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Bladder tissue engineering: A literature review
ADR-12709; No of Pages 7 Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
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Bladder tissue engineering: A literature review☆,☆☆ Ornella Lam Van Ba, Shachar Aharony, Oleg Loutochin, Jacques Corcos ⁎ Department of Urology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
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Available online xxxx Keywords: Bladder Tissue engineering Scaffold Biomaterial Bladder reconstruction
a b s t r a c t Purpose of review: In bladder cancer and neuro-bladder, reconstruction of the bladder requires bowel segment grafting for augmentation cystoplasty or neo-bladder creation. However, even if currently considered as the gold standard, it is associated with potentially severe short- and long-term adverse effects. Thus, bladder tissue engineering is a promising approach to bladder reconstruction. Recent findings: In the last few years, progress has been made with the development of new biomaterials for bladder tissue replacement and in deciphering the role of stem cells as well as their contribution to bladder scaffold integration and tissue regeneration. Summary: This review of recently published articles allows us to forecast the characteristics of efficient and safe bladder biomaterials. However, several factors, such as native bladder traits, the specific involvement of urine, and bladder tissue replacement indications, have to be assessed with caution before including bladder tissue engineering in clinical trials. Many authors agree that these challenging techniques could deliver significant benefits with clinical application, reducing morbidity and global long-term costs. © 2014 Published by Elsevier B.V.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . Biomaterials . . . . . . . . . . . . . . . . . . 2.1. Biological scaffolds . . . . . . . . . . . . 2.1.1. Naturally derived biomaterials . . 2.1.2. Acellular tissue matrices . . . . . 2.2. Synthetic scaffolds . . . . . . . . . . . . 2.2.1. Synthetic polymers (poly-α-esters) 2.2.2. Silk-based materials . . . . . . . 2.3. Comparison between biomaterials . . . . 2.3.1. Collagen and acellular matrices . . 2.3.2. Synthetic matrices . . . . . . . . 3. Cell sources . . . . . . . . . . . . . . . . . . 3.1. Choice of cell sources . . . . . . . . . . 3.1.1. Autologous cells . . . . . . . . . 3.1.2. Stem cells . . . . . . . . . . . 3.1.3. Human cell reprogramming . . . 4. Clinical experience . . . . . . . . . . . . . . . 4.1. Unseeded acellular matrix studies . . . . . 4.2. Seeded matrix studies . . . . . . . . . . 4.3. General comments on clinical studies . . . 5. Conclusion . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: iPSC, induced pluripotent stem cells; MSCs, mesenchymal stromal cells; PGA, polyglycolic acid; SIS, small intestinal submucosa; VEGF, vascular endothelial growth factor. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Regenerative Medicine Strategies in Urology”. ☆☆ The authors state they have no conflicts of interest related to tissue engineering. ⁎ Corresponding author at: Department of Urology, Jewish General Hospital, McGill University, 3755 Côte-Sainte-Catherine Road, Montreal, QC H3T 1E2, Canada. E-mail address: [email protected] (J. Corcos).
http://dx.doi.org/10.1016/j.addr.2014.11.013 0169-409X/© 2014 Published by Elsevier B.V.
Please cite this article as: O. Lam Van Ba, et al., Bladder tissue engineering: A literature review, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.11.013
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O. Lam Van Ba et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
1. Introduction
2.2. Synthetic scaffolds
Bladder tissue engineering is an important research axis in urology. To be optimal, it implies: i) a complete regeneration of the replaced bladder wall, including its particular histological aspects (i.e., urothelial, muscular and adventitial layers), to ensure good functional results, ii) a solid and rapid tissue reconstitution to prevent any complications, such as early urine leakage or bladder rupture and iii) a safe, long-term evolution, particularly in the context of oncological risks [1]. So far, when bladder replacement or augmentation is needed, the gold standard technique for bladder reconstruction is the implantation of bowel segments (gastric, small or large bowel tissue) for vesical reservoir restoration [2]. Important and serious reported adverse events of this technique, such as metabolic anomalies, vitamin deficiencies, intravesical mucus production, urinary tract infection, stone formation and even cancer, have led to develop research in bladder tissue engineering [2]. This research includes the development of unseeded and cell-seeded biomaterials [3]. Biomaterials appear to be brilliant options for restoring bladder anatomy and avoiding complications. However, the bladder is a complex organ particularly because of its specific storage and voiding functions, implying good compliance (elasticity) in association with volume and contractility variations. These functions are challenging to reproduce in bladder tissue engineering. Beyond the complexity of bladder physiology other important factors influence the success of bladder tissue engineering. First, among usual available biomaterials, cell-seeded matrix ones seem to be more effective in tissue regeneration. Therefore research on cell sourcing is booming. However, such biomaterials can be difficult to use for bladder replacement, as the major indication in bladder wall replacement stands for oncological diseases. Therefore the use of autologous cells, theoretically the best choice to induce tissue integration and regeneration, can not usually be possible for long-term safety reasons [1]. Second, urine toxicity can alter seeded matrix properties [4, 5]. Considering all these requirements, bladder tissue engineering is a promising but still challenging option to provide a safe alternative to gastrointestinal reconstructive techniques for bladder wall replacement. Despite extensive research, no ideal biomaterials have yet been designed. The purpose of this article is to provide an overview of recent advances made in the domain of biomaterials and cell sources for bladder tissue engineering along with the principal results of clinical trials.
