临界尺寸骨缺损动物模型的研究进展
Research Advances in Animal Models of Critical-Size Bone Defects
DOI: 10.12677/acm.2025.153635, PDF,    科研立项经费支持
作者: 何建朋, 李博宇, 侯 林, 李红东:内蒙古民族大学临床医学院,内蒙古 通辽;刘金山*:内蒙古民族大学附属医院关节与运动医学科,内蒙古 通辽
关键词: 临界尺寸骨缺损动物模型评价指标影像学Critical-Size Bone Defect Animal Model Evaluation Indexes Radiology
摘要: 骨质疏松、严重创伤、骨肿瘤及骨感染等导致的临界尺寸骨缺损(critical-size bone defects, CSD)给许多患者造成了严重影响,CSD的修复及后续的临床转归一直是骨科医师面临的重要难题。随着临床新技术的发展及骨组织生物材料的新兴,各种临床技术与药物及骨组织材料联合治疗CSD的研究层出不穷,由于伦理要求,各种技术及其联合在应用于临床之前,需要进行大量的实验研究,那么构建与人体相似的、符合伦理的、适宜操作的以及可重复的CSD动物模型就显得尤为重要。为了总结CSD动物模型的研究进展,本文查阅国内外近年有关动物CSD模型的文献,从动物种类选择、建模方式以及评价方式等方面进行了综述。动物种类选择上包括小鼠、大鼠、兔、犬、猪和绵羊等;建模方式因致病原因的不同可分为创伤性骨缺损模型、骨肿瘤性骨缺损模型、感染性骨缺损模型、骨质疏松性骨缺损模型;评价方式包括大体观察、影像学、组织学检测、生化指标及生物力学等。通过对CSD动物模型研究进展的综述,为CSD各种治疗方法的研究及新型人工骨替代材料的研发提供更多的依据。
Abstract: Critical-size bone defects (CSD) caused by osteoporosis, severe trauma, bone tumors and bone infections have caused serious impacts on many patients, and the repair of CSD and the subsequent clinical regression have been an important challenge for orthopedic surgeons. With the development of new clinical techniques and the emergence of bone tissue biomaterials, there are numerous studies on the combination of various clinical techniques with drugs and bone tissue materials for the treatment of CSD. Due to the ethical requirement that a large number of experimental studies need to be carried out on various techniques and their combinations before they can be applied to the clinic, it is particularly important to construct a similar, ethical, operable, and reproducible animal model for CSD that is similar to that of the human body. In order to summarize the research progress of CSD animal models, this paper reviews the literature on animal CSD models in recent years, both at home and abroad, and reviews the aspects of animal species selection, modeling methods and evaluation methods. The selection of animal species includes mice, rats, rabbits, dogs, pigs, sheep, etc. The modeling methods can be divided into traumatic bone defect model, bone tumor bone defect model, infectious bone defect model and osteoporotic bone defect model according to the different causes of the disease; the evaluation methods include gross observation, imaging, histological detection, biochemical indexes and biomechanics. By reviewing the research progress of CSD animal models, we can provide more evidence for the research of various therapeutic methods of CSD and the research and development of new artificial bone substitution materials.
