EURURO Vol. 72 No. 4

605 656

one or more previous treatments, for example, dilation,
urethrotomy, or urethroplasty, before attempting the tissue
engineered constructs. The requirement of animal models
with injury or disease has been shown in other fields
and should also be considered in tissue engineering, in this
particular situation by inducing strictures.
Clinical studies provided a low level of evidence due to
their setup, making the true effect of tissue engineering as
surrogate for the current standard treatment unclear. Only
El-Kassaby et al ) performed a small randomized
controlled study. To improve the level of evidence, more
randomized controlled studies are needed, preferably with
larger numbers of patients and longer follow-up. Compared
with the preclinical studies, reporting of important
parameters was much better, notably regarding drop-outs
and adverse events. Nevertheless, to further improve the
quality of the clinical studies, the study protocol should be
published with the manuscript and a detailed description of
patient inclusion criteria (eg, sex, age, and medical history)
should be provided.
The level of evidence is further limited by original
research’s susceptibility to publication bias which may
lead to overestimation of the treatment effect in preclinical
studies. Recognition of this bias may partly explain the poor
translation of tissue engineering techniques to the clinic.
Furthermore, preclinical studies should better support
the clinical need: the majority of preclinical studies involves
full circumferential repair, where clinicians mainly perform
inlay repair . This may be explained by preclinical
researchers attempting to prove the effectiveness of the
experimental treatment for the most problematic (circum-
ferential) procedures, assuming that it will also be effective
in less complicated (inlay) approaches.
Finally, inclusion of cells remains challenging in a
clinical setting as no beneficial effect was seen (in
11 patients), even though this significantly improved
preclinical outcome. It is possible that inclusion of cells
was perceived as too problematic, despite better results in a
preclinical setting and that in the final assessment the
choice was driven by parameters other than preclinical
outcome. To consider cells for clinical applications, its
efficacy has to be proven as the use of cells involves
extensive regulatory requirements which may hamper
clinical application . In addition, the costs of
cellular implants will be higher compared with off-the-
shelf acellular implants, since two procedures are needed
(cell harvesting in urine or biopsy, and urethroplasty) and
in vitro cell expansion may be needed
5. Conclusions
The efficacy of tissue engineering for urethra repair could
not be determined due to a lack of controlled (pre)clinical
studies. However, meta-analysis outcomes (side effects,
functionality, and study completion) were comparable to
current treatment options described in literature, indicating
the potential of tissue engineering for urethra repair. The
findings of this systematic review may result in improved
study design which may aid the translation of tissue
engineered urethras to the clinic as an alternative for
autografts.
Author contributions: Willeke F. Daamen had full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Versteegden, de Jonge, van Kuppevelt,
Oosterwijk, Feitz, de Vries, Daamen.
Acquisition of data: Versteegden, de Jonge.
Analysis and interpretation of data: Versteegden, de Jonge, IntHout, de
Vries, Daamen.
Drafting of the manuscript: Versteegden, de Jonge.
Critical revision of the manuscript for important intellectual content:
IntHout, van Kuppevelt, Oosterwijk, Feitz, de Vries, Daamen.
Statistical analysis: IntHout.
Obtaining funding: van Kuppevelt, Oosterwijk, Feitz, Daamen.
Administrative, technical, or material support: None.
Supervision: van Kuppevelt, Oosterwijk, Feitz, de Vries, Daamen.
Other: None.
Financial disclosures: Willeke F. Daamen certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: PIDON (NovioTissue Project), a
combined subsidiary program of the Dutch Ministry of Economic Affairs,
and the states of Gelderland and Overijssel (PID101020).
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
.
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