Preclinical and early clinical safety of intra-articular spheroid adipose-derived stem cells for knee osteoarthritis: A translational study

Objective: To evaluate preclinical and early clinical safety of intra-articular spheroid adipose-derived stem cells (S-ADSCs) for knee osteoarthritis and to summarize exploratory outcomes. Methods: cells) in 5 mL. Preclinical assessments included clinical monitoring, laboratory tests, necropsy, and H exploratory outcomes included pain (visual analog scale VAS) and function (KOOS and WOMAC). Exploratory quadratic mixed-effects models assessed non-linear time trends. Results: Minipigs showed no abnormal clinical signs, laboratory changes, or treatment-related findings at necropsy or on knee histology through Day 31. All five patients completed 52-week follow-up; no treatment-related adverse events or serious adverse events, infections, hemarthroses, or acute post-injection flares requiring medical treatment occurred. Exploratory outcomes were heterogeneous: two participants showed sustained improvement through Week 52, whereas the remaining three showed non-sustained patterns; two improved early with partial return toward baseline, and one experienced transient pain worsening at Week 4 without objective inflammation or infection followed by later recovery. Quadratic models suggested early improvement with later attenuation. Conclusion: Intra-articular S-ADSC spheroids at this dose demonstrated acceptable safety in a large-animal model and a first-in-human cohort, supporting further controlled studies. Trial registration: Japan Registry of Clinical Trials (jRCTb050200097; first public release December 17, 2020).