Orthobiologics are used widely in modern orthopaedic and sports medicine practice, yet the biologic rationale for cell-based therapies is often oversimplified. Mesenchymal stem cells (MSCs) were initially understood as multipotent progenitors capable of regenerating mesenchymal tissues through engraftment and differentiation. However, continued translational research, including the isolation and characterization of muscle-derived stem cells, has refined this model. MSC-like tissues are closely associated with the perivascular microenvironment, and their clinical effect seems to be mediated largely by paracrine signaling, angiogenesis, immunomodulation, and recruitment of host reparative cells rather than simply tissue replacement by donor cells. This mechanistic shift supports Arnold I. Caplan's term "medicinal signaling cells" and has important implications for orthopaedic surgeons when counseling patients, selecting biologic adjuncts, interpreting outcome data, and designing future clinical trials. Aging, osteoarthritis, cellular senescence, culture expansion, and disruption of the native stem cell microenvironment are all mechanisms that can impair biologic potency of MSCs. As a result, senolytic and antifibrotic approaches, minimally manipulated bone marrow and adipose preparations, exosome-based therapies, and engineered feedback-regulated cells are active areas of investigation in optimizing patient outcomes with orthobiologics. This review translates these benchtop methodical concepts into practical considerations for surgeons integrating orthobiologics into everyday clinical practice.
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