There is no standard definition of “critical-size bone defect” in the literature. The term “critical” is often used to describe defects that do not heal spontaneously despite surgical stabilization and require additional bone reconstruction procedures. According to other definitions, these defects measure 2–2.5 cm in size and involve more than 50% loss of the bone’s circumference. Treating bone defects of critical size is a great challenge in bone surgery.
This review aims to identify the factors that influence the regeneration of bone defects and provide guidelines for their treatment. A comprehensive electronic search was performed using the following keywords: critical-size bone defect, treatment, management, bone graft, scaffold, and tissue engineering.
The analysis of the results demonstrated that the healing process depends not only on the defect’s size but also on various other factors, such as the volume and condition of the surrounding soft tissues, as well as the patient’s age and overall health status. Various treatment modalities have been suggested. Advances in tissue engineering have led to the development of new materials that closely resemble natural bone and facilitate successful anatomical and functional restoration.
GBD 2019 Fracture Collaborators. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2021 Sep;2(9):e580-e592. doi: 10.1016/S2666-7568(21)00172-0.
Keating JF, Simpson AH, Robinson CM. The management of fractures with bone loss. J Bone Joint Surg Br. 2005;87:142–150.
Nauth A, McKee MD, Einhorn TA, Watson JT, Li R, Schemitsch EH. Managing bone defects. J Orthop Trauma. 2011 Aug;25(8):462-6. doi: 10.1097/BOT.0b013e318224caf0.
Sanders DW, Bhandari M, Guyatt G, Heels-Ansdell D, Schemitsch EH, Swiontkowski M, et al. Critical-sized defect in the tibia: is it critical? Results from the SPRINT trial. J Orthop Trauma. 2014 Nov;28(11):632-5. doi: 10.1097/BOT.0000000000000194.
Roddy E, DeBaun MR, Daoud-Gray A, Yang YP, Gardner MJ. Treatment of critical-sized bone defects: clinical and tissue engineering perspectives. Eur J Orthop Surg Traumatol. 2018 Apr;28(3):351-362. doi: 10.1007/s00590-017-2063-0.
Dimitriou R, Tsiridis E, Giannoudis PV. Current concepts of molecular aspects of bone healing. Injury. 2005 Dec;36(12):1392-404. doi: 10.1016/j.injury.2005.07.019.
Fernandes GVO, Castro F, Pereira RM, Teixeira W, Gehrke S, Joly JC, et al. Critical-size defects reconstruction with four different bone grafts associated with e-PTFE membrane: A histomorphometric experimental in vivo study. Clin Oral Implants Res. 2024 Feb;35(2):167-178. doi: 10.1111/clr.14210.
Hinsche AF, Giannoudis PV, Matthews SE, Smith RM. Spontaneous healing of large femoral cortical bone defects: does genetic predisposition play a role? Acta Orthop Belg. 2003 Oct;69(5):441-6.
Blick SS, Brumback RJ, Lakatos R, Poka A, Burgess AR. Early prophylactic bone grafting of high-energy tibial fractures. Clin Orthop Relat Res. 1989 Mar;(240):21-41.
Robinson CM, McLauchlan G, Christie J, McQueen MM, Court-Brown CM. Tibial fractures with bone loss treated by primary reamed intramedullary nailing. J Bone Joint Surg Br. 1995 Nov;77(6):906-13.
Court-Brown CM, Keating JF, Christie J, McQueen MM. Exchange intramedullary nailing. Its use in aseptic tibial nonunion. J Bone Joint Surg Br. 1995 May;77(3):407-11.
Haines NM, Lack WD, Seymour RB, Bosse MJ. Defining the Lower Limit of a "Critical Bone Defect" in Open Diaphyseal Tibial Fractures. J Orthop Trauma. 2016 May;30(5):e158-63. doi: 10.1097/BOT.0000000000000531.
Miteva M, Gerova T. Bone repair materials used in guided tissue regeneration-advantages and disadvantages.Int J Sci Res 2019;8.10: 1490-94.
Gerova-Vatsova T, Peev S. Application of platelet-rich plasma (PRP) for regeneration of vertical bone defects. Journal of IMAB–Annual Proceeding Scientific Papers. 2023;29(3), 5103-5107. doi:10.5272/jimab.2023293.5103
Gerova-Vatsova T. Investigating the efficacy of regenerative therapy with autogenous platelet-rich plasma in vertical bone defects. Cureus.2024; 16(10), e72686. doi:10.7759/cureus.72686
Gerova-Vatsova T. Treatment approach to generalized severe periodontitis with the potential for additional tooth loss: a case report. Cureus. 2024; 16(11), e73336. doi:10.7759/cureus.73336
Gerova-Vatsova T. Beyond Bone Grafts: Exploring the Efficacy of Alternative Regenerative Therapies. Cureus. 2024;16(11), e73745. doi:10.7759/cureus.73745
Rezwan K, Chen QZ, Blaker JJ, Boccaccini AR. Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials. 2006 Jun;27(18):3413-31. doi: 10.1016/j.biomaterials.2006.01.039.
Kang Y, Scully A, Young DA, Kim S, Tsao H, Sen M, Yang Y. Enhanced mechanical performance and biological evaluation of a PLGA coated β-TCP composite scaffold for load-bearing applications. Eur Polym J. 2011 Aug 1;47(8):1569-1577. doi: 10.1016/j.eurpolymj.2011.05.004.
Ardeshirylajimi A, Farhadian S, Adegani FJ, Mirzaei S, Zomorrod MS, Langroudi L, et al. Enhanced osteoconductivity of polyethersulphone nanofibres loaded with bioactive glass nanoparticles in in vitro and in vivo models. Cell Prolif. 2015 Aug;48(4):455-64. doi: 10.1111/cpr.12198.
