Cell Therapy for Knee Osteoarthritis: What the Randomized Evidence Actually Says
The promise and the noise
Few areas of medicine attract as much hype as "stem cells for the knee". Clinics around the world advertise injections of bone-marrow concentrate, fat-derived cells or laboratory-expanded stromal cells as a cure for osteoarthritis, often with little evidence behind the claim. At the same time, serious academic groups have spent two decades running controlled trials of mesenchymal stromal cell (MSC) therapy, and the biology is genuinely promising.
Separating the promise from the noise requires looking at the randomized evidence as a whole. That is what a team from the University of São Paulo and Hospital Sírio-Libanês — including Spero Science founder Prof. Dr. Tiago Lazzaretti Fernandes as senior author — did in a systematic review and meta-analysis published in the Journal of Orthopaedic Translation in 2024. This article summarizes what they found and what it means for the next generation of cell-based products.
What mesenchymal stromal cells do in a joint
MSCs are multipotent cells found in bone marrow, adipose tissue, synovial membrane, umbilical cord, dental pulp and other tissues. In culture they can differentiate into cartilage, bone and fat. Inside an osteoarthritic joint, however, most of their benefit is thought to come not from turning into new chondrocytes but from what they secrete: growth factors, anti-inflammatory cytokines and extracellular vesicles (exosomes) that calm synovial inflammation, protect existing chondrocytes and modulate the local immune environment. This "paracrine" or immunomodulatory mechanism is why MSC therapy is often described as regulating the joint environment rather than simply replacing tissue.
The source of the cells matters. Synovial MSCs, for example, have a particularly strong chondrogenic tendency — a property that Spero Science's founders have exploited in their tissue-engineering work (see below).
The 2024 meta-analysis: 25 trials, 1,048 patients
The review was registered in PROSPERO (CRD42020158173), conducted according to the Cochrane Handbook and reported following PRISMA. It included 25 randomized controlled trials with a total of 1,048 participants, comparing advanced MSC therapy with either placebo or viscosupplementation (hyaluronic acid injection, the usual "gold standard" comparator) for knee osteoarthritis and chondral lesions. The certainty of the evidence was graded with the GRADE approach.
The main findings were:
Pain versus viscosupplementation. At 12 months, MSC therapy reduced pain by 1.91 points more on a 0–10 visual analogue scale than hyaluronic acid (95% CI −3.23 to −0.59). When trials at high risk of bias were excluded, the effect was similar (−1.54 points) and the certainty of evidence improved to moderate — meaning MSC therapy probably reduces pain slightly better than viscosupplementation.
Pain versus placebo. MSC therapy also produced lower pain scores than placebo, but the difference (0.99 points) was smaller and the evidence very uncertain.
Safety. There was no difference in serious adverse events between MSC therapy and either placebo or viscosupplementation, again with very uncertain evidence.
The authors' conclusion is deliberately balanced: advanced MSC therapy leads to lower pain than placebo or viscosupplementation at 12 months, with no signal of added harm — but the overall evidence is uncertain, and there is still a lack of well-designed studies that measure the real clinical impact of these therapies.
Why the evidence is still uncertain
The meta-analysis is not a story of a therapy that failed; it is a story of a field that has not yet standardized itself. The included trials used cells from different tissues, expanded under different conditions, at different doses, delivered with or without carriers, and measured outcomes with different instruments over different periods. Many studies were small and some carried a high risk of bias. Under those conditions, even a real biological effect produces noisy, low-certainty evidence.
Three things would change that picture:
Standardized, GMP-manufactured cell products with defined identity, potency and dose — so that "MSC therapy" means the same thing from one trial to the next.
Structural outcomes, such as quantitative MRI and histology, alongside pain and function scores, to show whether the cartilage itself is being protected or rebuilt.
Tissue-engineered formats that hold cells where they are needed instead of leaving them to disperse in the synovial fluid.
