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  • Review Article
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The decisive early phase of bone regeneration

Nature Reviews Rheumatology volume 19, pages 78–95 (2023)Cite this article

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Abstract

Bone has a remarkable endogenous regenerative capacity that enables scarless healing and restoration of its prior mechanical function, even under challenging conditions such as advanced age and metabolic or immunological degenerative diseases. However — despite much progress — a high number of bone injuries still heal with unsatisfactory outcomes. The mechanisms leading to impaired healing are heterogeneous, and involve exuberant and non-resolving immune reactions or overstrained mechanical conditions that affect the delicate regulation of the early initiation of scar-free healing. Every healing process begins phylogenetically with an inflammatory reaction, but its spatial and temporal intensity must be tightly controlled. Dysregulation of this inflammatory cascade directly affects the subsequent healing phases and hinders the healing progression. This Review discusses the complex processes underlying bone regeneration, focusing on the early healing phase and its highly dynamic environment, where vibrant changes in cellular and tissue composition alter the mechanical environment and thus affect the signalling pathways that orchestrate the healing process. Essential to scar-free healing is the interplay of various dynamic cascades that control timely resolution of local inflammation and tissue self-organization, while also providing sufficient local stability to initiate endogenous restoration. Various immunotherapy and mechanobiology-based therapy options are under investigation for promoting bone regeneration.

Key points

  • Bone healing is a dynamic yet stable process that occurs throughout an individuals’ lifespan; patient-specific factors can increase the risk of healing disorders but the causal relationship is incompletely understood.

  • The bone healing process is tightly regulated and very well orchestrated but might easily become disrupted; a relevant percentage of patients with a fracture experience unsatisfactory healing outcomes.

  • Emerging evidence highlights the patients’ immune competence as a decisive factor in the healing process; various components of the immune system have beneficial or detrimental effects.

  • Mechanical conditions promote bone regeneration, but this knowledge has not yet been exploited in daily clinical practice or current surgical treatment strategies.

  • The initial stages of bone healing are characterized by dynamic self-organization of the tissue that governs the healing outcome; invading immune and/or matrix-generating cells define the signalling pattern that guides healing.

  • New patient-specific treatment approaches are on the horizon that target immunomodulatory and biomechanical aspects.

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Fig. 1: The organization of various bone compartments.
Fig. 2: Intact and injured bone.
Fig. 3: The interdependent and overlapping phases of bone healing.
Fig. 4: Dynamic cellular environment of bone healing.
Fig. 5: Biomechanical events of bone healing.
Fig. 6: Progenitor cell recruitment for osteogenic differentiation.
Fig. 7: Angiogenic processes during bone healing.

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Acknowledgements

The authors acknowledge funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (SFB 1444).

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Authors and Affiliations

  1. Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany

    Georg N. Duda, Sven Geissler, Sara Checa, Serafeim Tsitsilonis, Ansgar Petersen & Katharina Schmidt-Bleek

  2. Berlin Institute of Health Centre for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany

    Georg N. Duda, Sven Geissler, Serafeim Tsitsilonis, Ansgar Petersen & Katharina Schmidt-Bleek

  3. Center for Musculoskeletal Surgery, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Serafeim Tsitsilonis

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G.N.D., S.G., S.C., A.P. and K.S.-B. researched data for the article and contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Georg N. Duda.

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Glossary

Callus

Cartilaginous (soft callus) or bony (hard callus) material forming a connecting bridge across a bone fracture during repair.

Cartilage hypertrophy

Cartilaginous tissue that is highly active and undergoing remodelling and calcification

Cortical bone

A dense bone layer that surrounds the bone marrow cavity.

Dynamization

A decrease in fixation stability to stimulate callus formation and bone formation.

Endochondral ossification

The process in which bone is formed indirectly through a cartilage intermediate.

Haematoma

A mass of mostly clotted blood that forms within an organ or tissue following blood vessel disruption.

Intramembranous ossification

The process in which bone is formed directly from mesenchymal connective tissue.

Lamellar bone

A mature form of bone consisting of collagen fibres organized in a regular and parallel fashion to form sheets (lamellae), which in turn form osteons to generate mechanically strong bone.

Matrix mineralization

The process by which organic bone matrix is enriched with calcium phosphate, the main inorganic component of bone.

Mechanotransduction

The mechanisms by which mechanical stimuli are converted into biological signals.

Mechanical loading

An external force (such as a weight), either constant or variable, that imposes physical stress on a system or component.

Mechanobiology

The study of how cells sense and respond to mechanical stimuli.

Mechanosensation

The transduction of mechanical stimuli into a cellular reaction.

Sprouting angiogenesis

The formation of new blood vessels (angiogenesis) from pre-existing vessels.

Stress relaxation

A time-dependent decrease in stress under a constant strain.

Trabecular bone

A honeycomb-like network (75–95% porosity) of interconnected bone rods and plates.

Woven bone

A primitive form of bone, consisting of haphazardly organized collagen fibres that are mechanically weak.

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Duda, G.N., Geissler, S., Checa, S. et al. The decisive early phase of bone regeneration. Nat Rev Rheumatol 19, 78–95 (2023). https://doi.org/10.1038/s41584-022-00887-0

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