A REVIEW OF ANIMAL MODELS FOR BONE FRACTURE NONUNION AND THEIR ROLE IN STUDYING BIOLOGICAL THERAPY EFFICACY

Authors

  • Petro Vorontsov Sytenko Institute of Spine and Joint Pathology National Academy of Medical Sciences of Ukraine, Kharkiv, Ukraine
  • Valentyna Maltseva Sytenko Institute of Spine and Joint Pathology National Academy of Medical Sciences of Ukraine, Kharkiv, Ukraine

DOI:

https://doi.org/10.15674/0030-59872024281-87

Keywords:

Rat, rabbit, mice, osteotomy, femur, tibia, periosteum, bone regeneration.

Abstract

The bone healing impairment, such as non-union fractures after injuries of long bones, lead to loss of working capacity and result in significant financial costs, which emphasizes the socioeconomic significance of the problem. However, it is not known which method of modeling the non-union bone fractures is more optimal for further research into the effectiveness of biological therapy aimed at treating bone healing impairment. For a detailed study of methods of non-union fracture treatment of, it is necessary to determine the developed animal models. The objective was to analyze the existing animal models of fracture nonunion in long bones in vivo and to consider the possibility of their further use to evaluate the effectiveness of the use of modern biotechnologies for the in the management of fracture nonunion. It was found that the majority of developed animal models of atrophic long bone non-union were created using small animals, namely rats, mice, and rabbits. A more common method of modeling bone non-union is performing an osteotomy with the formation of a defect of different widths between the bone fragments and subsequent removal of the periosteum proximal and distal to the osteotomy site; damage to the endosteum or removal of bone marrow. Also, in such animal models, researchers use a silicone spacer, a polysulfone plate, or a latex-silicone foil to physically prevent fracture union. In these animal models, studies using mesenchymal stromal cells, platelet-rich plasma or bone morphogenetic protein-2 (BMP-2) have already been conducted for the management of non-union bone fractures. At the same time, the clinical results of the application of various biological therapies are ambiguous, which determines the conduct of further experimental studies, in particular, in vivo. However, there are disagreements about which in vivo modeling methods give a reproducible result and prevent bone union, which determines the need for further analysis of existing modeling tools for  conducting research in this direction.

Author Biographies

Petro Vorontsov, Sytenko Institute of Spine and Joint Pathology National Academy of Medical Sciences of Ukraine, Kharkiv

MD, PhD in Traumatology and Orthopaedics

Valentyna Maltseva, Sytenko Institute of Spine and Joint Pathology National Academy of Medical Sciences of Ukraine, Kharkiv

Phd in Biol. Sci.

