Future perspectives on mesenchymal stromal cell-derived secretomes in knee osteoarthritis

Table 1 Comparative analysis of regenerative approaches for knee osteoarthritis

Parameter	MSC secretomes	Whole-cell MSCs	PRP	Hyaluronic acid
Mechanism	Paracrine signaling via EVs, growth factors, cytokines	Paracrine + potential differentiation	Growth factor delivery, platelet-derived factors	Viscosupplementation, mild anti-inflammatory
Standardization	Moderate challenge; biochemical characterization possible	High challenge; cellular variability	High variability; preparation method dependent	Well-established; pharmaceutical-grade products
Storage/stability	Freeze/Lyophilize possible; moderate stability	Requires cryopreservation; viability concerns	Fresh preparation typically required	Excellent; room temperature stable
Regulatory pathway	Evolving; biological therapeutic	Complex; cellular product regulations	Variable; may be considered device or biologic	Established; device or drug depending on claims
Manufacturing scalability	Good potential with optimization	Limited; donor and passage constraints	Limited; autologous preparation	Excellent; large-scale synthesis feasible
Immunogenicity risk	Minimal; cell-free	Low to moderate depending on allogeneic vs autologous	Minimal; typically autologous	Minimal; well-tolerated
Chondroprotective mechanism	Direct: Matrix synthesis, MMP inhibition	Direct and indirect through secretome	Indirect: Growth factor stimulation	Minimal direct chondroprotection
Anti-inflammatory potency	High; multiple mechanisms	High; primarily via secretome	Moderate; transient	Mild
Subchondral bone effects	Demonstrated in preclinical models	Demonstrated in preclinical models	Limited evidence	Minimal
Clinical evidence level	Phase I/II; early data	Phase II/III; mixed results	Multiple RCTs; modest benefit	Extensive RCTs; modest, transient benefit
Cost considerations	Moderate; dependent on manufacturing scale	High; labor-intensive production	Low to moderate	Low; established manufacturing
Practical advantages	Off-the-shelf potential, consistent dosing	Potentially more potent for severe disease	Point-of-care preparation, familiar to clinicians	Established reimbursement, physician familiarity
Practical limitations	Novel product; limited clinical data	Viability concerns, regulatory complexity	High preparation variability	Limited efficacy; short duration

MSC: Mesenchymal stromal cell; PRP: Platelet-rich plasma; EVs: Extracellular vesicles; MMP: Matrix metalloproteinase; RCTs: Randomised controlled trial.