Tissue engineering as a potential

alternative or adjunct to surgical

reconstruction in treating pelvic organ
prolapse
M.Boennelycke, S.Gras & G.Lose

International Urogynecology Journal

Including Pelvic Floor Dysfunction
ISSN 0937-3462
Int Urogynecol J
DOI 10.1007/s00192-012-1927-4

1 23

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Int Urogynecol J
DOI 10.1007/s00192-012-1927-4

ORIGINAL ARTICLE

Tissue engineering as a potential alternative or adjunct

to surgical reconstruction in treating pelvic organ prolapse
M. Boennelycke & S. Gras & G. Lose

Received: 13 July 2012 / Accepted: 11 August 2012

# The International Urogynecological Association 2012

Abstract
Introduction and hypothesis Cell-based tissue engineering
strategies could potentially provide attractive alternatives to
surgical reconstruction of native tissue or the use of surgical
implants in treating pelvic organ prolapse (POP).
Methods Based on a search in PubMed, this review focuses
on candidate cell types, scaffolds, and trophic factors used in
studies examining cell-based tissue engineering strategies to
treat POP, stress urinary incontinence (SUI), and the closely
related field of hernias.
Results In contrast to the field of SUI, the use of cell-based
tissue engineering strategies to treat POP are very sparsely
explored, and only preclinical studies exist.
Conclusion The available evidence suggests that the use of
autologous muscle-derived cells, fibroblasts, or mesenchymal stem cells seeded on biocompatible, degradable, and
potentially growth-promoting scaffolds could be an alternative to surgical reconstruction of native tissue or the use of
conventional implants in treating POP. However, the vagina
is a complex organ with great demands of functionality, and
the perfect match of scaffold, cell, and trophic factor has yet
to be found and tested in preclinical studies. Important
issues such as safety and economy must also be addressed
before this approach is ready for clinical studies.
Keywords Cell-based . Tissue engineering . Pelvic organ
prolapse . Stem cells

M. Boennelycke : S. Gras (*) : G. Lose

Department of Obstetrics and Gynecology,
Copenhagen University Hospital,
Herlev, Denmark
e-mail: s.gras@dadlnet.dk

Abbreviations
POP
Pelvic organ prolapse
SUI
Stress urinary incontinence
PP
Polypropylene
MDSC Muscle-derived stem cells
SIS
Small intestine submucosa
MPEG Methoxy-poly-ethylene-glycol
PLGA Polylactic-co-glycolic acid
PGA
Poly-glycolic acid
MSC
Mesenchymal stem cells
BMSC Bone marrow mesenchymal stem cells
ADSC Adipose-tissue-derived stem cells

Introduction
To improve the outcome of surgical treatment for pelvic organ
prolapse (POP), increasing numbers and types of surgical
implants have been launched over the last decade. Primarily,
permanent synthetic implants but also biodegradable synthetic
implants or biological products derived from animals
(xenografts) or cadavers (allografts) have been marketed. Evidence of efficacy for these products is lacking [1], and rates of
complications such as erosions, pain, infections, and vaginal
shrinkage [25] are unacceptably high at around 10 % [6].
Permanent synthetic meshes made of polypropylene (PP)
have dominated the market, and despite attempts to increase
biocompatibility for these products [7], problems still exist
[8]. Biodegradable meshes (synthetic or biological) appear
to be less harmful, but their long-term effects are undetermined, and evidence indicates that biodegradable mesh
materials over time do not generate sufficiently strong new
tissue [914]. Clearly, new concepts are needed, and tissue

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engineering, an emerging field in regenerative medicine,

could provide attractive alternatives alone or as an adjunct
to surgical reconstruction procedures [1518].

