Tubularized urethral reconstruction using everted saphenous vein graft in a beagle model

Abstract

Background
A long segment stricture in the anterior urethra is a challenge in urology. We conducted a study to investigate the efficacy of anterior urethral reconstruction using an everted saphenous vein graft (SVG) in a tubular fashion.

Methods
Twelve male beagles were randomly divided into three groups: experimental group (n = 5), control group (n = 5) and normal group (n = 2). A 3 cm defect in the anterior urethra was created. Autologous SVG was harvested. In the experimental group, urethral defect was replaced by an everted SVG in a tubular fashion. In the control group, urethral reconstruction was performed using an uneverted SVG. Beagles in all groups received retrograde urethrography to evaluate urethral patency and were killed for histological examination 6 months after operation.

Results
Four beagles in the experimental group had no voiding difficulty and the other one could not void spontaneously. Retrograde urethrography showed the four beagles in experimental group had wide urethral lumens. Ether urethral stricture or fistula were detected in all animals in the control group. Histological analysis of the four beagles in the experimental group indicated the everted SVG completely integrated into the urethra. The reconstructed urethra contained a wide lumen and was completely covered by urothelium. The periurethral collagen and muscle fibers formed and were highly organized. Everted SVG showed a high ability of neovascularization. In the control group, the reconstructed segment showed a fibrotic urethral lumen where the urothelium was not intact. Only few new capillaries were formed.

Conclusions
Everted SVG demonstrates for a promising strategy for potential urethral stricture repair.

Full text

Lietal. BMC Urol (2021) 21:63
https://doi.org/10.1186/s12894-021-00833-4
RESEARCH ARTICLE
Tubularized urethral reconstruction using
everted saphenous vein graft inabeagle model
Dan Li1, Zhou Shen2 and Yujie Xu3*
Abstract
Background: A long segment stricture in the anterior urethra is a challenge in urology. We conducted a study to
investigate the efficacy of anterior urethral reconstruction using an everted saphenous vein graft (SVG) in a tubular
fashion.
Methods: Twelve male beagles were randomly divided into three groups: experimental group (n = 5), control group
(n = 5) and normal group (n = 2). A 3 cm defect in the anterior urethra was created. Autologous SVG was harvested.
In the experimental group, urethral defect was replaced by an everted SVG in a tubular fashion. In the control group,
urethral reconstruction was performed using an uneverted SVG. Beagles in all groups received retrograde urethrogra-
phy to evaluate urethral patency and were killed for histological examination 6 months after operation.
Results: Four beagles in the experimental group had no voiding difficulty and the other one could not void sponta-
neously. Retrograde urethrography showed the four beagles in experimental group had wide urethral lumens. Ether
urethral stricture or fistula were detected in all animals in the control group. Histological analysis of the four beagles in
the experimental group indicated the everted SVG completely integrated into the urethra. The reconstructed urethra
contained a wide lumen and was completely covered by urothelium. The periurethral collagen and muscle fibers
formed and were highly organized. Everted SVG showed a high ability of neovascularization. In the control group, the
reconstructed segment showed a fibrotic urethral lumen where the urothelium was not intact. Only few new capillar-
ies were formed.
Conclusions: Everted SVG demonstrates for a promising strategy for potential urethral stricture repair.
Keywords: Urethral stricture, Saphenous vein graft, Urethral reconstruction, Tubularized urethroplasty
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Background
Adult and pediatric disorders of the urethra including
hypospadias, trauma, and stricture require substituted
urethroplasty to preserve the function of the urinary
tract. Reconstruction of the anterior urethra is one of the
most challenging problems in urology [1].
