Cell-based therapies have disease-modifying effects on osteoarthritis in animal models: A systematic review by the ESSKA Orthobiologic Initiative. Part 3: Umbilical cord, placenta, and other sources for cell-based injectable therapies

Abstract

Purpose: This systematic review aimed to investigate in animal models the presence of disease-modifying effects driven by non-bone marrow-derived and non-adipose-derived products, with a particular focus on umbilical cord and placenta-derived cell-based therapies for the intra-articular injective treatment of osteoarthritis (OA).

Methods: A systematic review was performed on three electronic databases (PubMed, Web of Science and Embase) according to PRISMA guidelines. The results were synthesised to investigate disease-modifying effects in preclinical animal studies comparing injectable umbilical cord, placenta, and other sources-derived products with OA controls. The risk of bias was assessed using the SYRCLE tool.

Results: A total of 80 studies were included (2314 animals). Cell therapies were most commonly obtained from the umbilical cord in 33 studies and placenta/amniotic tissue in 18. Cell products were xenogeneic in 61 studies and allogeneic in the remaining 19 studies. Overall, 25/27 (92.6%) of studies on umbilical cord-derived products documented better results compared to OA controls in at least one of the following outcomes: macroscopic, histological and/or immunohistochemical findings, with 19/22 of studies (83.4%) show positive results at the cartilage level and 4/6 of studies (66.7%) at the synovial level. Placenta-derived injectable products documented positive results in 13/16 (81.3%) of the studies, 12/15 (80.0%) at the cartilage level, and 2/4 (50.0%) at the synovial level, but 2/16 studies (12.5%) found overall worse results than OA controls. Other sources (embryonic, synovial, peripheral blood, dental pulp, cartilage, meniscus and muscle-derived products) were investigated in fewer preclinical studies. The risk of bias was low in 42% of items, unclear in 49%, and high in 9% of items.

Conclusion: Interest in cell-based injectable therapies for OA treatment is soaring, particularly for alternatives to bone marrow and adipose tissue. While expanded umbilical cord mesenchymal stem cells reported auspicious disease-modifying effects in preventing OA progression in animal models, placenta/amniotic tissue also reported deleterious effects on OA joints. Lower evidence has been found for other cellular sources such as embryonic, synovial, peripheral blood, dental-pulp, cartilage, meniscus, and muscle-derived products.

Level of evidence: Level II.

Keywords: cartilage; mesenchymal stromal cells (MSCs); placenta; stem cells; synovial; umbilical cord.

Figure 1

PRISMA flowchart of the study selection process. EVs, extracellular vesicles, OA, osteoarthritis.

Figure 2

Animal studies over the years on intra‐articular injections of cell therapies different to adipose tissue and bone marrow to address OA. X axis, year of publication; Y axis, number of published articles.

Figure 3

Disease‐modifying effects on OA joints induced by umbilical cord‐derived products. The bar chart shows the percentage of studies that met the specific effects. Positive effects (green) vs. no effects (orange) in imaging findings (n = 8), clinical results (n = 7), biomarker evaluation (n = 10), macroscopic results (n = 7), histological results (n = 23), and immunohistochemical results (n = 12). IHC, immunohistochemistry; OA, osteoarthritis.

Figure 4

Disease‐modifying effects on OA joints induced by placental tissue‐derived injectable products. The bar chart shows the percentage of studies that met the specific effects. Positive effects (green) vs. no effects (orange) vs. negative effects (red) in imaging findings (n = 4), clinical results (n = 6), biomarker evaluation (n = 10), macroscopic results (n = 4), histological results (n = 14) and immunohistochemical results (n = 3). IHC, immunohistochemistry; OA, osteoarthritis.

Figure 5

SYRCLE's risk of bias tool assessment of the included studies. The bar chart shows the percentage of all studies that met each quality item, scored as “Low risk”, “High risk”, or “Unclear”.