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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

Journal Including Pelvic Floor Dysfunction ISSN 0937-3462 Int Urogynecol J DOI 10.1007/s00192-012-1927-4 123
Journal Including Pelvic Floor Dysfunction ISSN 0937-3462 Int Urogynecol J DOI 10.1007/s00192-012-1927-4 123

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

ORIGINAL ARTICLE

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 mesenchy- mal stem cells seeded on biocompatible, degradable, and potentially growth-promoting scaffolds could be an alterna- tive 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

MSC

BMSC Bone marrow mesenchymal stem cells ADSC Adipose-tissue-derived stem cells

Poly-glycolic acid Mesenchymal 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. Evi- dence 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 undeter- mined, and evidence indicates that biodegradable mesh materials over time do not generate sufficiently strong new tissue [ 9 14 ]. Clearly, new concepts are needed, and tissue

over time do not generate sufficiently strong new tissue [ 9 – 14 ]. Clearly, new

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engineering, an emerging field in regenerative medicine, could provide attractive alternatives alone or as an adjunct to surgical reconstruction procedures [ 15 18 ].

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 bio- medical approaches, such as the use of stem or progenitor cells (cell-based therapies), regeneration induction by bio- logically active molecules, o r transplantation of in vitro grown organs and tissues are used. Cells are preferably autologous in origin. They can be freshly isolated or cul- tured 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). Sev- eral preclinical studies in various animal models have been published and a number of clinical trials have been con- ducted 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 myo- fibers 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 measure- ments in intact animals demonstrate that they become conti- nent. Results from a number of clinical studies involving approximately 500 patients are less convincing, and long- term 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 strate- gies 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

anatomy of POP dictates that a simple injection of cells to regenerate damaged vaginal tissue is

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 cell- based 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-muscle- derived stem cells (MDSC) cultured in vitro and seeded on scaffolds made from acellular porcine small intestine submu- cosa (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 biodegrad- able 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.

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 equiv- alent 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 mech- anisms in the vaginal tissue in this disorder [ 44 ]. Fibroblasts have also been used in an attempt to improve biocompati- bility of implanted meshes. Human fibroblasts cultured in vitro from the vagina, the foreskin, and the buccal mem- brane 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 [ 45 47 ]. Drewa et al., on the other hand, used 3 T3 mouse fibroblasts cultured in vitro and seeded on a biodegradable synthetic poly- glycolic 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 am- plified from bone marrow (BMSC) or adipose tissue [adipose- derived 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 diaphrag- matic hernias using BMSC seeded on a biodegradable PLGA/

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 intra- abdominal adhesion formation in rats [49]. Kunisaki et al. demonstrated that mesenchymal amniocytes seeded on a com- posite biological mesh made of acellular human dermis, SIS, and collagen were superior to fetal myoblasts for diaphrag- matic 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 microen- vironment at the implant site. In this way, autologous MSC, and in particular the easyily accessible ADSC, could be ideal for POP repair.

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 MPEG- PLGA)

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 interest- ing 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 manufac- tured 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 biomechan- ics of the pelvic floor [ 24 , 51 ]. The ideal scaffold for a cell- based 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

Although originally conceived otherwise, these approaches in many ways mimic tissue engineering strategies. Fresh

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autologous fascia tissue provides three-dimensional struc- ture, support, regenerative cells, and biocompatibility, as evidenced by the effects and safety of these treatments

[ 52 56 ].

Trophic factors

Cell-based tissue engineering therapy may benefit from the addition of bioactive molecules to the cell scaffold complex. This could enhance regenera tive 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, includ- ing basic fibroblast growth factor and transforming growth factor-β, 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 [ 61 65 ] by influencing fibroblast proliferation and collagen synthesis [ 66 ]. The importance of estrogen status in the development of POP is, however, controversial. Nei- ther 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 osteopo- rosis. The study was aborted after 10 months for that reason and other unexpected gynecological side effects [ 69 ]. Fur- ther controversy has emerged as Manodoro et al. found that estrogen increased resistance to deformation of mesh aug- mented 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 ap- proach, as demonstrated in orthopedic research by the heal- ing 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

suggests that the metabolism of the vaginal tissue is abnormal in POP [ 44 ]. Facilitated

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

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 sur- gery 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 ma- caque 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, explo- ration of new treatment strategies involving any type of scaf- fold/mesh must rely on other animal models, such as the abdominal defect models in rats or rabbits [28]. Traditionally, cell-based tissue engineering strategies em- ploy in vitro expanded cells, but several problems are inherent in this approach: The long-term risks of using in-vitro- expanded 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 effec- tive 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 envi- ronment for cell-based therapies will raise the costs even further. In addition, enzymatic processing and in vitro cultur- ing is unnecessary and may even adversely affect the regen- erative 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 need- ed, 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 tradi- tional approach using cells ex- panded in vitro is demonstrated on the right side . A proposed alternative approach using fresh muscle fibre fragments is dem- onstrated to the left

fresh muscle fibre fragments is dem- onstrated to the left in processing fresh, noncultured muscle fibers

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 Urogyneco- logical Association (IUGA) Grafts Roundtable emphasize the importance of considering safety issues when develop- ing 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 med- ical 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 treat- ment will be categorized as an advanced therapy medicinal product, and the regulatory demands will increase accord- ingly 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 growth- promoting scaffold could be an alternative to the use of conventional implants or an adjunct to surgical reconstruc- tion of native tissue. So far, only limited evidence exists, and additional animal studies are imperative before this ap- proach 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.

G Lose: Receives research support and/or works as a consultant for Contura, Phizer, Astellas and Johnson

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