Long-term safety and efficacy of treating symptomatic, partial-thickness rotator cuff tears with fresh, uncultured, unmodified, autologous, adipose-derived regenerative cells isolated at the point of care: 41 months follow-up of a prospective, randomized, controlled, first-in-human clinical trial

Background Symptomatic, partial-thickness rotator cuff tears (sPTRCT) are problematic. Management of sPTRCT with fresh, uncultured, unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs) isolated from lipoaspirate at the point of care is safe and leads to improved shoulder function without adverse effects. This study tested the hypothesis that management of sPTRCT with injection of UA-ADRCs is safe and more effective than injection of corticosteroid even in the long run. Methods Subjects who had completed a former randomized controlled trial were enrolled in the present study. At baseline these subjects had not responded to physical therapy treatments for at least six weeks, and were randomly assigned to receive either a single injection of an average 11.4 × 106 UA-ADRCs (n = 11) or a single injection of 80 mg of methylprednisolone (n = 5). Safety was assessed by rigorously documenting and evaluating treatment emergent adverse events. As per protocol efficacy was assessed using the ASES Total score, RAND Short Form-36 Health Survey (SF-36) Total score and VAS pain score at 24 weeks (W24) and W52 post-treatment as well as at 33.2 ± 1.0 (mean ± standard deviation) months (M33) and 40.6 ± 1.9 months (M41) post-treatment. Magnetic resonance imaging (MRI) of the index shoulder was performed at baseline, W24, W52, M33 and M41 post-treatment. Results There were no greater risks connected with injection of UA-ADRCs than those connected with injection of corticosteroid. Injection of UA-ADRCs resulted in significantly higher mean ASES Total scores at W24, W52 and M41, a significantly higher mean SF-36 Total score at W24, and significantly higher mean VAS Pain scores at W24 and W52 post-treatment than injection of corticosteroid (p<0.05). Treatment outcome could not be assessed using measurements of tear volume on MRI scans. On the other hand, MRI scans at W24 post-treatment allowed to “watch the UA-ADRCs at work”. There was no relationship between treatment outcome and baseline data, including those data characterizing UA-ADRCs that can be collected with a clinical test. Conclusions The present study further supports management of sPTRCT with injection of UA-ADRCs. Trial registration [Clinicaltrials.gov][1] [NCT04077190][2] (September 4, 2019). ### Competing Interest Statement Christopher Alt is Director of Medical and Scientific Affairs of InGeneron, Inc. (Houston, TX, USA). Eckhard U. Alt is Executive Chair of InGeneron. Christoph Schmitz is Advisory Medical Director of InGeneron. However, InGeneron had no role in study design, data collection and analysis, interpretation of the data, and no role in the decision to publish and write this manuscript. No other potential conflicts of interest relevant to this article were reported ### Clinical Trial NCT04077190 ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: WIRB Copernicus Group, Inc. (Olympia, WA, USA) gave ethical approval for this work for study site Sanford USD Medical Center, Sioux Falls, SD, USA on July 23, 2019, and for study site Sanford Orthopedic Sports Medicine Clinic, Fargo, ND, USA on September 29, 29 (IRB Tracking Number: 20191931). The present study received Investigational Device Exemption (IDE) from the U.S. Food and Drug Administration (FDA) on May 13, 2019 (no. 16956). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04077190&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F06%2F2022.12.14.22283447.atom