The Immune-Centric Revolution in the Treatment of Musculoskeletal Disease: Autologous PBMNC and PRP-PBMNC Enriched—A Narrative Review

For over two decades, mesenchymal stem cells (MSCs) have been recognised as the cornerstone of orthobiologic treatments for musculoskeletal diseases. However, clinical evidence increasingly indicates that MSC engraftment in inflamed tissues is minimal and transient, with effects mainly driven by paracrine and immunomodulatory mechanisms induced by macrophage efferocytosis. This evolving paradigm emphasises the immune system as the central orchestrator of tissue repair. Peripheral blood mononuclear cells (PBMNCs) have emerged as potent effectors of regenerative inflammation, mediating apoptotic cell clearance through efferocytosis, facilitating the transition of macrophages from pro-inflammatory (M1) to reparative (M2) phenotypes, and releasing angiogenic and trophic factors that support vascularisation, matrix remodelling, and functional restoration. Clinical studies in critical limb ischemia and diabetic foot provide compelling evidence that autologous PBMNC implantation yields meaningful outcomes in conditions refractory to conventional therapies. Concurrently, platelet-rich plasma (PRP), long regarded as a reservoir of growth factors, is now recognised as a potent recruiter of PBMNCs, where platelet-derived chemokines, such as Monocyte Chemoattractant Protein-1, (MCP-1), Regulated upon Activation, Normal T Cell Expressed and Secreted (RANTES), and Stromal cell-derived factor-1 (SDF-1), establish chemotactic gradients that attract immune cells to injury sites. Neutrophil-depleted, monocyte-enriched PRP formulations demonstrate therapeutic promise in the treatment of osteoarthritis, tendinopathy, and muscle injury. This review consolidates the current scientific rationale and clinical evidence supporting an immune-centric framework, in which PBMNCs, delivered alone or enriched within PRP, constitute a promising next-generation of orthobiologic therapies for musculoskeletal regeneration.