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.

Table 2 Critical challenges in mesenchymal stromal cell-derived secretome translation and proposed solutions

Challenge category	Specific issues	Current status	Proposed solutions	Timeline to resolution
Product standardization
Source MSC variability	Donor age, tissue source, comorbidities affect secretome	Widely recognized; limited consensus	Establish standardized donor selection criteria; focus on allogeneic young, healthy donors; develop potency-based lot selection	2-3 years
Isolation method heterogeneity	Multiple protocols yield different products	MISEV guidelines provide research framework	Develop GMP-compliant isolation protocols; comparative studies of methods vs clinical outcomes	3-5 years
Batch-to-batch consistency	Manufacturing variability affects reproducibility	Early-stage optimization in progress	Implement process analytical technology; establish critical quality attributes	3-5 years
Quality control
Potency assay development	Lack of validated functional assays	Multiple candidate assays under evaluation	Validate multi-parameter potency testing; correlate with clinical outcomes	4-6 years
Characterization complexity	Thousands of components; incomplete understanding of active elements	Improving with advanced analytics	Employ systems biology approaches; identify critical therapeutic components	5-7 years
Stability testing	Degradation kinetics poorly defined	Limited systematic data	Conduct comprehensive stability studies across formulations; develop real-time potency monitoring	2-4 years
Delivery optimization
Rapid intra-articular clearance	Limits sustained therapeutic effect	Well-documented in preclinical models	Develop sustained-release formulations; explore biomaterial carriers; optimize injection timing	3-5 years
Limited cartilage penetration	Chondrocyte targeting inefficient	Recognized challenge; solutions in early development	Engineer targeting moieties; optimize EV size for matrix penetration	4-6 years
Dosing regimen uncertainty	Single vs multiple injections; optimal intervals unknown	Clinical trials using variable regimens	Conduct systematic dose-finding and dose-timing studies	5-7 years
Clinical validation
Lack of phase III data	Efficacy vs placebo unproven	Phase I/II ongoing; phase III planning	Execute large, adequately powered RCTs with appropriate controls	5-8 years
Patient selection optimization	Ideal disease stage and phenotype undefined	Exploratory analyses in early trials	Develop predictive biomarkers; conduct stratified analyses	4-6 years
Outcome measure sensitivity	Traditional outcomes require large N and long duration	Alternative outcomes under evaluation	Validate imaging and biochemical biomarkers; incorporate patient-reported outcomes	3-5 years
Regulatory challenges
Classification ambiguity	Unclear regulatory pathway	Ongoing agency discussions	Establish precedent through lead product approvals; develop guidance documents	3-5 years
Manufacturing requirements	GMP standards incompletely defined for secretomes	Evolving with agency feedback	Develop industry consensus standards; leverage existing biologic manufacturing frameworks	3-5 years
Economic challenges
Reimbursement pathway	Unclear payer coverage for novel biologic	No established codes or reimbursement	Demonstrate cost-effectiveness vs current care; establish value-based pricing	5-10 years
Manufacturing economics	Production costs potentially prohibitive	Economies of scale not yet achieved	Optimize yields; develop scalable processes; explore biosimilar pathways post-approval	5-7 years

MSC: Mesenchymal stromal cell; GMP: Good manufacturing practice; MISEV: Minimal Information for Studies of Extracellular Vesicles; EV: Extracellular vesicle.