The human skeleton has remarkable regenerative properties, being one of the few structures in the body that can heal by recreating its normal cellular composition, orientation and mechanical strength. When the healing process of a fractured bone fails owing to inadequate immobilization, failed surgical intervention, insufficient biological response or infection, the outcome after a prolonged period of no healing is defined as non-union. Non-union represents a chronic medical condition not only affecting function but also potentially impacting the individual’s psychosocial and economic well-being. This Primer provides the reader with an in-depth understanding of our contemporary knowledge regarding the important features to be considered when faced with non-union. The normal mechanisms involved in bone healing and the factors that disrupt the normal signalling mechanisms are addressed. Epidemiological considerations and advances in the diagnosis and surgical therapy of non-union are highlighted and the need for greater efforts in basic, translational and clinical research are identified.
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M.J.S. and R.G.R. thank the support from the AO Foundation. A.I. is supported by the Collaborative Research Center CRC1149 (DFG, German Research Foundation; Project number 251293561).
The authors declare no competing interests.
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Healing tissue that connects the bone ends.
Necrotic tissue separated from the surrounding tissue.
- Interfragmentary movement
Axial compression, tension and shear movements in the callus area.
- Progenitor cells
Cells with the potential to differentiate in a more specific cell type.
Physiological process of bone resorption and formation that occurs in mature bone and during healing.
- Intramembranous ossification
Direct transformation of mesenchymal tissue into bone.
- Endochondral ossification
Bone formation via an intermediate cartilage template.
Cells of mesenchymal origin that produce cartilaginous matrix.
Bone-forming cells of mesenchymal origin that produce extracellular matrix and are responsible for mineralization.
Bone-resorbing cells of haematopoietic origin.
Terminally differentiated osteoblasts embedded in the mineralized tissue that are important for bone homeostasis.
Shaft of a long bone, mainly cortical bone.
Neck portion of a long bone, mainly trabecular bone.
- Primary bone healing
Direct healing without an intermediate cartilage template and without callus formation.
- Osteocyte-lacuno-canalicular network
Communication network in bone.
- Haversian systems
Canals that contain capillaries and nerve fibres, surrounded by concentric layers of mineralized tissue (lamella) forming osteons (substructures of bone tissue).
- Secondary bone healing
Indirect healing with callus formation and intramembranous as well as endochondral ossification.
Differentiated monocytes that phagocytize dying and dead cells and cell debris and modulate the inflammatory milieu.
- Healing phases
Fracture, haematoma formation, inflammation, repair with soft and hard callus formation, remodelling.
Formation of new blood vessels from existing vessels.
- Soft callus
Fibrous and cartilaginous tissue.
- Interfragmentary strain
Axial interfragmentary movement divided by the fracture gap size.
Cell-rich membrane covering the outer bone surface, important for bone healing.
Type of white blood cell, part of the innate immune system.
- Cortical bone
Dense structure that forms the outer shell of long bones.
- Trabecular bone
Porous bone formed from an interconnective network of rods and plates that are alined along the lines of stress.
- Delayed union
Delay in healing of a fractured bone within the expected time.
- Primary cilia
Immotile tubules that project from the cell surface like antennas.
- Hard callus
False joint, special form of non-union.
Avascular death (necrosis) of bone.
A bone without normal shape or size owing to congenital, developmental or post-traumatic reasons.
- Judet decortication
Part of the surgical procedure and local approach to non-unions in which the surface of the local bone is peeled up in thin flakes with an osteotome in continuity with overlying soft tissue to enhance the bleeding area and, therefore, bone formation.
- Critical-size defect
Substantial bone loss that does not heal spontaneously despite surgical stabilization.
- Ilizarov technique
A surgical procedure based on the application of a ring external fixator to the bone, which can provide mechanical support together with the ability to progressively change the position of the rings and bone to move bone in space.
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Wildemann, B., Ignatius, A., Leung, F. et al. Non-union bone fractures. Nat Rev Dis Primers 7, 57 (2021). https://doi.org/10.1038/s41572-021-00289-8