Trauma: Fracture Healing and Pathophysiology of the Pseudoarthrosis

Selin ÖNENa , Petek KORKUSUZa,b

aMiddle East Technical University MEMS Center, Ankara, Türkiye
bHacettepe University Faculty of Medicine, Department of Histology and Embryology, Ankara, Türkiye

ABSTRACT
Bone is a mechanosensitive dynamic specialized connective tissue with multiple vital functions such as being a metabolic machine for mineral storage and glucose metabolism, a niche component where the hematopoiesis takes place and a convenient origin of multipotent and progenitor stem cells. In fractures, bone is remodeled 100% with a high level of regenerative capacity and can renew itself in terms of cellular content and mechanical strength. However, some problems in fracture healing may be observed in the clinic due to the structure of the fracture, unsuccessful surgical interventions, or impaired biological response. Non-union or mal-union fractures can occur in some fractures due to those physical or chemical events. Pseudoarthrosis is defined as non-fusion of bone correctly after an injury or surgery, and secondary revision-purpose surgical interventions are applied to these patients in the clinic, with a success rate of nearly 50-65%. To fully solve this problem, the cellular, chemical and physical microenvironment of bone, fracture types and fracture healing mechanism must be well understood. Research on immunotherapy, stem cell-based therapy, and mechanobiological therapy are promising for preventing and treating cases of pseudoarthrosis.
Keywords: Fracture healing; pseudoarthrosis; fractures, malunited; bone and bones

