An Open Phase I/IIa Study Evaluating Safety, Patient-Reported Outcomes, and Voice Function After Surgery, Local Administration of Mesenchymal Stromal Cells, and Voice Training in Patients with Vocal Fold Scarring and Dysphonia

Abstract

Background: Damage to the vocal folds can result in scarring, leading to chronic, severe voice impairments for which lasting and effective treatments are currently lacking. The aim of this clinical trial was to evaluate the safety and effectiveness of autologous bone marrow-derived Mesenchymal Stromal Cell (MSC) therapy for patients with vocal fold scarring and severe dysphonia. Additionally, the study sought to propose a post-operative voice training protocol and explore its potential role in facilitating voice improvement. Methods: Eight patients with vocal fold scarring and chronic dysphonia underwent surgical scar resection and autologous MSC injection, followed by voice training. Safety was continuously monitored for up to 36 months postoperatively. Data to evaluate therapeutic efficacy was collected pre-treatment, 3 and 12 months post-treatment. Assessments included analysis of vocal fold vibrations, Phonation Threshold Pressure, and Maximum Phonation Time. Patient-reported measures were collected using the Voice Handicap Index, the Vocal Fatigue Index, and ratings of major symptoms and their impact on daily life. Treatment effectiveness was analyzed at both group and individual levels, with clinically relevant changes predefined. Results: No treatment-related side effects were reported within the 36 months of follow-up. Group-level analysis of the self-reported outcomes indicated positive treatment effects, with Voice Handicap Index scores reduced by −25.9 points (95% CI [−48, −3.6]) between pre-treatment and 12 months post-treatment. Group-level aerodynamic changes were small with Phonation Threshold Pressure showing a marginal positive change on average (−0.94 cmH₂O), as did Maximum Phonation Time (+0.2 s). At the individual level, clinically relevant improvements were observed in 63–88% of patients depending on the parameter analyzed. Three patients (38%) achieved relevant improvement on ≥5/6 selected parameters in combination. All participants in voice training reported reduced vocal strain following training. Conclusions: This preliminary, uncontrolled study indicates that local administration of autologous bone marrow-derived MSCs appears safe and is associated with clinically relevant patient-reported outcome improvements in a majority of patients. Larger, controlled trials are needed in the future to establish efficacy and possibly disentangle contributions of MSCs versus voice training. Trial registration: This clinical trial is registered in ClinicalTrials.gov (NCT04290182).

1. Introduction

The vocal folds comprise three main layers: the vocalis muscle, the lamina propria, and the epithelium. The epithelium and superficial lamina propria vibrate independently of the deeper layers and the vocalis muscle. Mechanical stress, environmental factors, and pathological conditions can impair vocal fold pliability, leading to a range of voice disorders [1, 2].

Injury or damage to the vocal folds can result in scarring, causing stiff tissue that restricts lamina propria vibration and pliability, impairs vocal fold closure, and disrupts the vertical glottal mucosal wave essential for voice production [3]. Known causes include surgery, radiation therapy, phonotrauma, congenital or acquired conditions, severe inflammation, and infections. Vocal fold scarring often leads to severe dysphonia, vocal strain, and vocal fatigue [4, 5].