References

  1. Popsuishapka, O., Litvishko, V., Uzhegova, O., & Pidgaiska, O. (2020). Frequency of complications at shaft fractures according to kharkiv traumatological medical-social expert committee (MSЕC) data. ORTHOPAEDICS, TRAUMATOLOGY and PROSTHETICS, (1), 20–25. https://doi.org/10.15674/0030-59872020120-25
  2. SK, S. (2019). Fracture Non-Union: A Review of Clinical Challenges and Future Research Needs. Malaysian Orthopaedic Journal, 13(2), 1–10. https://doi.org/10.5704/moj.1907.001
  3. Harris, A. M., Althausen, P. L., Kellam, J., Bosse, M. J., & Castillo, R. (2009). Complications Following Limb-Threatening Lower Extremity Trauma. Journal of Orthopaedic Trauma, 23(1), 1–6. https://doi.org/10.1097/bot.0b013e31818e43dd
  4. Zura, R., Xiong, Z., Einhorn, T., Watson, J. T., Ostrum, R. F., Prayson, M. J., Della Rocca, G. J., Mehta, S., McKinley, T., Wang, Z., & Steen, R. G. (2016). Epidemiology of Fracture Nonunion in 18 Human Bones. JAMA Surgery, 151(11), e162775. https://doi.org/10.1001/jamasurg.2016.2775
  5. Mills, L. A., Aitken, S. A., & Simpson, A. H. R. W. (2017). The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults. Acta Orthopaedica, 88(4), 434–439. https://doi.org/10.1080/17453674.2017.1321351
  6. Smakaj, A., De Mauro, D., Rovere, G., Pietramala, S., Maccauro, G., Parolini, O., Lattanzi, W., & Liuzza, F. (2022). Clinical Application of Adipose Derived Stem Cells for the Treatment of Aseptic Non-Unions: Current Stage and Future Perspectives — Systematic Review. International Journal of Molecular Sciences, 23(6), 3057. https://doi.org/10.3390/ijms23063057
  7. Grygoriev, V. V. (2020). Use of biological activity of autofibrin in surgical treatment of fractures: dissertation of PhD in Medical Sciences. Kharkiv. [in Ukrainian]
  8. Nappe, C. E., Rezuc, A. B., Montecinos, A., Donoso, F. A., Vergara, A.. J., & B. Martinez. (2016). Histological comparison of an allograft, a xenograft and alloplastic graft as bone substitute materials. Journal of Osseointegration, 8(2), 20–26. https://doi.org/10.23805/jo.2016.08.02.02
  9. Jayankura, M., Schulz, A. P., Delahaut, O., Witvrouw, R., Seefried, L., Berg, B. V., Heynen, G., & Sonnet, W. (2021). Percutaneous administration of allogeneic bone-forming cells for the treatment of delayed unions of fractures: a pilot study. Stem Cell Research & Therapy, 12(1). https://doi.org/10.1186/s13287-021-02432-4
  10. Rollo, G., Bonura, E. M., Falzarano, G., Bisaccia, M., Iborra, J. R., Grubor, P., Filipponi, M., Pichierri, P., Hitov, P., Leonetti, D., Russi, V., Daghino, W., & Meccariello, L. (2020). Platet rich plasma or hyperbaric oxygen therapy as callus accellerator in aseptic tibial non union. Evaluate of outcomes. Acta Biomedica, 91(4), 1–11. DOI: 10.23750/abm.v91i4.8818
  11. Menger, M. M., Laschke, M. W., Nussler, A. K., Menger, M. D., & Histing, T. (2022). The vascularization paradox of non-union formation. Angiogenesis. https://doi.org/10.1007/s10456-022-09832-x
  12. Wildemann, B., Ignatius, A., Leung, F., Taitsman, L. A., Smith, R. M., Pesántez, R., Stoddart, M. J., Richards, R. G., & Jupiter, J. B. (2021). Non-union bone fractures. Nature Reviews Disease Primers, 7(1). https://doi.org/10.1038/s41572-021-00289-8
  13. Kostenuik, P., & Mirza, F. M. (2016). Fracture healing physiology and the quest for therapies for delayed healing and nonunion. Journal of Orthopaedic Research, 35(2), 213–223. https://doi.org/10.1002/jor.23460
  14. Garnavos, C. (2017). Treatment of aseptic non-union after intramedullary nailing without removal of the nail. Injury, 48, S76—S81. https://doi.org/10.1016/j.injury.2017.04.022
