Preparing the soil in knee osteoarthritis: a seed-systemic soil-local tissue soil framework for orthobiologic response heterogeneity.

Musculoskeletal regenerative medicine has traditionally been guided by a product-centered model in which therapeutic outcomes are primarily attributed to the biological characteristics of the administered orthobiologic. However, the marked variability in clinical response suggests that treatment efficacy may also depend on the biological condition of the patient and the receptivity of the target tissue. This integrative review proposes a translational seed-soil framework in which therapeutic response is interpreted through the interaction among the biologic product (seed), systemic host biological readiness (systemic soil), and target tissue receptivity (local tissue soil), with knee osteoarthritis as the primary clinical and evidence context. A structured literature search was conducted in PubMed/MEDLINE, Embase, Scopus, and Web of Science, complemented by citation tracking. Evidence from clinical trials, systematic reviews, observational, imaging, biomarker, mechanistic, and conceptual studies was integrated according to prespecified framework domains. Our synthesis suggests that heterogeneity in orthobiologic outcomes can be more coherently interpreted when three interacting biological layers are considered together: product composition and potency, systemic host factors, and local joint and tissue characteristics. Although several orthobiologic classes demonstrate meaningful clinical signals in knee osteoarthritis, treatment effects remain inconsistent because of variability in product processing and composition, contextual and placebo effects, the strength of active comparators, differences in pain phenotypes, and the multicomponent nature of osteoarthritic joint disease. Importantly, symptomatic improvement should be distinguished from structural regeneration, which remains inconsistently demonstrated across orthobiologic studies. Rigorous product characterization remains essential, but the proposed seed-soil framework extends this perspective by integrating product characteristics with systemic host biology and local tissue receptivity. Although optimization of systemic and local soil conditions has not yet been definitively validated in randomized trials, the proposed framework provides a biologically grounded structure for explaining response heterogeneity, improving patient stratification, and guiding the design of future translational and clinical studies.