JSES - 2026-06-15 - Journal Article
Preclinical Safety and Efficacy of an Allogeneic Adipose-Derived Mesenchymal Stem Cell Medicinal Product for Rotator Cuff Repair: A Two-Phase Experimental Study.
Lopiz Y, Ponz-Lueza V, Arvinius C, Rodríguez-Bobada C, Rojo-Pérez F, Tornero-Esteban P, Marco F
Topics
Key Takeaway
An allogeneic ASC-based cell therapy medicinal product showed no toxicity or tumorigenicity across doses up to 1000× the clinical dose, but failed to improve histological scores (median 2 vs 1, p=0.811) or load to failure (51.99 N vs 50.97 N, p=0.770) over vehicle control in a chronic rat rotator cuff repair model.
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Summary
This two-phase preclinical study evaluated an allogeneic adipose-derived MSC CTMP for rotator cuff repair augmentation: Phase I assessed safety in immunodeficient mice across doses from 10× to 1000× the clinical dose via IA and IV routes; Phase II tested efficacy in a validated 4-week chronic supraspinatus tear-and-repair rat model comparing ASC suspension to Hypothermosol vehicle. Phase I demonstrated no biochemical, histopathological, or tumorigenic toxicity, with human cell retention after IA injection at clinical dose limited to 21% of animals at 90 days and no systemic dissemination. Phase II showed no significant differences in any histological or biomechanical outcome between ASC and vehicle groups, with the authors citing cell retention failure, immune-mediated rejection, and mechanical displacement as likely explanatory mechanisms.
Key Limitation
The use of immunocompetent Sprague-Dawley rats for Phase II efficacy testing of allogeneic human ASCs introduces xenogeneic immune rejection as an uncontrolled confound that precludes definitive conclusions about intrinsic cell therapy efficacy.
Original Abstract
BACKGROUND
Cell therapy with adipose-derived mesenchymal stem cells (ASCs) is a promising biological augmentation strategy for rotator cuff repair; however, before clinical translation, regulatory frameworks mandate rigorous preclinical characterization of safety. We report the complete preclinical program evaluating both the safety of an allogeneic ASC-based cell therapy medicinal product (CTMP) and its efficacy in a chronic rotator cuff tear model.
METHODS
Phase I (safety, 164 immunodeficient nude BALB/c mice) assessed toxicity, biodistribution, and tumorigenicity after intra-articular (IA) and intravenous (IV) administration at doses ranging from 10× to 1000× the projected clinical dose. Toxicity was evaluated by biochemical panels and full-body histopathology at 90 days. Biodistribution was quantified by FDG-PET/CT (days 45 and 90) and human-specific qPCR (Alu-repeat) at 90 days. Tumorigenicity used an HT-29 positive-control model. Phase II (efficacy, 48 Sprague-Dawley rats) used a validated 4-week chronic supraspinatus tear-and-repair model; after repair, animals received ASCs in suspension (n=24) or Hypothermosol vehicle (n=24) and were assessed histologically (Åström-Rausing scale) and biomechanically (Instron 4411) at 4 months.
RESULTS
In Phase I, no biochemical or histopathological toxicity attributable to the CTMP was detected at any dose or route. Three animals showed FDG-PET findings compatible with neoplasm but were histologically negative, confirming assay specificity. qPCR detected strong human DNA signals exclusively at the highest IV doses (≥500×), limited to the injection site (tail) and one heart sample; maximum retention was 1.75% at 90 days. After IA administration at the clinical dose (10×), human ASCs persisted locally in 21% of animals at 90 days with no systemic dissemination. In Phase II, no statistically significant differences between groups were found in total histological score (median: 2 vs 1; p=0.811), any individual histological parameter, maximum load to failure (51.99±9.1 N vs 50.97±9.1 N; p=0.770), tendon displacement (5.33±1.2 mm vs 5.53±1.4 mm; p=0.852), or stiffness (17.28±4.96 N/mm vs 14.85±4.01 N/mm; p=0.669).
CONCLUSIONS
This allogeneic ASC-based CTMP demonstrated a favorable safety profile across all tested doses and administration routes, supporting its candidacy for clinical development. Efficacy in suspension delivery over a repaired chronic tear was not demonstrated; immune-mediated rejection and mechanical displacement represent additional explanatory factors alongside cell retention failure, and should guide the design of next-generation delivery strategies.