  15. Uliana, C. S., Bidolegui, F., Kojima, K., & Giordano, V. (2020). Augmentation plating leaving the nail in situ is an excellent option for treating femoral shaft nonunion after IM nailing: a multicentre study. European Journal of Trauma and Emergency Surgery. https://doi.org/10.1007/s00068-020-01333-0
  16. Wu, X.-Q., Wang, D., Liu, Y., & Zhou, J.-L. (2021). Development of a tibial experimental non-union model in rats. Journal of Orthopaedic Surgery and Research, 16(1). https://doi.org/10.1186/s13018-021-02408-3
  17. Oktas, B. (2014). Effect of extracorporeal shock wave therapy on fracture healing in rat femural fractures with intact and excised periosteum. Joint Diseases and Related Surgery, 25(3), 158–162. https://doi.org/10.5606/ehc.2014.33
  18. Tawonsawatruk, T., Kelly, M., & Simpson, H. (2014). Evaluation of Native Mesenchymal Stem Cells from Bone Marrow and Local Tissue in an Atrophic Nonunion Model. Tissue Engineering Part C: Methods, 20(6), 524–532. https://doi.org/10.1089/ten.tec.2013.0465
  19. Shimizu, T., Akahane, M., Morita, Y., Omokawa, S., Nakano, K., Kira, T., Onishi, T., Inagaki, Y., Okuda, A., Kawate, K., & Tanaka, Y. (2015). The regeneration and augmentation of bone with injectable osteogenic cell sheet in a rat critical fracture healing model. Injury, 46(8), 1457–1464. ttps://doi.org/10.1016/j.injury.2015.04.031
  20. Onishi, T., Shimizu, T., Akahane, M., Okuda, A., Kira, T., Omokawa, S., & Tanaka, Y. (2020). Robust method to create a standardized and reproducible atrophic non-union model in a rat femur. Journal of Orthopaedics, 21, 223–227. https://doi.org/10.1016/j.jor.2020.03.040
  21. Schmidhammer, R., Zandieh, S., Mittermayr, R., Pelinka, L. E., Leixnering, M., Hopf, R., Kroepfl, A., & Redl, H. (2006). Assessment of Bone Union/Nonunion in an Experimental Model Using Microcomputed Technology. The Journal of Trauma: Injury, Infection, and Critical Care, 61(1), 199–205. https://doi.org/10.1097/01.ta.0000195987.57939.7e
  22. Skaliczki, G., Weszl, M., Schandl, K., Major, T., Kovács, M., Skaliczki, J., Redl, H., Szendrоi, M., Szigeti, K., Mаtе D., Dobо-Nagy, C., & Lacza, Z. (2012b). Compromised bone healing following spacer removal in a rat femoral defect model. Acta Physiologica Hungarica, 99(2), 223–232. https://doi.org/10.1556/aphysiol.99.2012.2.16
  23. Schutzenberger, S., Kaipel, M., Schultz, A., Nau, T., Redl, H., & Hausner, T. (2014). Non-union site debridement increased the efficacy of rhBMP-2 in a rodent model. Injury, 45(8), 1165–1170. https://doi.org/10.1016/j.injury.2014.05.004
  24. Cheng, A., Krishnan, L., Pradhan, P., Weinstock, L. D., Wood, L. B., Roy, K., & Guldberg, R. E. (2019). Impaired bone healing following treatment of established nonunion correlates with serum cytokine expression. Journal of Orthopaedic Research®, 37(2), 299–307. https://doi.org/10.1002/jor.24186
  25. Oetgen, M. E., Merrell, G. A., Troiano, N. W., Horowitz, M. C., & Kacena, M. A. (2008). Development of a femoral non-union model in the mouse. Injury, 39(10), 1119–1126. https://doi.org/10.1016/j.injury.2008.04.008
  26. Chaubey, A., Grawe, B., Meganck, J. A., Dyment, N., Inzana, J., Jiang, X., Connolley, C., Awad, H., Rowe, D., Kenter, K., Goldstein, S. A., & Butler, D. (2013). Structural and biomechanical responses of osseous healing: a novel murine nonunion model. Journal of Orthopaedics and Traumatology, 14(4), 247–257. https://doi.org/10.1007/s10195-013-0269-4
  27. Lu, C., Miclau, T., Hu, D., & Marcucio, R. S. (2006). Ischemia leads to delayed union during fracture healing: A mouse model. Journal of Orthopaedic Research, 25(1), 51–61. https://doi.org/10.1002/jor.20264
