Precision Orthobiologics for Chronic Musculoskeletal Pain: Matching Biology, Pathology, and Patient Phenotype—A Narrative Review of Current Evidence and Future Directions in Regenerative Pain Medicine

Background and Objectives: Orthobiologic injectables—principally platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), cell-based therapies and, increasingly, extracellular vesicles—are widely used for chronic musculoskeletal (MSK) pain, yet their evidence base is inconsistent and guideline endorsement is heterogeneous. One frequently proposed contributor to this inconsistency is the use of biologically dissimilar products as interchangeable, one-size-fits-all injections in poorly stratified populations. This narrative review examines current evidence through a conceptual “precision” framework organized around three axes—the biology of the product, the pathology of the target tissue, and the phenotype of the patient—and around image-guided delivery as the procedural context in which these axes are operationalized. It spans osteoarthritis, tendinopathy, plantar fasciopathy, discogenic and spinal pain, and impaired bone healing, with emphasis on PRP, BMAC, and platelet- and cell-derived extracellular vesicles. Materials and Methods: PubMed/MEDLINE, Embase, Cochrane CENTRAL and Web of Science were searched from inception to 15 January 2026 and updated on 31 August 2026; 4812 de-duplicated records were screened by two authors independently, and 435 full texts were assessed, from which 76 sources are cited (36 clinical studies and evidence syntheses, 11 guidelines, consensus statements or reporting standards, and 29 narrative, mechanistic, regulatory or methodological references). Evidence was prioritized as guidelines and formal consensus, then syntheses with a certainty assessment, then individual trials, with neutral and negative trials given equal weight. This is a narrative, not a systematic, review; SANRA was used as a critical-appraisal checklist, not as a reporting guideline. Results: Across indications, pooled efficacy signals are frequently positive but of low-to-moderate certainty, with substantial risk of bias, small-study effects, and inconsistent product reporting; adequately controlled trials in knee osteoarthritis, Achilles and lateral-elbow tendinopathy, and discogenic pain have returned neutral results. Candidate response modifiers—structural phenotype, inflammatory and metabolic status, pain-processing phenotype, intraprocedural signals, and machine-learning models—are at present largely prognostic associations rather than validated treatment-effect modifiers. Guideline positions diverge, reflecting differences in methodology and evidence thresholds as well as in the underlying evidence. Conclusions: We present the three-axis framework as a testable hypothesis and a structure for stratified prospective trials, not as a validated clinical algorithm. We classify its components by clinical readiness, distinguish prognostic from predictive biomarkers, temper regenerative language where only symptomatic benefit is demonstrated, and identify platelet- and cell-derived extracellular vesicles as an early-stage, predominantly preclinical direction whose translational promise remains to be established.