EURURO Vol. 72 No. 4

Introduction

Congenital birth defects of the urethra, such as hypospadias

(1 in every 300 births)

[1,2]

, and acquired urethral

abnormalities, such as urethral strictures (1 in every

1000 men

65 yr of age

[3] )

, represent major clinical

entities. Treatment usually involves a surgical procedure

with risk of (recurrence of) strictures or fistula requiring

additional care or reintervention. Whenever possible, local

tissue flaps or stricture resection in combination with end-

to-end anastomosis are used for urethra reconstruction

[4,5]

. Generally, two surgical approaches exist for urethral

reconstruction: partial replacements using onlay or inlay

techniques or the full circumferential procedure, which is

used in rare cases with significant urethral scarring or lichen

sclerosis. Depending on patient and local factors, proce-

dures can be performed as one-stage procedure or as

planned multistage procedure

[3] .

Autologous tissue transplantation such as buccal mucosa

or free skin grafts are the standard treatments

[6–9] .

However, due to the limited quantity of available donor

tissue, accompanying donor site morbidity (16–32% for

buccal mucosa grafts) and complications (eg, recurrences or

infections), alternative treatment options are needed to

improve long-term outcomes

[10]

. Tissue engineering may

overcome some of the aforementioned disadvantages by

providing a temporary template to guide tissue regenera-

tion

[11]

. In general, tissue engineered templates include

decellularized tissue or de-novo prepared materials from

natural or synthetic origin

[12–14]

. Templates can be

seeded with (stem) cells from the patient prior to

implantation. These cells may stimulate tissue remodeling

by excreting cytokines and growth factors and contributing

to cellular population of the template

[15,16]

Despite the potential of tissue engineering shown in in

vitro research and preclinical studies, clinical translation is

limited. To improve translation, an evidence-based ap-

proach, such as systematic reviews, can be applied when

designing new tissue engineering strategies. This will avoid

unnecessary replication of studies and will help to select the

most optimal experimental design and model. We are the

first to perform a comprehensive systematic review of

evidence for the efficacy of urethral tissue engineering in

preclinical and clinical studies. A meta-analysis was used to

compare different experimental designs based on clinically

relevant outcomes. This systematic review aims to improve

the translation of urethral tissue engineering from bench to

bedside.

Evidence acquisition

2.1.

Literature search

To identify all available studies on urethral tissue engineer-

ing published and indexed up until June 1, 2016, a systematic

search strategy was applied in PubMed (Supplementary data

1) and Embase (via OvidSP; Supplementary data 2). This

strategy combined a tissue engineering search component

containing synonyms for tissue engineering related terms

[17]

with a customized search component for urethra or

urethra-related diseases. Medical Subject Headings terms

and EMTREE terms were used in PubMed and Embase,

respectively, together with separate words or word combi-

nations in title or abstract. Next, either an animal filter

[18]

or de Vries et al

(Embase)

[19]

was applied (Supplementary data 1 and 2,

search component 3A) or a custom filter for clinical studies

(Supplementary data 1 and 2, search component 3B). In

addition, retrieved reviews were screened for primary

studies not found using the search strategy. Clinical studies

found during animal search strategy were marked and

screened for relevance and vice versa.

2.2.

Study selection

Duplicates in retrieved articles were removed in EndNote

(Version X7.2, Thomson Reuters, PA, USA). Studies were

assessed independently by LV and PdJ. First, clearly

irrelevant studies were excluded based on title. Next, titles

and abstracts of the remaining articles were screened for

relevance in Early Review Organizing Software (Buenos

Aires, Argentina,

www.eros-systematic-review.org

) using

the following exclusion criteria: (1) no urethra, (2) no tissue

engineering, (3) no animals or patient, (4) no primary study.

A study was considered to be about tissue engineering when

a processed template was used. Studies on tissue trans-

plants or reconstructive surgery without the use of a

template or without a urethra defect were excluded. Of

the remaining studies, full texts were screened using the

same exclusion criteria. Articles not available as full text

were excluded at this stage. No language restrictions were

applied in the screening phase. If necessary, Google

translate was used. Retrieved studies from search updates

were directly screened in Endnote according to the same

principles. In all stages of the selection process, discrepan-

cies between reviewers were discussed until consensus was

reached.

2.3.

Study characteristics

From all included studies, general information (author,

year) and study characteristics (age range of patients,

animal species, sex, surgical procedure, type of biomaterial,

type of cells) were extracted and listed in

Table 1

for

preclinical studies and

Table 2

for clinical studies. For

languages other than English, German, and French, Google

Translate was used to retrieve study characteristics.

2.4.

Extraction outcome data

Three outcome measures were used to evaluate study

outcome: (1) incidence of side effects, for example,

strictures, stenosis, fistulae, and infections, (2) functionality,

defined as the ability to void with continence, and (3)

study completion, for animals defined as survival until

predetermined endpoint and for clinical studies as

available for follow-up or no additional urethroplasty

required. Only English, German, and French studies were

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