They comprise several materials, such as polyvinyl sponges, Teflon, Vicryl (polyglycolic acid, PGA) matrices, silicone and silk derivatives [11]. The two most commonly either used or promising are described in the sections that follow.
2. Biomaterials Currently available biomaterials in bladder tissue engineering are classified as biological or synthetic [3].
2.1. Biological scaffolds Biological scaffolds are described in the two sections that follow.
2.1.1. Naturally derived biomaterials They can be made of i) collagen, a ubiquitous structural protein, or ii) of alginate, isolated from seaweed, which belong to a family of D-mannuronate and L-guluronate copolymers [3].
2.1.2. Acellular tissue matrices Usually extracted from pigs, they are made from different types of tissue, such as bladder submucosa, small intestine submucosa (SIS), derma, bladder and gallbladder [6–9]. Amniotic tissue has also been proposed [10].
2.2.1. Synthetic polymers (poly-α-esters) This includes poly (L-lactide), PGA, and poly (lactide-co-glycolic acid) [12]. They have the advantage of being non-toxic, possibly biodegradable and easy to process with modulation of their structure. So far they are the most commonly used synthetic biomaterials. 2.2.2. Silk-based materials They are produced by the domesticated silkworm Bombyx mori and are composed of 2 protein types: i) Sericin, an antigenic gum-like protein surrounding the silk fibers, and ii) Fibroin, the core filament of silk comprised of highly-organized b-sheet crystalline and semicrystalline regions responsible for silk's elasticity. Initially, silk components were used for sutures but silk matrices are now being considered as potential biomaterials in bladder tissue engineering thanks to their physical properties, including high structural strength and elasticity, processing plasticity, and tunable biodegradability [13–15]. Initial problems of biocompatibility were reported (type I allergic reactions) and are now explained by the presence of Sericin in virgin silk that induced hypersensitivity. Sericin has been removed from silk biomaterials and the tolerance of these latters now appears to be comparable to most other biomaterials [13]. Thus silk-based materials constitute a promising therapeutic option in synthetic biomaterials. 2.3. Comparison between biomaterials Bladder tissue engineering is a recent research area with abundant literature reports comparing several biomaterials in experimental studies. These investigations mostly focused on feasibility design, with short follow-up and contrasting results on acellular and synthetic [12,16–19]. Few studies contained a control group utilizing techniques for gastrointestinal tissue replacement, which generally limited the interpretation of their results [12,20]. A recent review, focusing on animal models in experiments on tissue engineering for urinary diversion, revealed that each animal model had its own specificity which limited the extrapolation of the results to humans [21]. For example, because of the chemical composition of their urine, rabbits implanted with exogenous bladder material may develop bladder stones more often than any other animal species [22,23]. Thus, specific aspects of each animal model need to be considered before drawing conclusions about biomaterials tested. Despite the potential limitations mentioned above, we listed below the potential advantages/disadvantages of each biomaterial. 2.3.1. Collagen and acellular matrices As compared with synthetic biomaterials, we feel that acellular matrices exhibit the following advantages: i) Good biodegradability. This is a well-recognized property of acellular matrices as demonstrated in a study employing a radioactive tracer on SIS scaffolds implanted in dog bladders: 3 months after implantation of initially “100% traced” SIS scaffolds, only 10% of the original 14C radioactive tracer could be found, indicating good biodegradability [24]. ii) Good potential of biocompatibility [3]. iii) Persistence of growth factors embedded in scaffolds despite decellularization. Decellularization is aimed at obtaining optimized acellular scaffolds to avoid remnant cellularity that could induce immunological responses [25]. Preservation of structural proteins and growth factors constitute an additional challenging requirement of decellularization techniques. Indeed, although some authors have demonstrated the feasibility of being conservative [26–28], others have reported that acellular matrices, such as SIS, though they did contain growth factors, were unable to provide optimal tissue integration