Gurumurthy B, Janorkar AV. Improvements in mechanical properties of collagen-based scaffolds for tissue engineering. Current Opinion in Biomedical Engineering. 2021 Mar 1;17:100253.
Xu Y, Xia D, Han J, Yuan S, Lin H, Zhao C. Design and fabrication of porous chitosan scaffolds with tunable structures and mechanical properties. Carbohydr Polym. 2017 Dec 1;177:210-216. doi: 10.1016/j.carbpol.2017.08.069.
Farokhi M, Jonidi Shariatzadeh F, Solouk A, Mirzadeh H. Alginate based scaffolds for cartilage tissue engineering: a review. International Journal of Polymeric Materials and Polymeric Biomaterials. 2020 Mar 3;69(4):230-47.
Villa MM, Wang L, Huang J, Rowe DW, Wei M. Bone tissue engineering with a collagen-hydroxyapatite scaffold and culture expanded bone marrow stromal cells. J Biomed Mater Res B Appl Biomater. 2015 Feb;103(2):243-53. doi: 10.1002/jbm.b.33225.
Koo Y, Lee H, Lim CS, Kwon SY, Han I, Kim GH. Highly porous multiple-cell-laden collagen/hydroxyapatite scaffolds for bone tissue engineering. Int J Biol Macromol. 2022 Dec 1;222(Pt A):1264-1276. doi: 10.1016/j.ijbiomac.2022.09.249.
Liu H, Wang C, Sun X, Zhan C, Li Z, Qiu L, et al. Silk Fibroin/Collagen/Hydroxyapatite Scaffolds Obtained by 3D Printing Technology and Loaded with Recombinant Human Erythropoietin in the Reconstruction of Alveolar Bone Defects. ACS Biomater Sci Eng. 2022 Dec 12;8(12):5245-5256. doi: 10.1021/acsbiomaterials.2c00690.
Marcacci M, Kon E, Moukhachev V, Lavroukov A, Kutepov S, Quarto R, Mastrogiacomo M, Cancedda R. Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study. Tissue Eng. 2007 May;13(5):947-55. doi: 10.1089/ten.2006.0271.
Zhang Y, Yang C, Gu M, Zhang X, Zhang X, Li G. Multi-functional epoxides cross-linked collagen sponges for tissue engineering scaffolds. Collagen and Leather. 2023 Dec;5(1):29.
Tierney CM, Haugh MG, Liedl J, Mulcahy F, Hayes B, O'Brien FJ. The effects of collagen concentration and crosslink density on the biological, structural and mechanical properties of collagen-GAG scaffolds for bone tissue engineering. J Mech Behav Biomed Mater. 2009 Apr;2(2):202-9. doi: 10.1016/j.jmbbm.2008.08.007.
Jiang YH, Lou YY, Li TH, Liu BZ, Chen K, Zhang D, et al. Cross-linking methods of type I collagen-based scaffolds for cartilage tissue engineering. Am J Transl Res. 2022 Feb 15;14(2):1146-1159.
Raghav PK, Mann Z, Ahlawat S, Mohanty S. Mesenchymal stem cell-based nanoparticles and scaffolds in regenerative medicine. Eur J Pharmacol. 2022 Mar 5;918:174657. doi: 10.1016/j.ejphar.2021.174657.
Stamnitz S, Klimczak A. Mesenchymal Stem Cells, Bioactive Factors, and Scaffolds in Bone Repair: From Research Perspectives to Clinical Practice. Cells. 2021 Jul 29;10(8):1925. doi: 10.3390/cells10081925.
Jun SH, Lee EJ, Jang TS, Kim HE, Jang JH, Koh YH. Bone morphogenic protein-2 (BMP-2) loaded hybrid coating on porous hydroxyapatite scaffolds for bone tissue engineering. J Mater Sci Mater Med. 2013 Mar;24(3):773-82. doi: 10.1007/s10856-012-4822-0.
Shi Y, Quan R, Xie S, Li Q, Cao G, Zhuang W, et al. Evaluation of a Novel HA/ZrO2-Based Porous Bioceramic Artificial Vertebral Body Combined with a rhBMP-2/Chitosan Slow-Release Hydrogel. PLoS One. 2016 Jul 11;11(7):e0157698. doi: 10.1371/journal.pone.0157698.
Mariner PD, Wudel JM, Miller DE, Genova EE, Streubel SO, Anseth KS. Synthetic hydrogel scaffold is an effective vehicle for delivery of INFUSE (rhBMP2) to critical-sized calvaria bone defects in rats. J Orthop Res. 2013 Mar;31(3):401-6. doi: 10.1002/jor.22243.
Shekaran A, García JR, Clark AY, Kavanaugh TE, Lin AS, Guldberg RE, et al. Bone regeneration using an alpha 2 beta 1 integrin-specific hydrogel as a BMP-2 delivery vehicle. Biomaterials. 2014 Jul;35(21):5453-61. doi: 10.1016/j.biomaterials.2014.03.055.
Alonzo M, Primo FA, Kumar SA, Mudloff JA, Dominguez E, Fregoso G, et al. Bone tissue engineering techniques, advances and scaffolds for treatment of bone defects. Curr Opin Biomed Eng. 2021 Mar;17:100248. doi: 10.1016/j.cobme.2020.100248.
Lipskas J, Deep K, Yao W. Robotic-Assisted 3D Bio-printing for Repairing Bone and Cartilage Defects through a Minimally Invasive Approach. Sci Rep. 2019 Mar 6;9(1):3746. doi: 10.1038/s41598-019-38972-2.