Regenerative medicine, tissue engineering,

and cell-based therapy
Regenerative medicine is an interdisciplinary field that aims
at replacing or regenerating human cells, tissues or organs to
restore or establish normal function [19]. A variety of biomedical approaches, such as the use of stem or progenitor
cells (cell-based therapies), regeneration induction by biologically active molecules, or transplantation of in vitro
grown organs and tissues are used. Cells are preferably
autologous in origin. They can be freshly isolated or cultured in vitro for injection purposes, or they can be cultured
with other cell types, bioactive agents, and/or scaffolds to
create tissues or organs for transplantation. The latter is
generally referred to as tissue engineering, and typical
examples are the creation and transplantation of a neovagina
in rabbits [20] or a neourethra in humans [21].

Regenerative medicine in urogynecology

In urogynecology, researchers and clinicians have focused
on cell-based injection therapy to regenerate the urethral
sphincter for treating stress urinary incontinence (SUI). Several preclinical studies in various animal models have been
published and a number of clinical trials have been conducted or are ongoing [22, 23]. The majority of these studies
used autologous muscle-derived stem or progenitor cells
cultured in vitro and injected into the urethral sphincter.
The animal studies demonstrate that cells survive injection
and that a repair process resembling the normal regenerative
process in skeletal muscles is initiated. New innervated myofibers are formed, and smooth muscle cells, loose interstitial
tissue, and vessels may also form. Functional tests on isolated
urethral tissue support the findings, and urodynamic measurements in intact animals demonstrate that they become continent. Results from a number of clinical studies involving
approximately 500 patients are less convincing, and longterm results are lacking. Nevertheless, 2050 % of patients
become continent, which is comparable with the effect of
conventional urethral bulking agents, and importantly, only
minor complications have been observed [22, 23].
The potential use of cell-based tissue engineering strategies to treat POP appears to be more intricate. The vagina is
a complex organ with great demands of functionality, and
parameters such as strength and elasticity of the native tissue
vary interpersonally [24]. Furthermore, the pathological
anatomy of POP dictates that a simple injection of cells to

regenerate damaged vaginal tissue is not feasible. Most

mammalian cells are anchorage dependent and will die if
no cell-adhesion substrate is available. A biodegradable
scaffold provides such a three-dimensional substrate in
which cells can be delivered at high loading efficiency,
grow, and form new tissue. A biodegradable scaffold will,
in addition, provide temporary mechanical support to the
weakened supportive tissues of the pelvic floor, and as the
scaffold gradually disappears, it will allow cells to grow and
provide permanent support either directly by generating new
tissue from transplanted cells or indirectly by paracrine
stimulation of resident-tissue stem cells.
The idea of using cell-based strategies to treat POP has been
very sparsely explored in preclinical experiments [2527], and
no published or ongoing clinical studies have been identified
(www.clinicaltrials.gov and www.clinicaltrialsregister.eu).
The field of reconstructive surgery for hernias is, however,
closely related to that of POP [28, 29], and a number of tissue
engineering approaches have already been explored in this
field [3040]. In addition, biological properties of new or
modified implants for use as reinforcement during surgical
treatment of POP are usually tested in vivo in laboratory
animal hernia models [29]. A few studies also used a cellbased tissue engineering strategy to create a midurethral sling
for treating SUI [41, 42].
Based on the combined experiences in these areas, the
following sections focus on candidate cell types, scaffolds,
and trophic factors for cell-based POP therapy.

Candidate cell types

Skeletal-muscle-derived cells
The first to introduce the idea of cell-based therapy for treating
POP were Ho et al., who succeeded in stimulating vaginal
repair in a rat model. They used murine skeletal-musclederived stem cells (MDSC) cultured in vitro and seeded on
scaffolds made from acellular porcine small intestine submucosa (SIS) [25]. Skeletal muscle is easily accessible, and
different populations of muscle-derived stem or progenitor
cells cultured in vitro have previously been used successfully
for myofascial hernia repair in experimental studies [30,
3237, 39, 40]. Striated muscle is not inherent to the vaginal
wall, but Ho et al. demonstrated that the MDSC differentiated
into smooth muscle cells when implanted in the rat vagina,
which could have important implications for the use of such
cells in POP surgery in humans [25]. Whether this finding was
the result of true transdifferentiation of multipotent muscle
stem cells or was caused by heterogeneity of the transplanted
cell population is still unclear.
The use of stem or progenitor cells cultured in vitro is time
demanding, expensive, and subject to strict and increasing