文章引用:何建朋, 李博宇, 侯林, 李红东, 刘金山. 临界尺寸骨缺损动物模型的研究进展[J]. 临床医学进展, 2025, 15(3): 445-453. https://doi.org/10.12677/acm.2025.153635

参考文献

[1] Bayat, M., Asgari, M., Abdollahifar, M., Moradi, A., Zare, F., Kouhkheil, R., et al. (2024) Photobiomodulation and Mesenchymal Stem Cell-Conditioned Medium for the Repair of Experimental Critical-Size Defects. Lasers in Medical Science, 39, Article No. 158. [Google Scholar] [CrossRef] [PubMed]
[2] Schmidt, A.H. (2021) Autologous Bone Graft: Is It Still the Gold Standard? Injury, 52, S18-S22. [Google Scholar] [CrossRef] [PubMed]
[3] Ziroglu, N., Koluman, A., Kaleci, B., Tanriverdi, B., Tanriverdi, G., Kural, A., et al. (2024) Modified and Alternative Bone Cements Can Improve the Induced Membrane: Critical Size Bone Defect Model in Rat Femur. Injury, 55, Article ID: 111627. [Google Scholar] [CrossRef] [PubMed]
[4] Dahl, M.T. and Morrison, S. (2021) Segmental Bone Defects and the History of Bone Transport. Journal of Orthopaedic Trauma, 35, S1-S7. [Google Scholar] [CrossRef] [PubMed]
[5] Viale, G.J., Garabano, G., Pesciallo, C. and Sel, H.D. (2021) Structural Allograft and Induced Membrane Technique for Treatment of 10-cm Segmental Femoral Bone Defect: A Case Report. JBJS Case Connector, 11, e21.00372. [Google Scholar] [CrossRef] [PubMed]
[6] Valtanen, R.S., Yang, Y.P., Gurtner, G.C., Maloney, W.J. and Lowenberg, D.W. (2021) Synthetic and Bone Tissue Engineering Graft Substitutes: What Is the Future? Injury, 52, S72-S77. [Google Scholar] [CrossRef] [PubMed]
[7] Migliorini, F., La Padula, G., Torsiello, E., Spiezia, F., Oliva, F. and Maffulli, N. (2021) Strategies for Large Bone Defect Reconstruction after Trauma, Infections or Tumour Excision: A Comprehensive Review of the Literature. European Journal of Medical Research, 26, Article No. 118. [Google Scholar] [CrossRef] [PubMed]
[8] Mauffrey, C., Barlow, B.T. and Smith, W. (2015) Management of Segmental Bone Defects. Journal of the American Academy of Orthopaedic Surgeons, 23, 143-153. [Google Scholar] [CrossRef] [PubMed]
[9] Nauth, A., Schemitsch, E., Norris, B., Nollin, Z. and Watson, J.T. (2018) Critical-Size Bone Defects: Is There a Consensus for Diagnosis and Treatment? Journal of Orthopaedic Trauma, 32, S7-S11. [Google Scholar] [CrossRef] [PubMed]
[10] Kalaiselvan, E., Maiti, S.K., Shivaramu, S., Banu, S.A., Sharun, K., Mohan, D., et al. (2024) Bone Marrow-Derived Mesenchymal Stem Cell-Laden Nanocomposite Scaffolds Enhance Bone Regeneration in Rabbit Critical-Size Segmental Bone Defect Model. Journal of Functional Biomaterials, 15, Article 66. [Google Scholar] [CrossRef] [PubMed]
[11] Hollinger, J.O. and Kleinschmidt, J.C. (1990) The Critical Size Defect as an Experimental Model to Test Bone Repair Materials. Journal of Craniofacial Surgery, 1, 60-68. [Google Scholar] [CrossRef] [PubMed]
[12] Kessler, F., Arnke, K., Eggerschwiler, B., Neldner, Y., Märsmann, S., Gröninger, O., et al. (2024) Murine IPSC-Loaded Scaffold Grafts Improve Bone Regeneration in Critical-Size Bone Defects. International Journal of Molecular Sciences, 25, Article 5555. [Google Scholar] [CrossRef] [PubMed]
[13] Awadeen, M.A., Al-Belasy, F.A., Ameen, L.E., Helal, M.E. and Grawish, M.E. (2020) Early Therapeutic Effect of Platelet-Rich Fibrin Combined with Allogeneic Bone Marrow-Derived Stem Cells on Rats’ Critical-Sized Mandibular Defects. World Journal of Stem Cells, 12, 55-69. [Google Scholar] [CrossRef] [PubMed]
[14] 李福兵, 徐永清, 潘兴华, 等. 小鼠胫骨中段1/3不同缺损直径单层骨皮质缺损模型比较研究[J]. 中国修复重建外科杂志, 2012, 26(10): 1218-1222.
