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REVIEW ARTICLE

Mechano-encoding hydrogel microspheres for extracellular and pericellular matrix remodeling in musculoskeletal organoids

Xingkuan Wang1,2,3† ,  Jinping Chen1,2,3† ,  Jianye Tan1,2,3 ,  Shengwen Cheng1,2,3 ,  Lifu Jia4 ,  Charlotte A. E. Hauser5,6* ,  Tiziano Serra7* ,  Wei Huang1,2,3* ,  Yiting Lei1,2,3,8* ,  Pengcheng Xiao1,2,3*
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1 Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
2 Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Chongqing Medical University, Chongqing, China
3 Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing Medical University, Chongqing, China
4 Department of Orthopaedics, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
5 Institute of Health Care Engineering with European Testing Center of Medical Devices, Graz University of Technology, Graz, Austria
6 Laboratory for Nanomedicine, Division of Biological and Environmental Science and Engineering, King Abdullah University of Science and Technology, Saudi Arabia
7 AO Research Institute Davos, Davos, Switzerland
8 Department of Biomedical Engineering, Faculty of Engineering, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
†These authors contributed equally to this work.
OR, 026090013 https://doi.org/10.36922/OR026090013
Received: 28 February 2026 | Revised: 21 May 2026 | Accepted: 25 May 2026 | Published online: 24 July 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

Organoids—three-dimensional, self-organizing living micro-tissue entities—are fundamentally reshaping the outcome of modern biomedical research through their remarkable capacity to recapitulate the topographical complexity and physiological fidelity of native tissues. Additionally, organoids are able to recapitulate the genetic and epigenetic signature of individual human beings, which is a crucial stepping stone for all personalized and regenerative medicine approaches. However, despite their ability to express selected lineage-specific markers, existing organoid culture platforms exhibit fundamental deficiencies in the spatiotemporal precision of extracellular matrix (ECM) and pericellular matrix (PCM) organization—a vexating limitation rooted in the absence of sophisticated spatiotemporal mechano-coding. Consequently, organoids frequently remain arrested in immature phenotypic states, severely constraining their translational efficacy in regenerative medicine. Addressing this critical bottleneck, hydrogel microsphere-mediated engineering strategies have emerged as a transformative paradigm. This review centers on innovative approaches with a focus on osteomuscular organoid models, elucidating their rational biomaterial design principles, unique mechano-coding advantages, and the core mechanisms by which they orchestrate the secretion and microstructural remodeling of endogenous ECM/PCM components. We conclude by prospectively exploring the potential of these microsphere-mediated systems to enhance their physiological accuracy and clinical translatability of in vitro musculoskeletal models.

Graphical abstract
Keywords
Hydrogel microspheres
Osteomuscular organoid
Mechano-coding
Extracellular/pericellular matrix
Tissue regeneration
Biomechanotransduction
Matrix remodeling
Funding
This work was supported by the Chongqing City Postdoctoral Innovative Talent Support Plan (CQBX202411); the Postdoctoral Fellowship Program of CPSF (GZC20251501), the Postdoctoral Fellowship Program (2025MD784153); Hong Kong Scholars Program (XJ2024017); Project of North Sichuan Medical College (CBY23-QNA01) (2024MPZK013); and Sichuan Science and Technology Program (2025ZNSFSC0650).
Conflict of interest
The authors declare no conflict of interest.
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