Tissue Engineering for Human Urethral Reconstruction: Systematic Review of Recent Literature
February
Tissue Engineering for Human Urethral Reconstruction: Systematic Review of Recent Literature
Vincent de Kemp 0 1
Petra de Graaf 0 1
Joost O. Fledderus 0 1
J. L. H. Ruud Bosch 0 1
Laetitia M. O. de Kort 0 1
0 Academic Editor: Feng Zhao, Michigan Technological University , UNITED STATES
1 1 Department of Urology, University Medical Centre Utrecht , Utrecht , The Netherlands , 2 Department of Nephrology and Hypertension, University Medical Center Utrecht , Utrecht , The Netherlands
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Considerable experience is available with tissue engineering of urethral tissue in vitro,
produced with cells of different origin. Clinical and in vivo experiments show promising results.
Urethral reconstruction continues to be a challenging field for urologists. Whilst for some
conditions only one or few procedures are standard, over 300 techniques are known for urethral
stricture and hypospadias repair [1]. This diversity illustrates the complexity of these
conditions and also indicates the lack of one perfect procedure. In addition to the surgeons skill,
successful outcome of any procedure depends on the availability of appropriate tissue. A wide
variety of tissues such as (vascularized) skin grafts, bladder and buccal mucosa have been used
in urethral repair. However, all of these substitutes have limitations compared to the
autologous urethral tissue, which can lead to complications (e.g. stricture formation, graft failure).
Also, the amount of tissue that can be harvested from a donor site is limited; especially in the
case of long defects, this could pose a problem. To overcome these problems, alternative
materials for urethral reconstruction have been explored.
In the field of regenerative medicine, tissue engineering (TE) is defined as an
interdisciplinary field that applies the principles of engineering and life sciences toward the development of
biological substitutes that restore, maintain, or improve tissue function or a whole organ [2]. As
early as the 1980s the first steps were made in culturing urothelial cells (UC) [3]. Initially, these
cultures were used as an in vitro system to study the effects of exogenous substances on tissue.
When TE started to evolve, the aim of culturing tissues changed to the replacement of damaged
or absent organs. The rationale behind this latter strategy is that, with a limited amount of
material (e.g. a small biopsy), a larger graft of autologous cells can be created. Since cells are
autologous the problems with rejection are bypassed and, when implanted in vivo, the tissue
possesses properties similar to those of surrounding tissue.
The native male urethra (with a length of about 1820 cm) consists of three cell layers: the
urethral epithelium, fibroblasts, and smooth muscle cells (SMC). The epithelial lining changes
along the length of the urethra.
The urethra consists of three parts. The first short proximal segment is surrounded by the
prostate and is called the pars prostatica; this is lined with urothelium of the same type as that
of the bladder. The second very short segment (about 18 mm long) is called the pars
membranacea and extends from the apex of the prostate to the bulb of the corpus spongiosum penis; it
is lined with stratified or pseudostratified columnar epithelium. The third portion, called the
pars spongiosa, has a length of about 15 cm and is also lined with stratified or pseudostratified
columnar epithelium, but patches of stratified squamous epithelium are common in the pars
spongiosa. Stratified squamous epithelium is also found in the terminal widened part of the
canal that is surrounded by the glans penis.
The urethra is embedded in the corpus spongiosum, which is required for its blood supply.
Ideally, a tissue-engineered urethra mimics the native urethra, i.e. it consists of multiple cell
layers of different origin, protects the underlying tissue as an efficient barrier from urine, is
vascularized, and is resistant to mechanical forces during surgery.
Several cell types or tissues are of interest for reconstruction: i) urethral epithelial lining
(urothelium of [pseudo]stratified columnar epithelium) and SMC, because they form the most
important layers of the urethra, ii) buccal mucosa, as this is often used as a graft in
urethroplasties, iii) bladder urothelium, as this is easy to expand from small bladder biopsies or
can be grown from cells isolated either from bladder washings or urine, and iv) spongious or
cavernous tissue, as this surrounds the urethra. Stem cells from non-urologic tissue (such as
adipose tissue) are also under investigation because they are easier to obtain and have the capacity
to differentiate to urothelial and myogenic lineages.
In TE, the three main approaches for urethral repair are: reconstruction using only cultured
autologous cells, reconstruction using biomaterials (called scaffolds or matrices), and a
combination of both techniques using cell-seeded scaffolds. However, because cell-only constructs
are often (...truncated)