. (In Russ.)