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REVIEW ARTICLE

The rise of callus organoids for skeletal repair: Embedding developmental biology principles in technology-based tissue engineering

Jiarun Bai1,2 ,  Sijia Leng1,2 ,  Liuqi Peng1,2 ,  Hanna Svitina1,2 ,  Ioannis Papantoniou1,2*
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1 Skeletal Biology and Engineering Research Centre, Department of Development and Regeneration, KU Leuven, Leuven, Flemish Brabant, Belgium
2 Prometheus, Leuven Research and Development Translational Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Flemish Brabant, Belgium
OR, 026090011 https://doi.org/10.36922/OR026090011
Received: 26 February 2026 | Revised: 31 March 2026 | Accepted: 3 April 2026 | Published online: 22 May 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Treating critical-sized bone defects is challenging because successful repair relies on proper tissue transitions and timely vascular access, rather than on a single cell fate. Creating fully mature, defect-scale bone grafts in vitro remains constrained by scale, mass transport, and reproducibility, motivating strategies that deliver a programmed starting state and rely on in vivo progression. Organoid systems offer a useful paradigm in this context, as self-organizing microtissues can mimic developmental processes and produce consistent intermediate states. In this developmental engineering framework, callus organoids are cartilage-primed microtissues designed to follow an endochondral callus-to-bone path after implantation. This review synthesizes the mechanisms by which callus organoids are programmed to transition from chondrogenesis to hypertrophy, vascular invasion, ossification, and remodeling. It compares callus organoids to bone organoids and traditional scaffold-based bone tissue engineering, focusing on trajectory control, phase transitions, and timed integration with host transport and vascular systems. Key design variables include the endochondral potential of initial cells, the sequencing of biochemical and mechanical signals, and the timing of maturation and implantation to maintain vascular readiness. The review also discusses bioassembly and biofabrication in relation to diffusion limits and process-compatible potency assessment and quality attributes. Finally, donor variability, mass-transport limitations, incomplete multicellular complexity, and manufacturing standardization are key challenges driving priorities in perfusion and vascularization, architecture-informed fabrication, staged integration of vascular and immune components, and the development of extracellular matrix-based callus-mimetic templates. Overall, the emphasis shifts from building mature bone in vitro to manufacturing standardized callus-like building blocks whose potency is defined by their ability to execute orderly endochondral progression after implantation.

Graphical abstract
Keywords
Organoid
Callus organoid
Endochondral ossification
Developmental engineering
Critical-sized bone defects
Bioassembly
Biofabrication
Funding
This study was supported by Interne Fondsen KU Leuven/ Internal Funds KU Leuven (C24M/22/058) and Research Foundation Flanders (FWO) (G042425N). Jiarun Bai is a PhD student funded by the Chinese Scholarship Council (202206230070). Liuqi Peng is a PhD student funded by the Chinese Scholarship Council (202108440118). Sijia Leng is a PhD student funded by the Research Foundation Flanders (FWO) (S.L: 1SA4B26N).
Conflict of interest
The authors declare they have no competing interests.
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Organoid Research, Electronic ISSN: 3082-8503 Published by AccScience Publishing
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