Minimally manipulated adipose tissue and bone marrow cellular products for bone tissue regeneration: what to choose? A systematic review

According to numerous data presented in the scientific sources, the use of minimally manipulated cellular products with their own mesenchymal stem cells (MSCs) improves the results of surgical treatment of bone injuries. However, there is currently no consensus on the preferred use of MSCs from bone marrow or from adipose tissue. This is due to the accumulation of positive experience of their use in the restoration of bone defect. The purpose of the work. Determination of the optimal source of mesenchymal stem cells for surgical reconstruction of a bone defect. Material and methods. The search for publications for the period 2021–2025 was carried out in the databases PubMed, eLIBRARY.RU, Google Scholar and other scientific sources. The selected studies contained data on the use of MSCs from bone marrow and adipose tissue, as well as on the technique of their use. According to the PRISMA criteria, 16 publications were screened, of which 10 did not contain the necessary data on the concentration of cellular components and the technique of their application. Thus, a quantitative analysis of the data from 6 publications was carried out. Results and discussion. Currently, the technique of obtaining and preparing minimally manipulated cellular products with bone marrow MSCs for surgical treatment in traumatology and orthopedics is technically simpler and requires less time than the technique with adipose tissue MSCs. This may be one of the reasons for the prevalence of publications describing the use of bone marrow MSCs in clinical practice. The use of mesenchymal stem cells in the area of surgical reconstruction of a bone defect is necessary, however, there is no consensus on the best source of MSCs. Conclusions. According to the conducted analysis of literary sources, the technique using bone marrow MSCs has an advantage due to the reduction of the duration of the operation, however, the effectiveness of the cellular fraction of the bone marrow aspirate can be significantly reduced by errors in the collection technique and the composition of the aspirate itself. Techniques using adipose tissue MSCs have fewer errors, but a longer intervention time. At the same time, reliably important factors for increasing the effectiveness of bone defects surgical treatment with using minimally manipulated cellular products with MSCs are: heterogeneity and a sufficient amount of cellular fraction (no more than 1 million cells), as well as the presence of a carrier matrix.

1. Khominets V.V., Kalyuzhnaya-Zemlyanaya L.I., Grankin A.S., Fedorov R.A., Volov D.A., Komarov A.V. Evolution of methods, technologies and materials for bone tissue defects replacement (review). Profilakticheskaya i klinicheskaya meditsina = Preventive and Clinical Medicine. 2022;(4):25–34. [In Russian]. doi: 10.47843/2074-9120_2022_4_25

2. Bone cell biomechanics, mechanobiology and bone diseases. Eds. A.R. Qian, L. Hu. Elsevier, 2023. P. 229–234.

3. Anastasieva E.A., Cherdantseva L.A., Tolstikova T.G., Kirilova I.A. Deproteinized bone tissue as a matrix for tissue-engineered construction: experimental study. Travmatologiya i ortopediya Rossii = Traumatology and Orthopedics of Russia. 2023;29(1):46–59. [In Russian]. doi: 10.17816/2311-2905-20164.

4. Cherdantseva L.A., Anastasieva E.A., Egorikhina M.N., Aleynik D.Ya., Medvedchikov A.E., Sharkeev Yu.P., Kirilova I.A. The effect of structural characteristics of deproteinized spongy bone on activity of adipose tissue mesenchymal stromal cells. Bull. Exp. Biol. Med. 2024;176(4):515–518. doi: 10.1007/s10517-024-06058-3

5. Physico-chemical and mechanical properties of the extracellular matrix as signals for controlling cell proliferation, differentiation, motility and taxation. Ed. I.A. Kirilova. Moscow: Fizmatlit, 2021. 243 p. [In Russian].

6. Serchan W.A. Adipose stem cell-seeded scaffolds for regeneration of segmental bone defects: abstract of thesis ... doct. med. sciences. Thessaloniki, 2024.

7. Revokatova D.P., Zurina I.M., Gorkun A.A., Saburina I.N. Modern approaches to bone tissue vascularization. Patologicheskaya fiziologiya i eksperimental’naya terapiya = Pathological Physiology and Experimental Therapy. 2022;66(3):151–165. [In Russian]. doi: 10.25557/0031-2991.2022.03.151-165

8. Pramanik K. Stem cell and tissue engineering: bone, cartilage, and associated joint tissue defects. CRC Press, 2024, 354 p.

