Mesenchymal Stromal Cell Spheroids as an Emerging Regenerative Strategy for Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is a progressive ischemic bone disorder that may lead to subchondral fracture, femoral-head collapse, and total hip arthroplasty. Impaired regeneration reflects persistent ischemia, endothelial dysfunction, defective angiogenesis and bone remodeling, inflammation, oxidative stress, and dysfunction of endogenous mesenchymal stromal cells (MSCs). Although MSC therapy, particularly with core decompression in precollapse ONFH, is a promising joint-preserving approach, conventional two-dimensional (2D)-expanded MSCs are limited by poor survival and retention, anoikis, disrupted cell-cell and cell-extracellular matrix interactions, and loss of potency during ex vivo expansion. Three-dimensional MSC spheroids may overcome several of these limitations by preserving intercellular and matrix interactions and enhancing resistance to ischemic stress, paracrine signaling, angiogenic activity, immunomodulation, and osteogenic competence. Hypoxia-responsive signaling, autophagy, trophic-factor secretion, and extracellular vesicle-mediated communication may promote angiogenesis-osteogenesis coupling and the restoration of the ischemic bone-vascular niche. This review summarizes the pathophysiological barriers to ONFH regeneration, current evidence and limitations of conventional MSC therapy, biological mechanisms underlying MSC-spheroid activity, and emerging strategies for therapeutic optimization. Importantly, direct evidence demonstrating the superiority of MSC spheroids over conventional MSC preparations specifically in ONFH remains limited. Future translation will require disease-specific comparative studies, standardized GMP-compatible manufacturing, validated potency assays and clinically practical delivery systems.