[15] 熊伟, 袁灵梅, 钱国文, 等. 临界骨缺损动物模型评估骨组织工程支架成骨效能的价值[J]. 中国组织工程研究, 27(35): 5714-5720.
[16] Entezari, A., Wu, Q., Mirkhalaf, M., Lu, Z., Roohani, I., Li, Q., et al. (2024) Unraveling the Influence of Channel Size and Shape in 3D Printed Ceramic Scaffolds on Osteogenesis. Acta Biomaterialia, 180, 115-127. [Google Scholar] [CrossRef] [PubMed]
[17] Shaul, J.L., Hill, R.S., Bouxsein, M.L., Burr, D.B., Tilton, A.K. and Howe, J.G. (2022) AGN1 Implant Material to Treat Bone Loss: Resorbable Implant Forms Normal Bone with and without Alendronate in a Canine Critical Size Humeral Defect Model. Bone, 154, Article ID: 116246. [Google Scholar] [CrossRef] [PubMed]
[18] Cai, E.Z., Teo, N.M.H., Lee, Z.P., Yeo, J.Y.H., Liu, Y., Ong, Z.X., et al. (2023) Straight-Segment Mandibulectomy: A Reproducible Porcine Mandibular Critical-Size Defect Model. British Journal of Oral and Maxillofacial Surgery, 61, 53-60. [Google Scholar] [CrossRef] [PubMed]
[19] Garot, C., Schoffit, S., Monfoulet, C., Machillot, P., Deroy, C., Roques, S., et al. (2023) 3D‐Printed Osteoinductive Polymeric Scaffolds with Optimized Architecture to Repair a Sheep Metatarsal Critical‐size Bone Defect. Advanced Healthcare Materials, 12, e2301692. [Google Scholar] [CrossRef] [PubMed]
[20] Huang, Y., Jakus, A.E., Jordan, S.W., Dumanian, Z., Parker, K., Zhao, L., et al. (2019) Three-dimensionally Printed Hyperelastic Bone Scaffolds Accelerate Bone Regeneration in Critical-Size Calvarial Bone Defects. Plastic & Reconstructive Surgery, 143, 1397-1407. [Google Scholar] [CrossRef] [PubMed]
[21] Moest, T., Schlegel, K.A., Kesting, M., Fenner, M., Lutz, R., Beck, D.M., et al. (2019) A New Standardized Critical Size Bone Defect Model in the Pig Forehead for Comparative Testing of Bone Regeneration Materials. Clinical Oral Investigations, 24, 1651-1661. [Google Scholar] [CrossRef] [PubMed]
[22] Nau, C., Simon, S., Schaible, A., Seebach, C., Schröder, K., Marzi, I., et al. (2018) Influence of the Induced Membrane Filled with Syngeneic Bone and Regenerative Cells on Bone Healing in a Critical Size Defect Model of the Rat’s Femur. Injury, 49, 1721-1731. [Google Scholar] [CrossRef] [PubMed]
[23] 艾子政, 董谢平. 新西兰兔骨缺损模型的文献综述[J]. 中国矫形外科杂志, 2021, 29(20): 1863-1867.