9. Kavaseri K. Cell therapy and mechanical stimulation to enhance bone defect healing. McGill University (Canada), 2021.

10. Melerzanov A., Manturova N. Minimally manipulated cellular product in plastic surgery and regenerative medicine. Vrach = Doctor. 2015;26(8):78–80. [In Russian].

11. Airapetov G.A., Aksenenko A.V., Alekseeva L.I., Astrelina T.A., Akhpashev A.A., Akhtyamov I.F., Bonartsev A.P., Bialik E.I., Vorobyov K.A., Vorotnikov A.A., … Yarygin N.V. Minimally manipulated cellular products. Minimally manipulated cellular products. Priorov Readings 2021 «Orthobiology»: coll. thes. rep. IX Intern. conf., Moscow, April 23–24, 2021. Voronezh: Nauchnaya kniga, 2022. P. 100–121. [In Russian].

12. Understanding the minimal manipulation method of preparation for biologicals. Australian Regulatory Guidelines for Biologicals. Available at: https://www.tga.gov.au/resources/guidance/understanding-minimal-manipulation-method-preparation-biologicals

13. Bouhlouli M., Izadi N., Khojasteh A. Various cell therapy approaches for bone diseases in the controlled clinical trials: a systematic review and meta-analysis study. Curr. Stem. Cell. Res. Ther. 2021;16(4):481–492. doi: 10.2174/1574888X16666201201104927

14. Bai Y., Yin G., Huang Z., Liao X., Chen X., Yao Y., Pu X. Localized delivery of growth factors for angiogenesis and bone formation in tissue engineering. Int. Immunopharmacol. 2013;16(2):214–223. doi: 10.1016/j.intimp.2013.04.001

15. Ho-Shui-Ling A., Bolander J., Rustom L.E., Johnson A.W., Luyten F.P., Picart C. Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives. Biomaterials. 2018;180:143–162. doi: 10.1016/j.biomaterials.2018.07.017

16. Hu K., Olsen B.R. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J. Clin. Invest. 2016;126(2):509–526. doi: 10.1172/JCI82585

17. 17 Street J., Bao M., de Guzman L., Bunting S., Peale F.V. Jr., Ferrara N., Steinmetz H., Hoeffel J., Cleland J.L., Daugherty A., … Filvaroff E.H. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl. Acad. Sci. USA. 2002;99(15):9656–9661. doi: 10.1073/pnas.152324099

18. Li G., Li Z., Li L., Liu S., Wu P., Zhou M., Li C., Li X., Luo G., Zhang J. Stem cell-niche engineering via multifunctional hydrogel potentiates stem cell therapies for inflammatory bone loss. Advanced Functional Materials. 2023;33(2):2209466.

19. Boretti G., Giordano E., Ionita M., Vlasceanu G.M., Sigurjónsson Ó.E., Gargiulo P., Lovecchio J. Human bone-marrow-derived stem-cell-seeded 3d chitosan-gelatin-genipin scaffolds show enhanced extracellular matrix mineralization when cultured under a perfusion flow in osteogenic medium. Materials (Basel). 2023;16(17):5898. doi: 10.3390/ma16175898

20. Mc Ilvaine R. Mesenchymal stem cell time to confluence on 3d printed, porous, poly (propylene fumarate) scaffolds for bone tissue engineering: abstract of thesis ... doct. med. sciences. Ohio, 2022.

21. Quek J., Vizetto-Duarte C., Teoh S.H., Choo Y. Towards stem cell therapy for critical-sized segmental bone defects: current trends and challenges on the path to clinical translation. J. Funct. Biomater. 2024;15(6):145. doi: 10.3390/jfb15060145

22. Zhang S., Lu C., Zheng S., Hong G.. Hydrogel loaded with bone marrow stromal cell-derived exosomes promotes bone regeneration by inhibiting inflammatory responses and angiogenesis. World J. Stem Cells. 2024;16(5):499–511. doi: 10.4252/wjsc.v16.i5.499

23. Banimohamad-Shotorbani B., Karkan S.F., Rahbarghazi R., Mehdipour A., Jarolmasjed S., Saghati S., Shafaei H. Application of mesenchymal stem cell sheet for regeneration of craniomaxillofacial bone defects. Stem Cell Res. Ther. 2023;14(1):68. doi: 10.1186/s13287-023-03309-4