Please cite this article as: O. Lam Van Ba, et al., Bladder tissue engineering: A literature review, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.11.013
O. Lam Van Ba et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
and regeneration [20,29–34]. As a consequence, this can induce a scar tissue, which prevents bladder contractility in scaffolds, producing non-optimal functional results. Among the disadvantages of acellular matrices possible lack of modulation in the healing process or initial hypoxia within implanted scaffolds should be noticed [1,35,36]. Indeed, the establishment of vascularization in implanted biomaterials in vivo is difficult, particularly in large tissue grafts. Non-optimal blood supply reduces oxygen and nutrient diffusion, resulting in tissue necrosis. To overcome this phenomenon, efforts are being made to incorporate additional growth factors in these scaffolds. Thus, in vitro and in vivo studies tended to demonstrate the benefit of artificial growth factor adjuncts to optimize bladder tissue regeneration [37–40]. However, these promising techniques are still experimental, non-physiological, and difficult to perform. The choice of growth factors, concentration and timing of growth factor delivery need to be investigated [41]. Eventual complications, such as overgrowth, fibrosis and even cases of cancer relapses have to be considered. Thus, it has been shown that over-expression of growth factors, such as vascular endothelial growth factor (VEGF), VEGF Receptor-1 and VEGF Receptor-2, was associated with disease stage and recurrence of bladder cancer. Moreover, platelet-derived growth factor receptor beta has been reported to be significantly increased in patients with non-invasive bladder tumor relapse. It is even considered as a non-invasive biomarker for the prediction of nonmuscle invasive bladder cancer recurrence [1,30,42,43]. 2.3.2. Synthetic matrices In our opinion, the advantage of synthetic biomaterial processing resides in the possibility of completely interfering with the physical properties of scaffolds, giving them more consistent and predictable physical behavior. Among available processing techniques, electrospinning is a simple technique that generates nano-fibrous structures while simultaneously providing macroscopic control over scaffold formation and architecture [44]. However, as compared with biological biomaterials, the lack of biological recognition and activity of synthetic biomaterial is a limitation that needs to be mentioned [3]. Given the contrasting findings of biological and synthetic scaffold implantation some authors have hypothesized that cell adjunction could improve bladder tissue regeneration and functional outcomes in bladder tissue engineering. It has enlarged research into potential cell sources available for this purpose [45]. 3. Cell sources Several studies have reported that seeded scaffolds provided better bladder tissue integration and urodynamic outcomes than unseeded ones [46–51]. As compared with other organs tissue engineering, the choice of bladder cell sources must be modulated according to the initial indication of bladder wall replacement. 3.1. Choice of cell sources 3.1.1. Autologous cells Theoretically, autologous cells are the best choice for the induction of tissue integration and regeneration. They also don't present the risk of inducing immunological responses. However, the use of autologous bladder cell may not constitute the best choice of cell sources for the following reasons. First, most indications of urinary diversion are oncological diseases [52]. Therefore, there exists a significant risk of cancer recurrence from autologous bladder cells in patients treated for invasive or non-invasive muscle bladder tumors [1]. Similarly, even if progress has been made recently in harvesting cells from urine, they may also be of tumoral origin. Urothelial tumors can develop simultaneously and spread to the urinary tract [53–56]. Second, non-oncological indications are mainly neurological bladder, which may contain abnormal bladder cells. Indeed, some authors reported that in vitro neuropathic bladder cells (smooth muscle and urothelial cells) had a lower