Autologous tissues have advantages of excellent bio-
logical compatibility as well as rapid and effective
neovascularization. Oral mucosa and penile skin flap are
preferred substituted materials for urethral reconstruc-
tion [2, 3]. Onlay urethroplasty and multi-stage repair
are commonly used techniques [4]. In some cases, these
methods have problems including stricture recurrence,
fistula formation and inadequate donor material. Har-
vesting oral mucosa is associated with donor site mor-
bidity, such as submucosal scarring, pain, numbness and
injury to salivary ducts [5, 6]. ese issues highlight a
critical need for the development of alternative material
and reconstructive strategies for anterior urethral repair.
e saphenous vein is commonly used as vascular
substitute material. It is easily harvested, and its associ-
ated wound complications were not dramatic, including
Open Access
*Correspondence: xyj_1213@126.com
3 Department of Urology, The First Affiliated Hospital of Wannan Medical
College (Yijishan Hospital of Wannan Medical College), 2 Zheshan West
Road, Wuhu 241000, Anhui Province, China
Full list of author information is available at the end of the article
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Lietal. BMC Urol (2021) 21:63
chronic pain, numbnes and paresthesia/dysesthesia [7].
We previously performed urethroplasty in a rabbit model
using everted SVG as an onlay graft and gained encour-
aging results [8]. e inner wall of blood vessels consist
of vascular endothelium. We hypothesized that everting
vein graft makes the outside vascular endothelium cling
to periurethral tissue. In turn, the endothelium quickly
attracts blood supply from the surrounding periurethral
tissues including dartos. Here, we compare differences
in neovascularization between everted SVG and non-
everted SVG.
In addition, saphenous vein has a similar caliber as
the urethra in humans. Even though tubularized grafts
have not shown to be a preferential form of substitu-
tion, it avoids multi-stage surgery of ventral and dorsal
onlay urethroplasty. Whether everted SVG can be used
for tubularized urethraplasty remains unkown. us, we
performed anterior urethral reconstruction in a beagle
model using everted SVG in the tubular form.
Methods
Urethroplasty using everted SVG
is experimental animal protocol was approved by the
Animal Experimentation Ethics Committee of Wannan
Medical College in accordance with the Guide for the
Care and Use of Laboratory Animals. Twelve male bea-
gle dogs (Animal Research Center of Wannan Medical
College. Wuhu, China) weighing 8–10kg were randomly
divided into three groups: experimental group (n = 5),
control group (n = 5) and normal group (n = 2).
After general anesthesia with 3% pentobarbital, the
beagles in the experimental group and control group
were placed on an operating table in supine position. e
right thigh and genital organ were shaved and prepared
with povidone-iodine solution. A 4-cm incision was per-
formed on the ventral skin of penis. A 3cm segment of
anterior urethra was removed between the external ure-
thral orifice and bulbar urethra, in order to make a ure-
thral defect (Fig.1a).
A 4-cm incision was carried out on the right thigh skin
and a 3-cm SVG was excised (Fig. 1b). In the experi-
mental group, the vein grafts were everted like taking off
sleeves,without longitudinally cutting the venous wall,
(in order to make the endothelium outside) (Fig.1c). A
8 F catheter was inserted into the urethra and was used
as a stent (Fig.1d). Urethral defect was repaired by the
everted SVG in tubular fashion with 6–0 vicryl separated
sutures (Fig.1e). In the control group, the urethral defect
was repaired using uneverted SVG in the same fashion.
Nonabsorbable sutures were placed at the anastomosis
margins for mark. Muscular tissue around the recon-
structed urethra and the skin incision in penis was closed
in layers (Fig.1f). In the normal group, no surgical inter-
vention was performed. e procedures for all animals
were performed under sterile conditions by the same
surgeon.
Fig. 1 Anterior urethral reconstruction with SVG. a A segment of anterior urethra was separated. b A 3-cm SVG was harvested. c The SVG was
everted in experimental group. d The urethral catheter was inserted as a stent. e The urethral defect was repaired by SVG in tubular fashion. f The
subdermal layer in penis and the skin was closed
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Lietal. BMC Urol (2021) 21:63
Postoperative care
An Elizabetan collar was placed around the neck of ani-
mal to prevent the catheter removal. e catheter was left
indwelling for two weeks. All animals in the experimental
group and control group received penicillin 100U/kg/day
intramuscularly for 14days.