24. Alemdar C. Mesenchymal stem cell therapy from bone marrow and associated orthobiologic treatments: stem cell therapy and orthopaedic. Ulus Medical Journal. 2023;1(3):66–73. doi: 10.5281/zenodo.10553463

25. Berveglieri L., Vannini F., Ramponi L., Boffa A., Cavallo C., Cenacchi A., Filardo G., Buda R., Faldini C. The influence of cell and platelet number on clinical outcomes provided by a one-step scaffold transplantation with bone marrow concentrate for the treatment of osteochondral lesions of the talus. Foot Ankle Surg. 2025;31(6):486–491. doi: 10.1016/j.fas.2025.01.014

26. Chow S.K., Gao Q., Pius A., Morita M., Ergul Y., Murayama M., Shinohara I., Cekuc M.S., Ma C., Susuki Y., Goodman S.B. The advantages and shortcomings of stem cell therapy for enhanced bone healing. Tissue Eng. Part C. Methods. 2024;30(10):415–430. doi: 10.1089/ten.TEC.2024.0252

27. Chen Y., Li Y., Lu F., Dong Z. Endogenous bone marrow-derived stem cell mobilization and homing for in situ tissue regeneration. Stem Cells. 2023;41(6):541–551. doi: 10.1093/stmcls/sxad026

28. El-Hashash A. Stem cell innovation in bone and joint health and diseases: general conclusions, challenges and prospectives. In: Joint and Bone. Texas: Academic Press, 2023. 205–211.

29. Wang L., Luo D., Wu J., Xie K., Guo Y., Gan Y., Wu W., Hao Y. A clinical study on bone defect reconstruction and functional recovery in benign bone tumors of the lower extremity, treated by bone marrow mesenchymal stem cell rapid screening-enrichment-composite system. World J. Surg. Oncol. 2021;19(1):98. doi: 10.1186/s12957-021-02198-2

30. Hernigou P., Homma Y., Hernigou J., Flouzat Lachaniette C.H., Rouard H., Verrier S. Mesenchymal stem cell therapy for bone repair of human hip osteonecrosis with bilateral match-control evaluation: impact of tissue source, cell count, disease stage, and volume size on 908 hips. Cells. 2024;13(9):776. doi: 10.3390/cells13090776

31. Velkovski V., Shabani I., Kamnar V., Gavrilovski A., Todorova T., Doksevska-Bogojevska M., Popovska D., Samardziski M., NikolikjDimitrova E.Analysis of results after surgical application of bone marrow aspirate stem cell concentrate in the treatment of avascular necrosis of the femoral head. Pril. (Makedon Akad. Nauk. Umet. Odd. Med. Nauki). 2023;44(1):79–87. doi: 10.2478/prilozi-2023-0009

32. Toosi S., Naderi-Meshkin H., Moradi A., Daliri M., Moghimi V., Majd H.M., Sahebkar A.H., Heirani-Tabasi A., Behravan J. Scaphoid bone nonunions: clinical and functional outcomes of collagen/pga scaffolds and cell-based therapy. ACS Biomater. Sci. Eng. 2023;9(4):1928–1939. doi: 10.1021/acsbiomaterials.2c00677

33. Zhang H., Xia D., Wu J., Hao Z., Wang P., Xu S., Zhang Y. Analysis of curative effect of percutaneous autologous bone marrow cell transplantation for treating nonunion under laser positioning and navigation guidance Materials Express. 2021;11(1):133–141. doi: 10.1166/mex.2021.1873

34. Kizu Y., Ishii R., Matsumoto N., Saito I. Retrospective study on the effect of adipose stem cell transplantation on jaw bone regeneration. Int. J. Implant Dent. 2024;10(1):3. doi: 10.1186/s40729-024-00523-4

35. 35 Gómez-Barrena E., Padilla-Eguiluz N.G., Rosset P., Hernigou P., Baldini N., Ciapetti G., GonzaloDaganzo R.M., Avendaño-Solá C., Rouard H., Giordano R., … On Behalf Of The Reborne Consortium. On behalf of the reborne consortium. Osteonecrosis of the femoral head safely healed with autologous, expanded, bone marrow-derived mesenchymal stromal cells in a multicentric trial with minimum 5 years follow-up. J. Clin. Med. 2021;10(3):508. doi: 10.3390/jcm10030508

