Urethral stricture disease is a common health problem amongst men in Western countries, often leading to an impaired quality of life. The current prevalence in industrialized countries is estimated at 1% of the male population. Current treatment options comprise both endoscopic and open surgical procedures. Endoscopic procedures show a high recurrence rate, varying from 60 to 80 percent. Although the success rate of open surgery is estimated somewhat higher (around 65 percent), this procedure is much more invasive with more burden. Over the years, many studies have evaluated the effectiveness of additional (local) therapies to improve the endoscopic success rate. Still, these additional methods are not included in clinical practice or the current treatment guidelines. This study aims to provide a systemic overview of the local therapy options in the treatment of urethral stricture disease and to analyze efficacy in preventing stricture formation or recurrence.

A literature search was performed in the PubMed and Embase databases restricted to the last 30 years and the English language. Search terms included: "Urethral Stricture" OR "urethra" OR "urothelium") AND ("Wound Healing" OR regeneration OR prevention OR "stricture formation"). The title and abstract screen was independently performed by two authors and the full text screen by three authors. Articles were excluded based on the written language (I), the paper format (II), the main outcome (III) or the use of systemic therapy as an intervention (IV).

The literature search yielded a total of 3724 articles. After the removal of duplicates, 3244 articles were included in the title and abstract screen. The full text screen was performed on a total of 57 articles, leading to 23 papers eligible for inclusion in the qualitative analysis (13 animal studies, 10 human clinical trials). Regarding the animal studies, local treatment with mitomycin-C (n=2 studies), adipose derived stem cells (ADSC’s) (n=2), a liquid buccal mucosal graft (n=1), halofuginone (n=2), rapamycin (n=1), docetaxel (n=1), metalloproteinase-I (n=1), collagenase clostridium histolyticum (n=1), dexpanthanol (n=1) and a honey solution (n=1) showed to have beneficial effects on one or more different outcomes. In 5/13 studies, urethral stricture formation was used as an outcome; histological analysis was performed in 11/13 studies and molecular and/or genetic expression was studied in 5/13 articles. 
In human studies, mitomycin-C (n=3 studies), steroids (n=5), captopril (n=1) and hyaluronic acid/carboxymethylcellulose (n=1) showed to be effective as a local therapy to prevent the occurrence or recurrence of urethral strictures. In 7/10 studies, local therapy was applied directly after the urethrotomy, in 6/7 studies the context of a randomized controlled trial,  using either mitomycin-C, triamcinolone or methylprednisolone as an additional intervention. A beneficial effect of additional prednisolone application was shown in the context of a non-randomized controlled trial. Using a different application method, hyaluronic acid/carboxymethylcellulose was applied once as instillation after a transurethral resection of the prostate (TURP), also as a randomized controlled trial. In the experimental group, urethral stricture formation was decreased after 24 weeks, measured by both uroflowmetry and urethrography. Furthermore, as an experimental clinical trial, clobetasol cream was applied twice a day for 2-3 months in biopsy proven lichen sclerosis patients. Successful management was defined as no subsequent therapy escalation during the first 2 to 3 months on the protocol, which resulted in a success rate of 89.3% at an average follow-up time of 24.8 months. Finally, daily use of captopril gel for one week, followed by treatment every other day for 2 to 3 weeks and subsequent twice a week for 4 to 6 weeks showed a beneficial effect on the recurrence or development of urethral strictures in a clinical phase II trial. In all studies, no significant adverse side effects were observed. In total, 712 male patients were enrolled in these studies.

Based on these studies, the use of (additional) local therapy in endoscopic treatment of urethral strictures to prevent occurrence or recurrence seems to be effective in both animal studies and (randomized) clinical trials.  Limitations of these results are the heterogeneity of the studied populations (both animals and human), the heterogeneity of the types of intervention as well as the difference in outcome measures. The risk of bias in these studies is under investigation.

Additional pharmacological local therapy in endoscopic treatment of urethral stricture seems to be effective. Before this treatment can be considered to be implemented in the current treatment guidelines, larger clinical trials using standardized dosages of pharmaceutical agents need to be performed.