Retrograde urethrography
Retrograde urethrography was performed every month
after operation. After general anesthesia, the animals
were placed obliquely on an examination table. A Foley
(6-F) catheter was inserted into the urethra until the
balloon entered the urethral orifice. Inflate the balloon
with 1ml sterilized water. X-ray images of urethra were
obtained under the fluoroscopy after contrast agent was
gently injected through the catheter.
Histological andimmunohistochemical analysis
Animals were euthanized by an overdose of 3% pento-
barbital and air embolization 6 months after opera-
tion. e penises were obtained and the segments of
the reconstructed urethra were extracted within the
area outlined by the marking sutures. ese segments
were placed in 10% formalin, dehydrated in graded alco-
hols, and then embedded in paraffin. Sections (5mm)
were cut and then stained with hematoxylin–eosin
(HE) staining, Masson’s trichrome(MT) staining, and
immunohistochemical(IHC) staining using CD-31 and
uroplakin-II(UP-II) antibodies.
IHC staining using CD-31 antibody were quantified to
compare neovascularization of the grafts using ImageJ
software, in 10 different fields for each tissue sample.
Data for these measurements are shown as mean ± SD.
Statistical analysis was performed using a t-test through
SPSS®, with p < 0.05 was considered as statistically
significant.
Radiologists and pathologists were blinded to the group
when they were evaluating.
Results
e surgical procedures were successfully performed on
all beagles. ere were no major intraoperative compli-
cations observed. During the 6months follow-up period,
four beagles in the experimental group showed no void-
ing difficulty and the other one could not spontaneously
void. Two beagles in control group could not sponta-
neously void and they underwent cystostomy with a
suprapubic catheter. Urogenic cutaneous fistula in penis
was detected in the other three animals in control group.
Retrograde urethrography
e retrograde urethrograms showed the urethral caliber
of four beagles in the experimental group were similar
to that of normal beagles (Fig.2a, b). e contrast agent
freely passed through the urethra without any signs of
stricture or contrast leak. ese indicate that the four
beagles in the experimental group maintained wide ure-
thral lumen 6 months postoperatively. e one beagle
in the experimental group could not void spontaneously
developed urethral stenosis. Ether significant urethral
stricture or fistula were detected in all animals in control
group (Fig.2c, d).
Histological andIHC examination
In the experimental group, HE staining indicated the ure-
thral lumen of the reconstructed segment was completely
covered by the urothelium (Fig.3e). ere was no obvi-
ous difference observed in the normal urethra (Fig.3a).
MT staining showed highly organized collagen fibers and
muscle tissue in the reconstructed urethra, but the mus-
cle tissue seemed to be less than what was present in the
normal urethra (Fig.3b, f). e UP-II antibody is a spe-
cial urothelium marker. IHC staining with UP-II antibody
showed positive expression in the urethral inner wall
(Fig.3g).
In the control group, the reconstructed segment
showed a narrow urethral lumen and the urothelium was
not intact (Fig.3i). MT staining showed abundant colla-
gen with strong blue staining, indicating severe fibrosis
Fig. 2 Retrograde urethrography. a Urethrogram in beagle in normal group. b Urethrogram in experimental group 6 months postoperatively. c
Urethral fistula in control group (red arrow point to the contrast leak). d Urethral stricture in control group (red arrow point to the stricture)
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Lietal. BMC Urol (2021) 21:63
6 months postoperatively (Fig. 3j). IHC staining with
UP-II antibody revealed a fragment of urothelium in the
urethral inner wall (Fig.3k).
IHC staining using a CD31 antibody was performed to
observe the neovascularization of implanted tissue. In the
experimental group, IHC staining with a CD31 antibody
showed newly formed dense capillaries after 6months
(Fig.3h). In the control group, IHC staining using a CD31
antibody indicated sparse vascular capillaries (Fig. 3l).