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contractility potential, with reduced proliferation and differentiation capacity [57,58]. In contrast, other authors did not evidence any phenotypic or functional differences between muscle cells obtained from urodynamically normal or neurogenic bladders when seeded on bladder scaffolds implanted in athymic mice [59]. In this context, mesenchymal stromal cells (MSCs) seem to be a good option as cell sources in bladder tissue engineering. 3.1.2. Stem cells MSCs are non-hematopoietic, multi-potent stem cells that have the ability to proliferate and differentiate in vitro and in vivo into various cell types [1,60,61]. They were reported to also have a paracrine effect, which could enhance tissue regeneration and angiogenesis even more efficiently than adjunction of pro-angiogenesis growth factors [62]. MSCs refer to amniotic fluid, bone marrow, adipose, hair follicle stem cells. The most frequently used are bone marrow derived MSCs [1]. MSCs were tested in various indications, particularly in hematooncology with promising results [1,60,61]. They were recently proposed for bladder tissue engineering [45]. Unlike embryonic stem cells, they don't present a risk of rejection. However, like embryonic stem cells, MSCs stem cells exhibit a theoretical potential risk of tumor induction, which must be considered when transplanting adult stem cells [63, 64]. At last as MSCs stem cells are not autologous bladder cells they are more prone to be altered by urine toxicity [4,5]. This can strongly influence the success of tissue regeneration. However, MSCs do not seem to be influenced by neurological initial pathology and it has been demonstrated that the use of multiple cell sources co-transplanted could enhance bladder tissue regeneration [65]. 3.1.3. Human cell reprogramming This is another source of stem cells for seeding into scaffolds to enhance tissue regeneration. Thanks to gene transcription techniques, cells are reprogrammed in pluripotent stem cells [66–68]. This has been successful reported in urology tissue with the constitution of prostate-induced pluripotent stem cells (iPSC) and urinary tract-iPSC. These cells were derived from parental stromal cells, the origin of which was confirmed by DNA fingerprinting. Their ability for sustained self-renewal and pluripotent differentiation (prostate, bladder and ureter) has been confirmed [69]. However, the risk of malignancies induced by these reprogrammed cells cannot be excluded. Research is ongoing with new protocols, including virus-free and transgene-free reprogramming as well as xeno-free approaches [70]. Alternative approaches have been proposed via vector-free human iPSC generation through episomal factor delivery as well as feeder- and albumin-free culture [71]. 4. Clinical experience So far, gastrointestinal techniques are considered the gold standard for bladder enlargement or replacement. In neurological indications, they were associated in the long-term with significant improvements in bladder capacity and decreased maximal detrusor pressure [72]. However, several adverse effects were reported such as metabolic acidosis, intra-vesical mucus production, urinary tract infection, stone formation and even cancer [2]. Bladder tissue engineering could represent an alternative, but still remains an area of research that has not been formally validated in current clinical practice. Few studies have examined this therapeutic option in humans and only for cases of neurogenic bladder related either to myelomeningocele or to spinal cord injury. The main results of these studies are summarized in Table 1. No study has assessed biomaterials in patients with oncological indications. Indeed, radical cystectomy is the recommended surgical treatment for localized invasive bladder muscle cancer. It involves whole organ replacement, which has not yet been designed in experimental studies.
Please cite this article as: O. Lam Van Ba, et al., Bladder tissue engineering: A literature review, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.11.013
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Study Population -n - Inclusion criteria - Age (mean, years) - Follow-up (months) Surgical procedure
Main results
Histological results
Side effects
Atala et al. [34]
Caione et al. [32]
Schaefer et al. [33]
Joseph et al. [74]
Zhang and Liao [73]
7 Myelomeningocele 11 (4–19) 46 (22–61) Cell-seeded matrix Autologous urothelial & smooth muscle cells Size: 70 to 150 cm2 Group a, n = 3: De-cellularized BSM matrix, no omental wrap Group b, n = 1: De-cellularized BSM matrix, omental wrap group Group c, n = 3: Composite decellularized BSM/PGA matrix, omental wrap group Mean BC Compliance
5 Post-complete exstrophy repair surgery 10.4 (8–17) 19.1 (max 48) Non-seeded SIS matrix (Surgisis®) Size: 20 cm2
6 Microbladder of mixed etiologya 9.8 (6.5–15.4) 24.4 (4.6–33.5) Non-seeded SIS matrix (Surgisis®) Size: 70 cm2
10 Myelomeningocele 8.2 (3–16) 36.0 Cell-seeded PGA matrix Autologous urothelial & smooth muscle cells Size: Non available, adapted to morphometric criteria