[24] Kim, Y. and Ku, J. (2023) Rat Calvaria Model Mimicking the Intraoral Lesion of Medication-Related Osteonecrosis in the Jaw: A Preliminary Test. Journal of Clinical Medicine, 12, Article 6731. [Google Scholar] [CrossRef] [PubMed]
[25] Saunders, W.B., Dejardin, L.M., Soltys-Niemann, E.V., Kaulfus, C.N., Eichelberger, B.M., Dobson, L.K., et al. (2022) Angle-Stable Interlocking Nailing in a Canine Critical-Sized Femoral Defect Model for Bone Regeneration Studies: In Pursuit of the Principle of the 3R’s. Frontiers in Bioengineering and Biotechnology, 10, Article 921486. [Google Scholar] [CrossRef] [PubMed]
[26] Finze, R., Laubach, M., Russo Serafini, M., Kneser, U. and Medeiros Savi, F. (2023) Histological and Immunohistochemical Characterization of Osteoimmunological Processes in Scaffold-Guided Bone Regeneration in an Ovine Large Segmental Defect Model. Biomedicines, 11, Article 2781. [Google Scholar] [CrossRef] [PubMed]
[27] Li, S., Zhou, H., Hu, C., Yang, J., Ye, J., Zhou, Y., et al. (2021) Total Flavonoids of Rhizoma Drynariae Promotes Differentiation of Osteoblasts and Growth of Bone Graft in Induced Membrane Partly by Activating Wnt/β-Catenin Signaling Pathway. Frontiers in Pharmacology, 12, Article 675470. [Google Scholar] [CrossRef] [PubMed]
[28] 徐石庄, 王进, 潘文振, 等. 兔股骨髁临界性骨缺损动物模型制备及临界骨缺损值[J]. 中国组织工程研究, 2020, 24(20): 3191-3195.
[29] Yin, N., Wang, Y., Ding, L., Yuan, J., Du, L., Zhu, Z., et al. (2020) Platelet-Rich Plasma Enhances the Repair Capacity of Muscle-Derived Mesenchymal Stem Cells to Large Humeral Bone Defect in Rabbits. Scientific Reports, 10, Article No. 6771. [Google Scholar] [CrossRef] [PubMed]
[30] Sargolzaei-Aval, F., Saberi, E.A., Arab, M.R., Sargolzaei, N., Sanchooli, T. and Tavakolinezhad, S. (2019) Octacalcium Phosphate/Gelatin Composite Facilitates Bone Regeneration of Critical-Sized Mandibular Defects in Rats: A Quantitative Study. Journal of Dental Research, Dental Clinics, Dental Prospects, 13, 258-266. [Google Scholar] [CrossRef] [PubMed]
[31] Schlund, M., Depeyre, A., Kotagudda Ranganath, S., Marchandise, P., Ferri, J. and Chai, F. (2022) Rabbit Calvarial and Mandibular Critical-Sized Bone Defects as an Experimental Model for the Evaluation of Craniofacial Bone Tissue Regeneration. Journal of Stomatology, Oral and Maxillofacial Surgery, 123, 601-609. [Google Scholar] [CrossRef] [PubMed]
[32] McGovern, J.A., Griffin, M. and Hutmacher, D.W. (2018) Animal Models for Bone Tissue Engineering and Modelling Disease. Disease Models & Mechanisms, 11, dmm033084. [Google Scholar] [CrossRef] [PubMed]
[33] 黄玉凡, 李晓青. 胫骨注射和左心室注射乳腺癌细胞小鼠骨定植模型的研究[J]. 天津医科大学学报, 2024, 30(3): 200-204.
[34] Beagan, M.L.C., Dreyer, C.H., Jensen, L.K., Jensen, H.E., Andersen, T.E., Overgaard, S., et al. (2024) The Potential of Sheep in Preclinical Models for Bone Infection Research—A Systematic Review. Journal of Orthopaedic Translation, 45, 120-131. [Google Scholar] [CrossRef] [PubMed]
[35] Zhao, Y., Su, J., Xu, C., Li, Y., Hu, T., Li, Y., et al. (2024) Establishment of a Mandible Defect Model in Rabbits Infected with Multiple Bacteria and Bioinformatics Analysis. Frontiers in Bioengineering and Biotechnology, 12, Article 1350024. [Google Scholar] [CrossRef] [PubMed]
