Mechanism of action behind the pain-relief effects of extracellular vesicles in microfragmented adipose tissue: an in vitro and in vivo study

Background: Trapeziometacarpal osteoarthritis (TMC OA) is a prevalent and debilitating condition that impairs hand functionality and reduces quality of life. Current treatments including conservative measures such as splinting and anti-inflammatory medications, as well as surgical interventions often exhibit limited efficacy or involve invasive procedures. Novel therapeutic approaches are necessary to address the pain and functional limitations experienced by affected patients. Methods: This study investigates the potential of extracellular vesicles (EVs) derived from autologous microfragmented adipose tissue (aMAT) as a minimally invasive treatment for TMC OA. EVs were characterized using morphological, proteomic, and functional analyses, revealing their ability to modulate cellular processes through proteins associated with extracellular matrix organization, wound healing, and inflammation regulation. Results: Functional studies demonstrated that EVs modulate calcium signaling and mitochondrial activity, enhancing cellular bioenergetics and mitigating inflammation-induced dysfunction. In a clinical study with 25 patients diagnosed with TMC OA (Eaton Stage II), aMAT-derived EVs demonstrated significant benefits. Pain scores, measured by the numeric rating scale, improved substantially both at rest and during activity. Functional assessments, including the Michigan Hand Outcomes Questionnaire and Kapandji opposition test, showed enhanced hand performance over 12 months. Strength tests indicated marked improvements in pinch grip, with no adverse effects or disease progression observed radiographically. Conclusions: The findings underscore the potential of aMAT-derived EVs as a novel, effective, and minimally invasive treatment for TMC OA, providing both pain relief and functional recovery. Further randomized trials are necessary to validate these results and investigate broader clinical applications. Trial registration: This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and adhered to all relevant national and institutional ethical guidelines for research involving human participants. Approval for the study was obtained from the Ethics Committee of Marche Region, protocol n. 154/2021. All participants provided written informed consent before enrollment in the study. They were informed about the study’s purpose, procedures, potential risks, and their right to withdraw at any time without consequences. Informed Patient Consent Statement: Informed consent was obtained from all individual participants included in the study, following the guidelines of the Human Research Approval Committee protocol number 2/2019.