8 Mixed etiology b 25.4 (14–54) 12.0 (11–36) Non-seeded SIS matrix (Surgisis®) Size: 70 cm2 if BC N100 ml 140 cm2 if BC b100 ml
BC and compliance +30% (p b 0.05) at 6 and 18 months from surgery
BC and compliance Increase of BC: yes/no: 66.7% (n = 4) Estimated improvement of compliance: No significant improvement at 36 yes/no: 0% (n = 6) Months 0% (n = 0)
Tri-layered structure: 100% (n = 5) i.e. normal transitional mucosa and sero-muscular layer containing smooth muscle fascicles, small nerve trunks and vessels within abundant type-3 collagen but muscle/collagen ratio in the regenerative bladder wall decreased compared with controls (native bladder) at 6 and 18 months (p b0.05) 2 non-febrile urinary tract infection: 40% (n = 2)
Complete conversion of SIS: 100% (n = 6) and: - Normal & distinct urothelial lining achievement: 33.3% (n = 2) - Squamous epithelial lining: 66.6% (n = 4)
Non available
Struvite bladder stone: 33.3% (n = 2) Bladder rupture: 16.7% (n = 1)
No adverse effect (n = 0) Bladder Rupture: 30.0%(n = 3) Bowel Obstruction: 30.0%(n = 3) Shunt malfunction: 10.0%(n = 1) Pelvic abscess: 10.0%(n = 1)
+15% −30% Group a +67% +22% Group b +279% +58% Group c Tri-layered structure: 100% (n = 7) i.e. urothelial cell-lined lumen surrounded by submucosa and muscle
Urinary tract infection: 14.2% (n = 1)
BC: Bladder, capacity; BSM: Bladder sub-mucosa; PGA: Polyglycolic acid; SIS: Small intestinal submucosa; Compliance: Δ Volume/Δ Detrusor Pressure. a Cloacal exstrophy repair (1 patient). Iatrogenic micro-bladder (1 patient). Spina bifida (2 patients). Bladder exstrophy repair (2 patients). b Myelomeningocele (6 patients). Spinal cord injury (2 patients).
BC, Compliance at 12 months BC: +126% (p b 0.05) Compliance: +515% (p b 0.01)
Double layer structure: (n = 3) i.e. inner layer: multilayered transitional epithelium outer layer: abundant connective tissue, fibroblast & small amount of muscular fibers
O. Lam Van Ba et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
Please cite this article as: O. Lam Van Ba, et al., Bladder tissue engineering: A literature review, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.11.013
Table 1 Published studies assessing augmentation cystoplasty with exogenous biomaterial in human patients.
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4.1. Unseeded acellular matrix studies The first study using unseeded acellular matrix (SIS, Surgisis®) in human for neurological bladder augmentation cystoplasty was published by Caione et al. in 2012 [32]. In a pediatric population of 5 patients suffering from extrophy–epispadias complex disease, with poor bladder capacity and compliance (Δ Volume/Δ Detrusor Pressure) after complete extrophy repair a non-seeded SIS scaffold, representing 70–90% of the native bladder surface, was implanted. After 6 months of follow-up although scaffold degradation was complete the new tissue contained few smooth muscle fiber. These disappointing histological results were confirmed by functional tests, which showed a low increase of bladder capacity and compliance at 6 and 18 months respectively [32]. Schaefer et al.'s pilot study conducted in 6 pediatric patients found similar incomplete histological results, failed to evidence any improvement of compliance but found an increase in bladder capacity in 4 patients and reported serious adverse complications during follow-up (1 bladder rupture and 2 struvite bladder stones) [33]. As compared with Caione's study [32], same non-seeded SIS scaffolds were implanted for bladder augmentation, but were of larger size. These two pilot results suggest that acellular matrices had contrasted histological and functional outcomes when used in augmentation cystoplasty indication [32,33]. However another study conducted in a heterogeneous adult population of neurological bladder (6 myelomeningocele and 2 spinal cord injury cases) found on contrary promising results [73]. At 12-month, Zhang and Liao [73] reported significant urodynamic improvements and continence was achieved in 75% (n = 6) of patients with clean intermittent catheterization. As compared with the studies of Schaefer [33] and Caione [32], patients were adult and SIS matrices were similar but much larger [32,33,73]. We feel that these results need to be cautiously interpreted because of the small sample size, of the fact that histological analysis was possible in only 3 patients all of them exhibiting sub-optimal smooth muscle fibbers concentrations. New studies are needed, enrolling larger number of patients with more homogeneous clinical indications. Use of seeded matrices could provide better results.