[36] Dao, A., O’Donohue, A.K., Vasiljevski, E.R., Bobyn, J.D., Little, D.G. and Schindeler, A. (2023) Murine Models of Orthopedic Infection Featuring Staphylococcus aureus Biofilm. Journal of Bone and Joint Infection, 8, 81-89. [Google Scholar] [CrossRef] [PubMed]
[37] Liu, W., Li, G., Li, J. and Chen, W. (2022) Long Noncoding RNA TRG-AS1 Protects against Glucocorticoid-Induced Osteoporosis in a Rat Model by Regulating miR-802-Mediated CAB39/AMPK/SIRT-1/NF-κB Axis. Human Cell, 35, 1424-1439. [Google Scholar] [CrossRef] [PubMed]
[38] Eskandarynasab, M., Doustimotlagh, A.H., Takzaree, N., Etemad-Moghadam, S., Alaeddini, M., Dehpour, A.R., et al. (2020) Phosphatidylserine Nanoliposomes Inhibit Glucocorticoid-Induced Osteoporosis: A Potential Combination Therapy with Alendronate. Life Sciences, 257, Article ID: 118033. [Google Scholar] [CrossRef] [PubMed]
[39] Cheng, M., Liang, X., Wang, Q., Deng, Y., Zhao, Z. and Liu, X. (2018) Ursolic Acid Prevents Retinoic Acid-Induced Bone Loss in Rats. Chinese Journal of Integrative Medicine, 25, 210-215. [Google Scholar] [CrossRef] [PubMed]
[40] Ren, M., Wang, X., Hu, M., Jiang, Y., Xu, D., Xiang, H., et al. (2022) Enhanced Bone Formation in Rat Critical-Size Tibia Defect by a Novel Quercetin-Containing Alpha-Calcium Sulphate Hemihydrate/Nano-Hydroxyapatite Composite. Biomedicine & Pharmacotherapy, 146, Article ID: 112570. [Google Scholar] [CrossRef] [PubMed]
[41] Guimarães, J.A.M., Scorza, B.J.B., Machado, J.A.P., Cavalcanti, A.D.S. and Duarte, M.E.L. (2023) Characterization of the Masquelet Induced Membrane Technique in a Murine Segmental Bone Defect Model. Revista Brasileira de Ortopedia, 58, e798-e807. [Google Scholar] [CrossRef] [PubMed]
[42] Beitlitum, I., Rayyan, F., Pokhojaev, A., Tal, H. and Sarig, R. (2024) A Novel Micro-CT Analysis for Evaluating the Regenerative Potential of Bone Augmentation Xenografts in Rabbit Calvarias. Scientific Reports, 14, Article No. 4321. [Google Scholar] [CrossRef] [PubMed]
[43] Alrumaih, S., Alshibani, N., Alssum, L., Alshehri, F.A., AlMayrifi, M.A., AlMayouf, M., et al. (2023) The Impact of Resolvin E1 on Bone Regeneration in Critical‐Sized Calvarial Defects of Rat Model—A Gene Expression and Micro‐CT Analysis. Journal of Periodontal Research, 59, 195-203. [Google Scholar] [CrossRef] [PubMed]
[44] 张娜, 刘学芳, 冯素香, 等. 肺癌骨转移动物模型研究进展[J]. 中国比较医学杂志, 2020, 30(10): 128-131, 137.
[45] 周浩伟, 王秉谦, 张宇辰, 等. 基于数据挖掘的骨质疏松症动物模型建立与分析[J]. 中国实验动物学报, 2023, 31(8): 1042-1050.
[46] Wang, Y., Zhang, X., Mei, S., Li, Y., Khan, A.A., Guan, S., et al. (2023) Determination of Critical-Sized Defect of Mandible in a Rabbit Model: Micro-Computed Tomography, and Histological Evaluation. Heliyon, 9, e18047. [Google Scholar] [CrossRef] [PubMed]
[47] Tian, M., Han, Y., Yang, G., Li, J., Shi, C. and Tian, D. (2023) The Role of Lactoferrin in Bone Remodeling: Evaluation of Its Potential in Targeted Delivery and Treatment of Metabolic Bone Diseases and Orthopedic Conditions. Frontiers in Endocrinology, 14, Article 1218148. [Google Scholar] [CrossRef] [PubMed]
[48] 许刚, 何纯青, 张飞, 等. 万古霉素/PLGA/TCP多孔复合材料修复羊感染性骨缺损[J]. 实用医学杂志, 2020, 36(24): 3317-3322.