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regulatory demands [22]. As a more economically favorable

and clinically relevant alternative, Boennelycke et al. used
fresh muscle fiber fragments seeded on synthetic biodegradable methoxy polyethylene glycol-polylactide-co-glycolic
acid (MPEG-PLGA) scaffolds implanted subcutaneously on
the abdomen of rats. After 8 weeks, new striated muscle was
created and the scaffolds had disappeared [26]. Muscle stem
cells (satellite cells) located on the freshly isolated fibers most
probably were responsible for the new tissue generation.
Whether such an approach can be applied to treating POP
remains to be clarified, but isolated autologous muscle or
muscle fragments have been used by others to treat SUI [43]
and abdominal hernias [39] in animal studies.

collagen hybrid mesh [38]. Dolce et al. demonstrated that

BMSC grow well on a PGA mesh and that the cell coating
induced improved biocompatibility by decreasing intraabdominal adhesion formation in rats [49]. Kunisaki et al.
demonstrated that mesenchymal amniocytes seeded on a composite biological mesh made of acellular human dermis, SIS,
and collagen were superior to fetal myoblasts for diaphragmatic hernia reconstruction in neonatal lambs [34]. MSC are
multipotent and may differentiate into various lineages, such
as bone, cartilage, adipocytes, tendon, ligament, and smooth
muscle. The differentiation process is driven by the microenvironment at the implant site. In this way, autologous MSC,
and in particular the easyily accessible ADSC, could be ideal
for POP repair.

Fibroblasts
Another strategy was employed by Hung et al., who used
human vaginal fibroblasts cultured in vitro and seeded on
synthetic biodegradable PLGA scaffolds. They were
implanted subcutaneously on the back of mice, and the
authors demonstrated that a tissue-engineered fascia equivalent was created [27]. The fibroelastic smooth muscular
tissue of the vaginal wall and its supporting tissue contain
many fibroblasts, and the idea of using autologous vaginal
cells for POP repair seems obvious but may in the end fail
due to the observed abnormal molecular and cellular mechanisms in the vaginal tissue in this disorder [44]. Fibroblasts
have also been used in an attempt to improve biocompatibility of implanted meshes. Human fibroblasts cultured in
vitro from the vagina, the foreskin, and the buccal membrane have been seeded on various PP and biological
meshes to provide a biological coating at the interface
between mesh and tissue. Seeding efficiency on PP meshes
in general is poor compared with biological meshes, but no
in vivo experiments have been performed [4547]. Drewa et
al., on the other hand, used 3 T3 mouse fibroblasts cultured
in vitro and seeded on a biodegradable synthetic polyglycolic acid (PGA) scaffold and used them successfully
to repair abdominal-wall defects in mice [31].
Mesenchymal stem cells
Mesenchymal stem cells (MSC) are easily isolated and amplified from bone marrow (BMSC) or adipose tissue [adiposederived stem cells (ADSC)] and have been widely used in
many medical fields to repair and regenerate damaged tissue
[17, 18]. In urogynecology, both BMSC and ADSC have been
injected for urethral sphincter repair of SUI in animal studies
[22, 48], and Zou et al. succeeded in treating SUI following
sciatic nerve section in rats by implanting a suburethral sling
engineered by BMSC seeded on a biodegradable knitted silk
sling [42]. Urita et al. successfully treated rats with diaphragmatic hernias using BMSC seeded on a biodegradable PLGA/

