About 1% of the male population suffers from strictures of the urethra, discover the breakthrough in tissue engineering with MukoCell.
Utilising tissue engineering, the product was established to be used as graft for urethroplasty in patients with urethral stricture.
Regenerative medicine for the plastic reconstruction of morbidly constricted urethras versus transplantation of large pieces of mucosa excised from the patients’ mouth is subject to comparison in a prospective randomised clinical trial.
About 1% of the male population suffers from strictures of the urethra. Patients are chronically ill, with severely diminished quality of life, suffering from low urinary flow, pain, chronic urinary infections, urinary stones, urinary reflux, and urinary damage and failure. If untreated, life-threatening urinary retention can occur.
Urethrotomy, an endoscopic procedure in which the urethra at the narrowed site is dilated by a longitudinal incision, usually leads to an improvement of the clinical picture only in the short term. If repeated, the success rate and duration to relapse will shorten and be reduced to zero after the third surgery.
Plastic reconstruction of the urethra, urethroplasty, is an open procedure with much better prospects. Based on literature data, for native oral mucosa as a transplant, the relapse rate is estimated at 30%.
For this purpose large segments of mucosa from the mouth of the patients are excised and transplanted to the urethra, causing multiple intraoral short- and long-term injuries with a significant impact on patients’ quality of life, e.g. intraoral pain, sensory loss and oral numbness, impaired lip mobility, impacted mouth opening, drinking, eating and speaking, permanent salivation, intraoral scarring and chronic oral ulcers, increased loss of teeth and implants, facial deformities, diminished facial expressions, and, in the long term, increased risk of oral cancer development.
According to literature, long-term oral complications after one year are lying in the range of about 20%. Due to this, urethroplasty has not become standard but a niche therapy. Only a minority of operative urologists carry out this procedure.
MukoCell®: a breakthrough in tissue engineering
MukoCell is a new therapeutic option, a breakthrough in tissue engineering. The product was developed to be used as graft for urethroplasty in patients with urethral stricture, while replacing native oral mucosa excision and hence avoiding complications associated with the harvest of native oral mucosa segments. MukoCell consists of oral mucosa cells obtained from a tiny piece of oral mucosa biopsy from the patient.
The biopsy, which is taken by the treating physician, is sent to a laboratory with legal authorisation for production of medicinal products. After aseptic cultivation and proliferation in designated and qualified clean rooms the cells are seeded on a resorbable carrier membrane.
The whole process has a duration of three weeks and is performed in strict compliance with the pharmaceutic principles of good manufacturing practices. Before product release, each batch is tested to ensure uniform, high quality. MukoCell is sent back to the clinic, ready to use as a transplant.
Learn about the evidence base
Efficacy and safety of MukoCell has been shown in different non-clinical and clinical studies. In a prospective multi-centre non-interventional clinical study with 99 patients suffering from urethral strictures,1 patients with comparatively unfavourable therapy prognoses were included, who in most cases had more than one previously performed unsuccessful surgical pre-treatment.
Complex, penile and longer strictures were included, factors known to be unfavourable to treatment success. Efficacy of MukoCell showed to be in a range comparable to the efficacy of native oral mucosa, as reported in literature. Safety exhibited to be distinctively superior to native oral mucosa, especially at the oral harvest site. No adverse events related to MukoCell have yet been reported.
In a long-term assessment at a median of 55 months’ follow-up, the safety, feasibility and efficacy of MukoCell in urethra reconstruction of 38 patients was satisfactory. 95% of the patients had undergone previous failed treatments. 32 out of 38 patients (84%) were successful. No local or systemic adverse reactions due to the use of engineered material were registered.
MukoCell was used in 65 patients having recurrent long urethral strictures with a medium length of 5.3cm and a mean of 2.6 previous endoscopic or anastomotic treatments.3
Location of the strictures in 35 cases was bulbar, which usually gives better results with traditional urethroplasty. In the other 30 patients the penile or membranous parts of the urethras were involved. In summary, this patient population is more difficult to treat due to the length and localisation of the strictures and the relatively high number of previous treatments. After a mean follow-up of 12.1 months, 82.5% were successful.