These are precisely the directions Spero Science is pursuing.
From injected cells to engineered tissue: the Smart Cells platform
Smart Cells is Spero Science's cell therapy and tissue engineering platform for musculoskeletal regeneration — cartilage, bone and tendon. It grows out of the founders' work on manufacturing human MSCs under Good Manufacturing Practice conditions for articular cartilage regeneration at the University of São Paulo, and on testing those products in a validated large-animal model.
In a 2024 preclinical study published in Pharmaceutics, the team compared scaffold-free tissue-engineered constructs (TECs) made from synovial-membrane MSCs and dental-pulp MSCs, produced under GMP, in fourteen miniature pigs with full-thickness cartilage defects in both knees. After six months, defects treated with synovial-cell constructs scored 65.7 on the MOCART MRI scale versus 46.2 for untreated defects, and 64.3 versus 42.1 on the ICRS-2 histological score — both statistically significant. T2 mapping showed no difference between treated defects and native cartilage, suggesting that the new tissue had a water and collagen composition close to the original. Synovial cells outperformed dental-pulp cells, consistent with their stronger chondrogenic profile.
The animal model itself was developed and published by the same group in 2018 in Stem Cell Reviews and Reports, using human dental pulp stem cells on a collagen scaffold in Brazilian miniature pigs — to our knowledge the first large-animal model of its kind — and has become a workhorse for the group's preclinical pipeline.
This is what "smart" means in Smart Cells: cells selected for the right lineage, manufactured to a defined standard, and delivered as an engineered tissue rather than a suspension. It is the route from the uncertain evidence of first-generation injections to products that can be tested rigorously and, if they work, registered.
Regulatory context in Brazil
Advanced cell therapies in Brazil are regulated by ANVISA as produtos de terapia avançada, with requirements for GMP manufacturing, preclinical safety and controlled clinical evaluation broadly aligned with international frameworks. Spero Science's platform is designed for this pathway and for eventual submissions abroad, in collaboration with the São Paulo hospital and university ecosystem where the founders practice and teach.
What this means for the field — and for partners
The randomized evidence says that cell therapy for knee osteoarthritis is real but immature: a modest, probable benefit over viscosupplementation, an acceptable safety profile, and a large opportunity for whoever brings standardized products and structural outcomes to the clinic. Spero Science's founders have published both the critical evidence review and the preclinical tissue-engineering data that point the way forward.
Research institutions, hospitals and industry partners interested in co-developing, licensing or investing in the Smart Cells platform can contact the Spero Science team. Read more about Smart Cells and about our injectable Chondroinductive Molecule.
References
Tabet CG, Pacheco RL, Martimbianco ALC, Riera R, Hernandez AJ, Bueno DF, Fernandes TL. Advanced therapy with mesenchymal stromal cells for knee osteoarthritis: Systematic review and meta-analysis of randomized controlled trials. J Orthop Translat. 2024;48:176-189. https://doi.org/10.1016/j.jot.2024.07.012
Fernandes TL, Santanna JPC, de Faria RR, Pastore ER, Bueno DF, Hernandez AJ. Tissue Engineering Construct for Articular Cartilage Restoration with Stromal Cells from Synovium vs. Dental Pulp — A Pre-Clinical Study. Pharmaceutics. 2024;16(12):1558. https://doi.org/10.3390/pharmaceutics16121558
Fernandes TL, Shimomura K, Asperti A, et al. Development of a Novel Large Animal Model to Evaluate Human Dental Pulp Stem Cells for Articular Cartilage Treatment. Stem Cell Rev Rep. 2018;14(5):734-743. https://doi.org/10.1007/s12015-018-9820-2
Fernandes TL, Bueno DF, Shimomura K, Shao Z, Gomoll AH. Editorial: Tissue Engineering and Cell Therapy for Cartilage Restoration. Front Cell Dev Biol. 2022;10:947588. https://doi.org/10.3389/fcell.2022.947588
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