Candidate scaffolds
Three types of biomaterials are normally used as scaffolds for
tissue engineering purposes [18] and have also been explored
in cell-based therapies aimed at treating POP, SUI, and
hernias:
1. Naturally derived materials (e.g., collagen and silk)
2. Biological, acellular tissue matrices (e.g., SIS and
dermis)
3. Synthetic polymers (e.g., PP, PGA, PLGA, and MPEGPLGA)
Ideally, a scaffold must be biocompatible. Widely used
permanent synthetic biomaterials such as PP have limited
biocompatibility despite numerous attempts to alter physical
properties, such as weaving, pore size, weight, and coating
[7]. Naturally derived biodegradable materials and acellular
tissue matrices in general have excellent biocompatibility
and growth-promoting abilities, which make them interesting candidates for tissue engineering approaches. However,
for all biological materials derived from animals or humans,
drawbacks such as limited availability, high cost, variable
host tissue response, and concerns for disease transmission,
exist [50]. Synthetic biodegradable biomaterials, on the
other hand, are attractive alternatives that can be manufactured under controlled circumstances and at a low cost [17,
18]. Degradation time can be altered and optimized for
tissue regeneration, and the biomechanical properties of
the material can be engineered to mimic normal biomechanics of the pelvic floor [24, 51]. The ideal scaffold for a cellbased POP treatment has yet to be defined. In this context, it
is tempting to recall that fresh autografts of fascia lata or
rectus fascia have been used successfully in reconstructive
POP surgery or as suburethral slings for SUI treatment.
Although originally conceived otherwise, these approaches
in many ways mimic tissue engineering strategies. Fresh

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autologous fascia tissue provides three-dimensional structure, support, regenerative cells, and biocompatibility, as
evidenced by the effects and safety of these treatments
[5256].

abnormal in POP [44]. Facilitated endogenous repair with

local gene transfer could be useful in these patients as a
causal treatment to correct the abnormalities.

Discussion
Trophic factors
Cell-based tissue engineering therapy may benefit from the
addition of bioactive molecules to the cell scaffold complex.
This could enhance regenerative processes by initiating
pathways for activation and recruitment of transplanted,
resident, or circulating stem cells [57, 58]. Acellular tissue
matrices such as SIS consist of extracellular matrix and
therefore already contain a variety of growth factors, including basic fibroblast growth factor and transforming growth
factor-, as well as several glycosaminoglycans and other
molecules of the extracellular matrix known to influence
cell and tissue growth [59, 60].
Animal and clinical studies show that estrogens play a
role in maintaining vaginal and pelvic floor supportive
tissue [6165] by influencing fibroblast proliferation and
collagen synthesis [66]. The importance of estrogen status
in the development of POP is, however, controversial. Neither positive nor negative effects of estrogen enrichment of a
MPEG-PLGA scaffold without cells were found in a rat
abdominal model [67], but a different outcome in the vagina
cannot be excluded. Takacs et al. showed that estrogen and
the selective estrogen receptor modifier, levormeloxifene,
promoted growth of vaginal smooth muscle cells but
inhibited production of elastin in vitro [68]. This might
explain the high rate of POP observed in a recent clinical
study examining the effect of levormeloxifene on osteoporosis. The study was aborted after 10 months for that reason
and other unexpected gynecological side effects [69]. Further controversy has emerged as Manodoro et al. found that
estrogen increased resistance to deformation of mesh augmented repair but reduced tensile strength in native tissue
repair in rats [70].
Nerve growth factor enrichment of injectable PLGA
microspheres and concomitant injection of ADSC improved
urinary sphincter function in an SUI rat model [48], and this
concept could be translated to treating POP, since PLGA
may also be processed into a mesh (Vicryl).
As new and safe procedures are emerging, gene transfer
therapy may also be added to the tissue engineering approach, as demonstrated in orthopedic research by the healing of osteochondral defects using plasmids for bone
morphogenetic protein [58]. In POP, imaging techniques
reveal that some patients have large muscular pelvic floor
defects [71, 72], and surgical techniques used currently do
not repair these defects. In addition, accumulating evidence
suggests that the metabolism of the vaginal tissue is