Only 12 patients developed a recurrence of the stricture, seven of them with bulbar localisation. No adverse reactions related to MukoCell were observed. For comparison, the long-term success rate of native oral mucosa according to literature is about 70%;4 however, the patient has to tolerate complications associated with the excision of large grafts from the oral mucosa.
MukoCell as alternative to native oral mucosa
Actually, to obtain reimbursement from health insurances, and in preparation of application of market authorisation by the European Medicines Agency (EMA) within the whole European Community, and by Swissmedic for Switzerland, a pivotal Phase III study will be conducted to scientifically evaluate safety and efficacy of MukoCell in comparison to native oral mucosa as a graft in urethral strictures. The study aims to unambiguously show that MukoCell is highly superior to native oral mucosa as a transplant in respect to safety in terms of complication rates at the graft harvest site, and equivalent in efficacy.
Since the conduct of such a study is expensive, MukoCell – as a young, small enterprise – has successfully been striving to receive an EU grant for the conduct of this clinical trial. The MukoCell study will have a comparatively high evidence level due to the sophisticated prospective design. Patients will be randomly assigned to one of the two treatment groups. Data monitoring and evaluation will be performed independently by a clinical research organisation.
In contrast, the efficacy and safety of native oral mucosa established as a transplant for urethroplasty is not nearly matched by today’s standards for clinical trials. Until today there are no controlled clinical trials. Relevant publications are usually based on retrospective evaluations of cases selected from certain points of view in order to optimise the publication result, without quality assurance measures and without independent monitoring. The risk of bias in this data is very high and the level of evidence is therefore very low.
The multicentre study is being conducted at renowned clinics in Germany, Switzerland and Italy, including the world’s leading Center for Reconstructive Urethral Surgery in Arezzo. The planned 200 patients will be recruited over a period of one and a half years. The main parameters for the comparison of the two therapies will be success rates in terms of recurrence rates and long-term damage in the mouth over a total assessment period of up to 24 months after urethroplasty, with a first evaluation after 12 months.
Expected outcomes of tissue engineering
Once MukoCell has proven to be superior to the native oral mucosa, this will allow for approval of one of the first tissue engineering products in the European sector. MukoCell will then be available for treatment of all patients with urethral stricture.
This will lead to the avoidance of the extensive removal of mucosa and complications and pain from the patient’s oral cavity. Physical integrity will be respected, and patients will not be considered as providers of gratis grafts because an appropriate alternative will be available.
At this time, there are many patients for whom there is no graft available for urethroplasty, patients who reject oral mucosal excision, particularly those for whom native oral mucosa is either not available or its excision would cause damages, e.g. patients with long urethral strictures, disturbed wound healing (e.g. diabetes patients), patients with a tendency to increased scar formation or with pre-existing oral mucosal damage, e.g. after previous removal of oral mucosa, patients with dentures or the risk of premature tooth loss, and furthermore patients standing in public life, for whom oral complications and impairment of physiognomy would be unacceptable due to the impact on job or social function, e.g. teachers, politicians, sales people or entertainers.
These patients are urgently in need of an appropriate graft like MukoCell. To help these patients, but also all patients with urethral stricture, MukoCell GmbH will immediately apply for market authorisation within the EC and Switzerland after evaluation of the clinical study. According to schedule, MukoCell will be available on the European market from 2022.
- Ram-Liebig G et al. EBioMedicine 2017;23:185–192
- Barbagli G et al. Urology 2018;199:e636
- Karapanos L et al. Abstract from AUA Congress in Chicago, 2019
- Yuri P et al. Acta Med Indones-Indones. J Intern Med 2016;48(1):17-27
Please note, this article will appear in issue 9 of Health Europa Quarterly, which will be available to read in April 2019.