Synthetic scaffolds functionalized with mesenchymal stem/stromal cells-derived extracellular matrix for bone tissue engineering: a review

Abstract

Bone-related injuries represent a major global challenge, particularly for the aging population. While bone has self-healing capabilities, large defects and non-union fractures often fail to completely regenerate, leading to long-term disability and the need for surgical intervention. Autologous bone grafts remain the gold standard for such procedures, but challenges such as limited donor availability and donor site comorbidity persist. Bone tissue engineering (BTE) presents an alternative approach for bone regeneration, using biomaterials, cells and growth factors that mimic the natural composition and structure of bone. Cell-derived decellularized extracellular matrix (dECM), particularly from mesenchymal stem/stromal cell (MSCs), is among the most promising biomaterials for BTE, as it closely mimics the composition of native bone ECM and provides immunomodulatory and trophic molecules that support bone regeneration. However, dECM's mechanical properties are often insufficient, requiring its combination with synthetic polymers to improve scaffold strength and structural integrity, critical to support hard tissues such as bone. This review explores the potential of MSC-dECM composite scaffolds developed for BTE, including 3D printed constructs, electrospun fibrous matrices, hydrogels and metallic scaffolds. It describes how the incorporation of MSC-dECM enhances the osteoconductive and osteoinductive properties of these scaffolds, leading to increased expression of osteogenic markers and calcium deposition in vitro, as well as enhanced bone formation in vivo. Finally, the review addresses the current challenges and future directions in advancing the application of MSC-dECM-enriched scaffolds towards clinically effective bone repair strategies, including the need to scale up MSC-dECM production, further elucidate its regenerative mechanisms, and integrate it into precise patient-tailored approaches.