The idea of using cell-based tissue engineering strategies to

treat POP is entirely new in urogynecology. The need for a
new treatment method is obvious, but so far, only limited
preclinical evidence exists to support the idea. Evidence
from the closely related field of reconstructive hernia surgery seems to provide some proof of concept in animal
models, but pelvic floor tissues and anatomy are complex
and entirely different from the abdominal wall. The perfect
match of scaffold, cell, and trophic factor has yet to be
found, and important issues such as economy and safety
must also be addressed before this approach is ready for
everyday urogynecological practice.
Unfortunately, a perfect POP animal model does not exist
[29, 73]. Some nonhuman primates, such as the rhesus macaque or the squirrel monkey, develop POP spontaneously,
but increasing public awareness has led to virtually banning
them as experimental animals, at least in Europe. Knockout
mice with defective extracellular matrix proteins (such as lysyl
oxidase-like 1 protein or fibulin-5) also develop POP, but their
size puts a limit to the character of surgical experiments. The
vagina of normal laboratory animals, such as rats, rabbits, and
sheep, reacts differently to that of the human vagina to mesh
implantation. Vaginal erosion rates of >50 % are reported in
these animals, and although extrapolation is difficult, exploration of new treatment strategies involving any type of scaffold/mesh must rely on other animal models, such as the
abdominal defect models in rats or rabbits [28].
Traditionally, cell-based tissue engineering strategies employ in vitro expanded cells, but several problems are inherent
in this approach: The long-term risks of using in-vitroexpanded cells are unknown, and as POP is a nonlethal
condition, serious complications are not acceptable. To enter
widespread clinical use, a technology must also be cost effective and suitable for easy and expedient clinical application. In
vitro laboratory procedures are time consuming and extremely
costly as yet. The rapid development of the regulatory environment for cell-based therapies will raise the costs even
further. In addition, enzymatic processing and in vitro culturing is unnecessary and may even adversely affect the regenerative potential of muscle progenitor cells [7476].
Alternative, clinically relevant, safe, and cost-effective
approaches are highly demanded. The fresh muscle fiber
fragment approach described earlier [26] is an example of
such an approach. Minimal transplant manipulation is needed, which minimizes potential risks, regulatory demands,
and costs. Figure 1 illustrates the fundamental differences

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Fig. 1 Fundamental
differences in the processing of
fresh, noncultured muscle fibers
with associated stem cells
versus cells cultured in vitro for
use in treating pelvic organ
prolapse (POP) or stress urinary
incontinence (SUI). The traditional approach using cells expanded in vitro is demonstrated
on the right side. A proposed
alternative approach using fresh
muscle fibre fragments is demonstrated to the left

in processing fresh, noncultured muscle fibers with associated

stem cells versus in vitro-cultured cells. New studies are
needed to establish the fate and function of newly created
tissue following implantation of fresh muscle fiber fragments
or other types of fragmented tissue in the vaginal wall.
Consensus papers from the 2nd International Urogynecological Association (IUGA) Grafts Roundtable emphasize
the importance of considering safety issues when developing new concepts in treating POP [77]. Regulatory demands
for medical implants are limited, but a more strict regulation
is anticipated. Suggested minimum standards for new medical devices in POP surgery have already been presented by
urogynecologists [29]. They will apply to cell-based tissue
engineering concepts as a minimum; however, with the use
of cells expanded in vitro and/or trophic factors, the treatment will be categorized as an advanced therapy medicinal
product, and the regulatory demands will increase accordingly even further.

In conclusion, new concepts are needed to treat POP.

Cell-based tissue engineering with autologous cells seeded
on a biocompatible, degradable, and potentially growthpromoting scaffold could be an alternative to the use of
conventional implants or an adjunct to surgical reconstruction of native tissue. So far, only limited evidence exists, and
additional animal studies are imperative before this approach is ready for clinical use.

Funding This study was supported by the Danish National

Advanced Technology Foundation

Conflicts of interest M Boennelycke: None

S Gras: None
G Lose: Receives research support and/or works as a consultant for
Contura, Phizer, Astellas and Johnson & Johnson.

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