  28. Brownlow, H. C., Reed, A., & Simpson, A. H. R. W. (2002). The vascularity of atrophic non-unions. Injury, 33(2), 145–150. https://doi.org/10.1016/s0020-1383(01)00153-x
  29. Reed, A. A. C., Joyner, C. J., Isefuku, S., Brownlow, H. C., & Simpson, A. H. R. W. (2003). Vascularity in a new model of atrophic nonunion. The Journal of Bone and Joint Surgery. British volume, 85-B(4), 604–610. https://doi.org/10.1302/0301-620x.85b4.12944
  30. Eckardt, H., Christensen, K. S., Lind, M., Hansen, E. S., Hall, D. W. R., & Hvid, I. (2005). Recombinant human bone morphogenetic protein 2 enhances bone healing in an experimental model of fractures at risk of non-union. Injury, 36(4), 489–494. https://doi.org/10.1016/j.injury.2004.10.019
  31. Ozturk, B. Y., Inci, I., Egri, S., Ozturk, A. M., Yetkin, H., Goktas, G., Elmas, C., Piskin, E., & Erdogan, D. (2012). The treatment of segmental bone defects in rabbit tibiae with vascular endothelial growth factor (VEGF)-loaded gelatin/hydroxyapatite “cryogel” scaffold. European Journal of Orthopaedic Surgery & Traumatology, 23(7), 767–774. https://doi.org/10.1007/s00590-012-1070-4
  32. Sharun, K., Pawde, A. M., Banu S, A., Manjusha, K. M., Kalaiselvan, E., Kumar, R., Kinjavdekar, P., & Amarpal. (2021). Development of a novel atrophic non-union model in rabbits: A preliminary study. Annals of Medicine and Surgery, 68, 102558. https://doi.org/10.1016/j.amsu.2021.102558
  33. Murao, H., Yamamoto, K., Matsuda, S., & Akiyama, H. (2013). Periosteal cells are a major source of soft callus in bone fracture. Journal of Bone and Mineral Metabolism, 31(4), 390–398. https://doi.org/10.1007/s00774-013-0429-x
  34. Giannoudis, P. V., Einhorn, T. A., & Marsh, D. (2007). Fracture healing: The diamond concept. Injury, 38, S3—S6. https://doi.org/10.1016/s0020-1383(08)70003-2
  35. Liu, H.-Y., Chiou, J.-F., Wu, A. T. H., Tsai, C.-Y., Leu, J.-D., Ting, L.-L., Wang, M.-F., Chen, H.-Y., Lin, C.-T., Williams, D. F., & Deng, W.-P. (2012). The effect of diminished osteogenic signals on reduced osteoporosis recovery in aged mice and the potential therapeutic use of adipose-derived stem cells. Biomaterials, 33(26), 6105–6112. https://doi.org/10.1016/j.biomaterials.2012.05.024
  36. Huang, Z., Gu, H., Yin, X., Gao, L., Zhang, K., Zhang, Y., Xu, J., Wu, L., Yin, J., & Cui, L. (2019). Bone regeneration using injectable poly (γ-benzyl-l-glutamate) microspheres loaded with adipose-derived stem cells in a mouse femoral non-union model. American Journal of Translational Research, 11(5), 2641–2656. PMCID: PMC6556664
  37. Liu, J., Zhou, P., Long, Y., Huang, C., & Chen, D. (2018). Repair of bone defects in rat radii with a composite of allogeneic adipose-derived stem cells and heterogeneous deproteinized bone. Stem Cell Research & Therapy, 9(1). https://doi.org/10.1186/s13287-018-0817-1
  38. Li, S., Xing, F., Luo, R., & Liu, M. (2022). Clinical Effectiveness of Platelet-Rich Plasma for Long-Bone Delayed Union and Nonunion: A Systematic Review and Meta-Analysis. Frontiers in Medicine, 8. https://doi.org/10.3389/fmed.2021.771252
  39. Ruiz-Ibаn, M. A., Gonzalez-Lizаn, F., Diaz-Heredia, J., Elіas-Martin, M. E., & Correa Gorospe, C. (2013). Effect of VEGF-A165 addition on the integration of a cortical allograft in a tibial segmental defect in rabbits. Knee Surgery, Sports Traumatology, Arthroscopy, 23(5), 1393–1400. https://doi.org/10.1007/s00167-013-2785-4

How to Cite

Vorontsov, P. ., & Maltseva, V. . (2024). A REVIEW OF ANIMAL MODELS FOR BONE FRACTURE NONUNION AND THEIR ROLE IN STUDYING BIOLOGICAL THERAPY EFFICACY. ORTHOPAEDICS TRAUMATOLOGY and PROSTHETICS, (2), 81–87. https://doi.org/10.15674/0030-59872024281-87

Issue

Section

DIGESTS AND REVIEWS