Referanslar

  1. Bilgiç E, Boyacıoğlu Ö, Gizer M, Korkusuz P, Korkusuz F, Chapter 6 - Architecture of bone tissue and its adaptation to pathological conditions, in Comparative Kinesiology of the Human Body. In: Angin S, Şimşek IE, eds. Academic Press; 2020. p.71-90. [Crossref]
  2. Duda GN, Geissler S, Checa S, Tsitsilonis S, Petersen A, Schmidt-Bleek K. The decisive early phase of bone regeneration. Nat Rev Rheumatol. 2023;19(2):78-95. [Crossref]  [PubMed]
  3. Mescher AL. Bone, in Junqueira's Basic Histology Text and Atlas. 16th ed. New York, NY: McGraw Hill; 2021.
  4. Köse S, Yersal N, Önen S, Korkusuz P. Comparison of Hematopoietic and Spermatogonial Stem Cell Niches from the Regenerative Medicine Aspect. Adv Exp Med Biol. 2018;1107:15-40. [Crossref]  [PubMed]
  5. Hurwitz SN, Jung SK, Kurre P. Hematopoietic stem and progenitor cell signaling in the niche. Leukemia. 2020;34(12):3136-48. [Crossref]  [PubMed]
  6. Carlson BM. Human Embryology and Developmental Biology: Human Embryology and Developmental Biology E-Book. Elsevier Health Sciences; 2023.
  7. Bolamperti S, Villa I, Rubinacci A. Bone remodeling: an operational process ensuring survival and bone mechanical competence. Bone Res. 2022;10(1):48. [Crossref]  [PubMed]  [PMC]
  8. Saul D, Menger MM, Ehnert S, Nüssler AK, Histing T, Laschke MW. Bone Healing Gone Wrong: Pathological Fracture Healing and Non-Unions-Overview of Basic and Clinical Aspects and Systematic Review of Risk Factors. Bioengineering (Basel). 2023;10(1):85. [Crossref]  [PubMed]  [PMC]
  9. Salhotra A, Shah HN, Levi B, Longaker MT. Mechanisms of bone development and repair. Nat Rev Mol Cell Biol. 2020;21(11):696-711. [Crossref]  [PubMed]  [PMC]
  10. Wildemann B, Ignatius A, Leung F, Taitsman LA, Smith RM, Pesántez R, et al. Non-union bone fractures. Nat Rev Dis Primers. 2021;7(1):57. [Crossref]  [PubMed]
  11. Li Z, Liu Y, Huang Y, Tan Q, Mei H, Zhu G, et al. Circ_0000888 regulates osteogenic differentiation of periosteal mesenchymal stem cells in congenital pseudarthrosis of the tibia. iScience. 2023;26(10):107923. [Crossref]  [PubMed]  [PMC]
  12. Kaymakoglu M, Ciftci E, Korkusuz P, Ozdemir E, Erden ME, Turhan E. Adrenomedullin has no effect on segmental bone defect healing but increases bone mineral density in rat model. Acta Orthop Traumatol Turc. 2023;57(5):221-8. [Crossref]  [PubMed]  [PMC]
  13. Thaeter M, Kobbe P, Verhaven E, Pape HC. Minimally Invasive Techniques in Orthopedic Trauma. Current Trauma Reports. 2016;2(4):232-7. [Crossref]
  14. Bal Z, Korkusuz F, Ishiguro H, Okada R, Kushioka J, Chijimatsu R, et al. A novel nano-hydroxyapatite/synthetic polymer/bone morphogenetic protein-2 composite for efficient bone regeneration. Spine J. 2021;21(5):865-73. [Crossref]  [PubMed]
  15. Dede EÇ, Gizer M, Korkusuz F, Bal Z, Ishiguro H, Yoshikawa H, et al. A pilot study: Nano-hydroxyapatite-PEG/PLA containing low dose rhBMP2 stimulates proliferation and osteogenic differentiation of human bone marrow derived mesenchymal stem cells. JOR Spine. 2023;6(3):e1258. [Crossref]  [PubMed]  [PMC]
  16. Minguella-Canela J, Calero JA, Korkusuz F, Korkusuz P, Kankılıç B, Bilgiç E, et al. Biological Responses of Ceramic Bone Spacers Produced by Green Processing of Additively Manufactured Thin Meshes. Materials (Basel). 2020;13(11):2497. [Crossref]  [PubMed]  [PMC]
  17. Kankilic B, Bayramli E, Korkusuz P, Eroglu H, Sener B, Mutlu P, et al. Vancomycin Containing PDLLA and PLGA/β-TCP Inhibit Biofilm Formation but Do Not Stimulate Osteogenic Transformation of Human Mesenchymal Stem Cells. Front Surg. 2022;9:885241. [Crossref]  [PubMed]  [PMC]
  18. Köse S, Kankilic B, Gizer M, Ciftci Dede E, Bayramli E, Korkusuz P, et al. Stem Cell and Advanced Nano Bioceramic Interactions. Adv Exp Med Biol. 2018;1077:317-42. [Crossref]  [PubMed]
  19. Baino F, Minguella-Canela J, Korkusuz F, Korkusuz P, Kankılıç B, Montealegre MÁ, et al. In Vitro Assessment of Bioactive Glass Coatings on Alumina/Zirconia Composite Implants for Potential Use in Prosthetic Applications. Int J Mol Sci. 2019;20(3):722. [Crossref]  [PubMed]  [PMC]
  20. Şahin Ş, Tuncel SA, Salimi K, Bilgiç E, Korkusuz P, Korkusuz F. Advanced Injectable Alternatives for Osteoarthritis. Adv Exp Med Biol. 2018;1077:183-96. [Crossref]  [PubMed]
  21. Çiftci Dede E, Korkusuz P, Bilgiç E, Çetinkaya MA, Korkusuz F. Boron Nano-hydroxyapatite Composite Increases the Bone Regeneration of Ovariectomized Rabbit Femurs. Biol Trace Elem Res. 2022;200(1):183-96. [Crossref]  [PubMed]
  22. Ciftci E, Bozbeyoglu N, Gursel I, Korkusuz F, Bakan Misirlioglu F, Korkusuz P. Comparative analysis of magnetically activated cell sorting and ultracentrifugation methods for exosome isolation. PLoS One. 2023;18(2):e0282238. [Crossref]  [PubMed]  [PMC]
  23. İşoğlu İA, Bölgen N, Korkusuz P, Vargel İ, Çelik HH, Kılıç E, et al. Stem cells combined 3D electrospun nanofibrous and macrochannelled matrices: a preliminary approach in repair of rat cranial bones. Artif Cells Nanomed Biotechnol. 2019;47(1):1094-100. [Crossref]  [PubMed]
  24. Vural AC, Odabas S, Korkusuz P, Yar Sağlam AS, Bilgiç E, Çavuşoğlu T, et al. Cranial bone regeneration via BMP-2 encoding mesenchymal stem cells. Artif Cells Nanomed Biotechnol. 2017;45(3):544-50. [Crossref]  [PubMed]
  25. Bal Z, Kushioka J, Kodama J, Kaito T, Yoshikawa H, Korkusuz P, et al. BMP and TGFβ use and release in bone regeneration. Turk J Med Sci. 2020;50(SI-2):1707-22. [Crossref]  [PubMed]  [PMC]
  26. Altay B, Dede EÇ, Özgul Ö, Atıl F, Koçyiğit İD, Orhan K, et al. Effect of Systemic Oxytocin Administration on New Bone Formation and Distraction Rate in Rabbit Mandible. J Oral Maxillofac Surg. 2020;78(7):1171-82. [Crossref]  [PubMed]
  27. Alici-Garipcan A, Korkusuz P, Bilgic E, Askin K, Aydin HM, Ozturk E, et al. Critical-size alveolar defect treatment via TGF-ß3 and BMP-2 releasing hybrid constructs. J Biomater Sci Polym Ed. 2019;30(5):415-36. [Crossref]  [PubMed]
  28. Kan B, Tasar F, Korkusuz P, Ersoy O, Cetinkaya A, Gur CZ, et al. Histomorphometrical and radiological comparison of low-level laser therapy effects on distraction osteogenesis: experimental study. Lasers Med Sci. 2014;29(1):213-20. [Crossref]  [PubMed]