36. Veronesi E., Murgia A., Caselli A., Grisendi G., Piccinno M.S., Rasini V., Giordano R., Montemurro T., Bourin P., Sensebé L., … Dominici M. Transportation conditions for prompt use of ex vivo expanded and freshly harvested clinical-grade bone marrow mesenchymal stromal/stem cells for bone regeneration. Tissue Eng. Part C. Methods. 2014;20(3):239–251. doi: 10.1089/ten.TEC.2013.0250

37. Homma Y., Kaneko K., Hernigou P. Supercharging allografts with mesenchymal stem cells in the operating room during hip revision. Int. Orthop. 2014;38(10):2033–2044. doi: 10.1007/s00264-013-2221-x

38. Gangji V., de Maertelaer V., Hauzeur J.P. Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: Five year follow-up of a prospective controlled study. Bone. 2011;49(5):1005–1009. doi: 10.1016/j.bone.2011.07.032

39. Horenberg A.L., Rindone A.N., Grayson W.L. Engineering bone from fat: A review of the in vivo mechanisms of adipose derived stem cell-mediated bone regeneration. Progress in Biomedical Engineering. 2021;3(4):042002. doi: 10.1088/2516-1091/ac1522

40. Romantsova T.I. Adipose tissue: colors, depot and functions. Ozhirenie i metabolism = Obesity and metabolism. 2021;18(3):282–301. [In Russian]. doi: 10.14341/omet12748

41. Labusca L. Adipose tissue in bone regeneration stem cell source and beyond. World J. Stem. Cells. 2022;14(6):372–392. doi: 10.4252/wjsc.v14.i6.372

42. Yuan D., El-Hashash A. Cutting edge research on stem cell applications in joint, cartilage, and bone repair and regeneration. In: Joint and Bone. Texas: Academic Press, 2023. P. 1–21.

43. Mc Cance, Kathryn L., Sue E. Huether. Pathophysiology: The Biologic Basis for Disease in Adults and Children. Utah: Mosby Elsevier, 2010. P. 4493–4497.

44. Li C., Mills Z., Zheng Z. Novel cell sources for bone regeneration. Med. Comm. 2021;2(2):145–174. doi: 10.1002/mco2.51

45. Issabekova A., Kudaibergen G., Sekenova A., Dairov A., Sarsenova M., Mukhlis S., Temirzhan A., Baidarbekov M., Eskendirova S., Ogay V. The therapeutic potential of pericytes in bone tissue regeneration. Biomedicines. 2023;12(1):21. doi: 10.3390/biomedicines12010021

46. Ganguly P., El-Jawhari J.J., Vun J., Giannoudis P.V., Jones E.A. Evaluation of human bone marrow mesenchymal stromal cell (MSC) functions on a biomorphic rattan-wood-derived scaffold: a comparison between cultured and uncultured MSCS. Bioengineering (Basel). 2021;9(1):1. doi: 10.3390/bioengineer-ing901000147.

47. Che X., Kim H.J., Jin X., Kim J.W., Park K.H., Lim J.O., Kyung H.S., Oh C.W., Choi J.Y. Bone marrow stem cell population in singleand multiplelevel aspiration. Biomedicines. 2024;12(12):2731. doi: 10.3390/biomedicines12122731

48. Mantripragada V.P., Boehm C., Bova W., Briskin I., Piuzzi N.S., Muschler G.F. Patient age and cell concentration influence prevalence and concentration of progenitors in bone marrow aspirates: an analysis of 436 patients. J. Bone Joint Surg. Am. 2021;103(17):1628–1636. doi: 10.2106/JBJS.20.02055

49. Yang Z.H., Zhang T.Y., Chen F.Z., Xie Y., Tan P.C., Li Q.F., Zhou S.B. Effect of age, harvest site and body mass index on the cell composition of the stromal vascular fraction. Plast. Reconstr. Surg. 2025;156(2):253–262. doi: 10.1097/PRS.0000000000011970

50. Karadağ Sarı E.Ç., Ovalı E. Factors affecting the population of mesenchymal stem cells in adiposederived stromal vascular fraction. Balkan Med. J. 2022;39(6):386–392. doi: 10.4274/balkanmedj.galenos.2022.2022-5-50