Authors: Prof. Guido Barbagli, Dr. med. Gouya Ram-Liebig
Native oral mucosa is implanted since many years as graft for urethroplasty. However, its excision from the mouth may be associated with potential complications and morbidities at oral site. Early complications include pain, numbness, bleeding, and infection while longer-term complications comprise oral tightness and restriction of mouth opening as a result of scarring and contraction. The latter may be associated with difficulty to eat, drink, and speak. Perioral neurosensory defect is an additional potential morbidity because of the procedure’s proximity to the mental nerve. Therefore, efforts should take place to avoid oral mucosa excision for urethral reconstruction. Substitute grafts would avoid the complications, associated with oral mucosa excision in patients with urethal stricture. In this matter, a first progress has been made since first tissue engineered grafts were used, substituting oral mucosa in a little number of patients. The respective data have been published sporadically in the past in a small number of papers. However these early phase reports had either a very low success rate, or were not further used in patients and hence had low therapeutic relevance for the routine clinical use. I met Dr. Gouya Ram-Liebig in European Association of Urology congress 2009 in Stockholm and we planned to cooperate for developing an autologous tissue engineered graft for urethroplasty, obtained from a tiny oral mucosa biopsy. Since then, a lot of work has been done. In addition to numerous complex and detailed quality and non-clinical studies, we performed a multicenter prospective observational clinical trial. In our study, the functionality and safety of our product MukoCell, which is worldwide the first and only authorized tissue-engineered oral mucosa graft, was assessed under routine clinical practice. From eight German centres with heterogenous levels of urethroplasty experience, 99 heavily pretreated patients with urethral stricture were treated with our product and included in this study. The strictures were previously treated unsuccessfully by surgical treatments and were of any aetiology, location and severity, displaying the heterogenic national urethral stricture recurrence population. Primary outcome was success rate at 12 months as assessed by Kaplan-Meier analysis. Secondary outcomes included safety and success rate at 24 months. A Cox proportional hazard analysis was conducted to identify risk factors for stricture recurrence. Our data show the safety and efficacy of MukoCell, with success rate of over 85% in the hand of the skilled surgeon. Preoperatively, mean ± SD peak flow rate (PFR) was 8·3 ± 4·7 mL/s (n=57) which increased to 25·4 ± 14·7 mL/s (n=51) postoperatively. On multivariate analysis, timing of catheter removal and number of prior surgeries were identified as independent risk factors for stricture recurrence.
In our study, all but one patient had already a non-successful surgical pretreatment, 45.8% had even 2-3 and 31.1% had ≥4 surgical pretreaments. This points to the highly pretreated patient cohort. Patients with bulbar or penile strictures, who had one previous treatment had the high success rate of over 80%. One can assume, that if patients with no previous operations were also included, the success rate would be even higher.
Considering that longer strictures have a higher recurrence rate than shorter ones, the results of our study with 30.8% of the stricture lengths longer than 4 cm, make it clear that urethroplasty with our tissue-engineered graft is an efficient method for strictures of any length. This particularly brings hope for patients with longer strictures, who are urgently in need for an appropriate material.
From the data of our study, a MukoCell® drug registry was established, comprising worldwide the first monitored multicenter prospective real-world urethroplasty data. First part of our results has been published in the valuable Journal “Advanced Drug Delivery Review”. Recently, 2 years follow-up data of the treated patients is published in “eBiomedicine”, the leading open access forum for basic and clinical biomedical research, published in collaboration with “Cell Press” and “The Lancet”. Meanwhile, follow up data of up to 5 years are available. Current data from our observational trial are reported to the Paul-Ehrlich-Institut (the regulatory body in Germany, responsible for marketing authorization of advanced drug medicinal products and approval of clinical trials), as well as to the European Medicine Agency (the European Union agency for the evaluation of medicinal products).
Our study is of major importance in urology, because it is the first prospective multicenter study in urethroplasty, has the largest series of patients, is monitored and assessed by an independent clinical research organization and hence underwent severe analysis and interpretation. Our data have shown that use of a TEOMG for reconstruction of the short and long bulbar and penile urethra is feasible, safe, and efficacious in a heavily pre-treated population. The results of our study in a non-preselected cohort showed a satisfactory clinical outcome after 12 and 24 months in the majority of patients. We reached the good results although some of the investigators implanted our product as last therapeutic option in highly complex cases with multiple previous unsuccessful surgical treatments. By the use of MukoCell, complications associated with the excision of large oral mucosa segments were avoided.
MukoCell is an autologous tissue-engineered graft, with a standardized and authorized manufacturing process. The product is authorized and on the market for years already in Germany and is used by different hospitals. It answers the patients‘ need to avoid the oral harvesting and associated complications.
Up to now, published urethroplasty results with native oral mucosa are restricted to mostly selective, retrospective and non-monitored data from one single specialized center, analyzed by the center itself (data with evidence level 3-4). Our results are prospective, multicenter (specialized and non-specialized clinics), monitored and analyzed by a licensed Clinical Research Organisation (data with evidence level 2a). Therefore, in our published articles we did not compare our results with reports from the literature, because the comparison of data of 2 different levels of evidence is not appropriate. In fact, level 2a data undergo more severe control analyses as level 3-4.
Unlike what has been published until today in the surgical treatment of urethral strictures, the results of our study represent for the first-time real world data, reflecting the use and results of urethroplasty in clinics with different levels of experience in urethroplasty in non-selectioned patients with urethal stricture recurrence. In this matter, we have shown that high levels of urethroplasty experience, as well as different post-surgical management are important factors for the success of urethroplasty. In this matter, the success rate ranged between 0% in a less experienced to 85.7% in a more experienced centre.
Our study has proven, that the concept of urethral reconstruction with an autologous tissue-engineered graft is safe and efficient and could open a route for application to the treatment of paediatric patients with hypospadias.
Finally, the positive results and the high quality of our data with highest level of evidence (2a) worldwide show that urethroplasty with MukoCell represents a new milestone in the treatment of urethral stricture. This is now the time to change.
Dr. med. Gouya Ram-Liebig
Telefon: +49 (0)231 97 42 63 70