Histomorphometric analysis found that the number of
newly formed capillaries in the experimental group was
higher than the control group (56.90 ± 1.57 vessels/mm2
vs 40.30 ± 1.06vessels/mm2, p < 0.01) (Fig.4).
Discussion
Various urethral conditions often require substitute ure-
thral reconstruction including long-segment urethral
strictures, traumatic defects, complicated hypospadias
and previous failed urethroplasty [9]. Several substituted
materials have been adopted for clinical urethroplasty,
including full-thickness skin graft, bladder mucosa, oral
mucosa (buccal or lingual mucosa) and colonic mucosa
[10–12]. Buccal mucosa and preputial skin graft remain
the widely used tissues for urethral replacement. How-
ever, there are associated complications, such as graft
necrosis, hair growth, stricture recurrence, and fis-
tula formation [13, 14]. In addition, harvesting buccal
mucosa may also lead to possible morbidities such as
intraoperative hemorrhage, submucosal scarring, pain,
postoperative infection, and injury to salivary ducts [3,
15]. Wood etal. [16] reported the morbidity of buccal
mucosa grafts harvested for urethroplasty in 57 patients.
Of these patients, 68% had perioral numbness that per-
sisted after 6months in 26% of the patients, 83% devel-
oped postoperative pain, 67% initially had difficulty with
mouth opening that persisted after 6months in 9% of the
Fig. 3 Histological and IHC analysis. a–d HE staining, MT staining, IHC staining with UP-II and CD31 antibodies of the reconstructed urethra in
normal group. e Wide urethral lumen was completely covered by endothelium in experimental group. f MT staining showed highly organized
collagen fibers and muscle tissue in subepithelium. g IHC staining with UP-II antibody showed expression of uroplakin in the endothelium. h IHC
staining with the CD31 showed dense capillaries in subepithelium. i HE staining showed a narrow urethral lumen and urothelium defect in control
group. j MT staining showed fibrosis with abundant collagen. k IHC staining with the UP-II revealed a fragment of urothelium. l Vascular capillaries
were sparse in control group
Fig. 4 Histomorphometric analysis of the extent of CD31 + vessels
present in the 3 groups. ※Signifificant difference among the
experimental and control groups (P < .01)
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Lietal. BMC Urol (2021) 21:63
patients, and 2% had a mucous retention cyst. When ure-
thral defects are complex, donor tissue extracted from
oral cavity or prepuce may be insufficient. For these rea-
sons, many attempts have been made to select alternative
tissues that can serve as adequate urethral substitutes.
Tissue engineering may be a promising option for the
generation of an artificial urethra. However, accompa-
nied techniques are complex containing multi-steps and
the results of preliminary clinical applications are not sat-
isfactory [17, 18]. Up to now, tissue engineered urethra is
mainly being performed in animal experiments and has
not made its way to the clinic [19].
Tuffer et al. performed urethral reconstruction using
vein graft for the first time in 1910 [14]. Subsequently,
several animal trials have been reported using vein grafts
for urethral reconstruction [20–22]. Kahveci et al. [20]
suggested that a vein graft mainly acts as a scaffold and
the endothelium sloughs off after 3days. Hubner etal.
[22] and Foroutan et al. [23] used everted vein grafts
and showed improved outcomes. ey believed their
modified technique eliminated negative effects on urine
stream from the valve inside the venous lumen. We pre-
viously performed urethroplasty in a rabbit model with
saphenous vein patch as onlay graft and gained encour-
aging results [8]. Results of everted vs non-everted vein
grafts showed more optimal results with the everted
graft.
To the best of our knowledge, one of the key factors
in reconstructing urethra is adequate blood supply and
fast neovascularization of the implanted graft [24, 25].
