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

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.