To investigate the safety and feasibility of a tissue-regenerative approach to treat stress urinary incontinence (SUI) in female patients with a novel transurethral injection therapy using autologous muscle precursor cells (MPCs) in a combination with neuro-muscular electromagnetic stimulation (NMES).

We conducted a prospective and randomized clinical trial using ultrasound-guided injections of autologous MPCs into the external urinary sphincter (EUS) muscle of female patients with SUI to assess the safety and feasibility of this therapy. Main inclusion criteria were female gender, age 20–60 years and clinical diagnosis of SUI grade ≥I since at least 6 months. Exclusion criteria were a history of anti-incontinence or prolapse surgery, urgency urinary incontinence due to urodynamically proven detrusor instability, history of urogenital cancer or pelvic radiotherapy, pregnancy or <12 months post-partum or an unstable systemic, neurological or genetically determined muscular disease. Standardized 1h pad test, incontinence and quality of life questionnaires (ICIQ), urodynamic studies, and MRI of the pelvis were performed at baseline and follow-up visits. MPCs were gained through an open surgical biopsy from the Soleus muscle of the lower limb. A muscle specimen ≥200mg was then transported in biopsy medium to the GMP facility for processing and cell expansion. Eighty to 100 x 106 cells were re-suspended in collagen solution for injection of the final product. The cooled (2-8°C) final product was then implanted with 8-12 injections under ultrasound guidance in the EUS using a Bard needle (20cm, 18G). After the injection, the study nurse unveiled the randomisation to the two treatment groups of either MPCs alone (Group A) or MPCs + NMES (Group B). NMES included two sessions per week for 20 minutes for 6 weeks (total of 12 sessions) on a BioCon-2000WTM chair (Marly Products, Germany). Follow-up visits were arranged at the first or second postoperative day and thereafter 1, 3 and 6 months after the injection. To analyse the safety and feasibility of our therapy, primary outcome was defined as any adverse event (AE) during the follow-up period. Secondary outcomes were 1h pad test, bladder capacity, functional urethral length (resting and stress profiles), urethral pressure profiles (resting and under stress), ICIQ questionnaires to evaluate quality of life, and the change in sphincter diameter in the follow-up MRI of the pelvis at 6 months. Paired Wilcoxon signed-rank test was used to compare medians between baseline and follow-up visits. Statistical significance was regarded as p < 0.05.

Ten female patients were included in the study, of which 9 received treatment and completed all follow-up visits during the study period between 01/2020 and 09/2021. Patients had SUI grade ≥I, a median age of 45 years (range: 32-58 y) and a median BMI of 24 kg/m2 (range 21.0-29.4 kg/m2). After MPC injection, patients were subsequently randomized either into Group A (n=5) or Group B (n=4). Eight adverse events (AEs) were registered, of which 2 (25%) were potentially related to the treatment. One urinary tract infection (UTI) was diagnosed three weeks after injection of MPC and was successfully treated with a single dose of oral Fosfomycin. Dysuria as of burning micturition was treated conservatively in one further patient. No severe AEs (SAEs) were registered. Median urethral closure pressure was 79 cmH2O at baseline compared to 71 cmH2O at 6 months follow-up (95% CI: -9 to 28.5, p = 0.859). Median functional urethral length (FUL) under stress was significantly shorter with 25 mm at baseline compared to 30mm at 6 months follow-up (95% CI: 2.5 to 7, p = 0.009). Median maximum bladder capacity was 610ml at baseline and 670ml at follow-up (95% CI: -45 to 140, p = 0.343). QoL questionnaires showed an improvement ICIQ-scores from median 7 points at baseline to median 4 points at 6 months follow-up (95% CI: -7 to -2.5, p-value = 0.035). The evaluation of MRI of the pelvis revealed no evidence of aberrant tissue formation or necrosis. Diameter of EUS muscle was measured with a median of 1.8 mm at baseline and 1.9 mm at follow-up (95% CI: 0.10 to 0.25, p = 0.009).

Our analysis demonstrated an objective improvement of the median FUL under stress in the urodynamic study 6 months after injection of autologous MPCs into the EUS muscle. Further, the subjective QoL improved with a lower median ICIQ-score 6 months after the intervention. However, these results need to be interpreted with caution since this was a phase I trial investigating safety and feasibility solely. Efficacy and durability of the treatment needs to be confirmed with larger patient cohorts and longer follow-ups in particularly designed and powered phase II and III trials.

The transurethral ultrasound-guided injection of autologous MPCs into the EUS muscle for the treatment of SUI in female patients can be regarded as safe and feasible. Only a minimal number of expected AEs were documented, and all AEs were well-treatable and healed without sequelae. No severe or unexpected AEs were diagnosed.

Continence 2S2 (2022) 100341
DOI: 10.1016/j.cont.2022.100341