Insufficient blood supply inevitably results in shrinkage
of grafts and the formation of fibrosis. In the study, the
saphenous vein was everted and the vascular endothe-
lium became outside. We hypothesized that everting the
vein graft making the vascular endothelium on the out-
side facilitates the everted SVG blood supply gain from
surrounding periurethral tissues including dartos. In this
study, IHC staining with CD31 antibody showed dense
vascular capillaries in the experimental group. Histomor-
phometric analysis demonstrated that compared to non-
everted SVG, everting the vein graft improved its ability
of neovascularization.
ere is a lack of studies investigating one-stage
reconstruction using a tubularized graft. Even though
tubularized grafts have not proven to be a preferential
substitution, they avoid multi-stage surgery of ventral
combined dorsal onlay urethroplasty. e saphenous
vein is a hollow tubular structure with a similar diam-
eter of the urethra. e saphenous vein is readily acces-
sible, even for the most extensive urethral reconstruction.
Adult male beagles were selected as our experimental
model because the urinary tract in beagle resemble the
urinary tract in human. Foroutan etal. [23] performed
histological study after euthanizing rabbits 7, 10, 14,
22, and 30days after operation, they found that gradual
uroepithelialization occurred within one month and
demonstrated that the vein graft functioned as a guide
for uroepithelium migration. e histological examina-
tion in our previous experiment revealed similar results
[8]. e everted vein graft showed full integration in the
neourethra. Urethral lumen was completely covered by
regenerative uroepithelium 6 months postoperatively.
Fistula formation and stenosis at the anastomosis were
noted in the animals of control group. e experimental
group showed improvement over the control group both
in retrograde urethrography and histologic analysis. e
MT staining showed that well-formed collagen and mus-
cle fibers in the experimental group. However, abundant
collagen fiber, narrow urethral lumen and urothelium
defect were observed in control group. e rapid survival
of the implant graft contributed to its function, serving
as a barrier against urine extravasation, as well as facili-
tating urothelium cell migration and proliferation in the
newly formed urethral tissue [26].
In this study, we create urethral defect models in the
healthy urethra of normal animals and cannot fully
resemble the exact clinical situation of urethral stricture
in humans, which is characterized by the fibrotic urethra
bed. Other limitations of this study includeasmallsam-
ple size and a short follow-up time. Further investiga-
tions with longer follow-up time are necessary to assess
its technical applicability and to translate this technology
into clinic.
Conclusion
We first used the everted SVG for tubularized urethral
reconstruction in a beagle model. In our study, 80% of
the experimental beagles showed no voiding difficulty
or urethral fistula. e animals showed wide urethral
lumen during the observation period. Everted SVG dem-
onstrates promise for anterior urethral stricture repair.
is study provides preclinical evidence and information
needed to move toward clinical studies of this technique.
Abbreviations
SVG: Saphenous vein graft; HE: Hematoxylin–eosin; MT: Masson’s trichrome;
IHC: Immunohistochemical; UP-II: Uroplakin-II.
Acknowledgements
Not applicable
Authors’ contributions
Protocol/project development: YX. Data collection or management: DL, ZS.
Manuscript writing/editing: YX, DL. All Authors read and approved the final
manuscript.
Funding
No funding or support received for this work.
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The datasets used and/or analysed during the current study available from the
corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The beagles in this research were acquired from the Animal Research Center
of Wannan Medical College. Ethics approval was taken from Animal Experi-
mentation Ethics committee of Wannan Medical College in accordance with
the ARRIVE guidelines for reporting animal research.
Consent for publication
Not applicable.
Competing interests
The authors report no conflicts of interest.
Author details
1 Department of General Practice, The First Affiliated Hospital of Wannan
Medical College (Yijishan Hospital of Wannan Medical College), Wuhu 241000,
China. 2 Department of Urology, Anhui Provincial Hospital, Anhui Medical
University, Hefei, Anhui, China. 3 Department of Urology, The First Affiliated
Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical Col-
lege), 2 Zheshan West Road, Wuhu 241000, Anhui Province, China.
Received: 12 September 2020 Accepted: 12 April 2021
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