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bowel obstruction (n = 3) and bladder rupture (n = 3), occurred in 36.4% (n = 4) patients were noticed [74]. 4.3. General comments on clinical studies Only two studies reported significant improvements in urodynamic results [73]. Thus, it appears that bladder tissue engineering, whether using seeded or unseeded matrices, only induces partial and incomplete bladder tissue regeneration. This phenomenon is associated with poor clinical and urodynamic results. Several factors could explain the failure of these studies as follows: i) Small graft size. Positive studies by Atala et al. [34] and Zhang and Liao [73] used large graft sizes between 70 and 150 cm2. Graft size in other studies was either smaller or not reported [32,33,74]. ii) Use of autologous bladder cells in a context of neurogenic bladder disease where their efficiency to induce bladder tissue regeneration is still being debated [57–59]. iii) A too brief period of or even an absence of bladder cycling in post-operative management. Indeed, data suggest that early exposure to bladder cycles (filling/emptying) could improve the graft healing process in a SIS or BSM dog bladder augmentation model study, comparing short-term versus long-term catheterization after surgery [75]. Beyond the problematic of effectiveness of bladder tissue engineering, issues concerning it safety must be underlined. Indeed, serious adverse effects have been reported in at least 2 of 5 human studies. The short follow-up (maximal follow-up 46 months) seems rather brief to detect long-term adverse effects. In order to reduce patient's discomfort and morbidity of the follow-up (endoscopy and bladder biopsy), a radiological by magnetic resonance imaging rather than an histological follow-up could be performed and represent a promising alternative. Experimental studies in animals showed that it could be possible to evaluating directly — or via incorporated iron oxide particles into collagen scaffolds parameters such as cell growth, distribution or scaffold viability as well as its composition and its degradation [76–79]. However, while these techniques present good sensitivity, they need to improve in specificity. 5. Conclusion
4.2. Seeded matrix studies The very first study using biomaterials for neurologic bladder in humans was performed by Atala et al. in 2006 and used seeded matrices with autologous cells [34]. It included 7 pediatric patients with myelomeningocele with high bladder pressure and poorly compliant bladder. At first seeded cells were harvested from bladder dome biopsy specimens and cultivated for a 7-week period with seeding on acellular or composite matrices. Matrix size for implantation was as large as in the study of Zhang and Liao [73] and adapted to patient age and analyzed by pelvic computerized tomography. After a follow-up of 46 months, histological and cystoscopic analyses revealed normal bladder aspects in all patients suggesting optimal tissue regeneration. In addition, good functional outcomes were also reported with decreased leak point pressure at capacity and increased bladder capacity as well as bladder compliance in the omental wrap composite matrix group but not in simple bladder submucosae seeded–non-covered matrix group (3 patients). No serious adverse effects were reported during a mean follow-up of 46 months. One patient required re-operative cystoplasty 4 years after the initial surgery for increasing bladder pressure. These results, which need to be interpreted in the context of a non-controlled pilot study, could suggest that seeded matrix may be effective, but only when a composite matrix is used. Using a synthetic PGA matrix seeded with autologous urothelial cells, Joseph et al. did not evidence any improvements in bladder capacity and compliance (0%) in 11 pediatric patients with myelomeningocele followed up 36-month. In addition, serious adverse effects, such as
So far, bladder tissue engineering failed to evidence strong benefits in humans with neurologic bladder. A better comprehension of the requirements for bladder tissue engineering in relation to patient pathology and bladder specificity as well as improvements in harvesting several stem cell sources could contribute to bladder restoration. However, bladder tissue engineering remains a promising and challenging alternative to gastrointestinal techniques for bladder enlargement or replacement. Further long-term in vivo studies in larger animal species with adequate control groups, consideration of different post-operative drainage techniques and the impact of neo-bladder function on the kidneys are warranted to evaluate the efficiency and safety of bladder tissue engineering. They would be useful to determine optimal procedures before considering application to larger clinical trials or the extension of indications to the oncology field. References [1] T. Drewa, J. Adamowicz, A. Sharma, Tissue engineering for the oncologic urinary bladder, Nat. Rev. Urol. 9 (2012) 561–572. [2] J.A. Nieuwenhuijzen, R.R. de Vries, A. Bex, H.G. van der Poel, W. Meinhardt, N. Antonini, et al., Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions, Eur. Urol. 53 (2008) 834–842 (discussion 842-4). [3] A. Atala, Tissue engineering of human bladder, Br. Med. Bull. 97 (2011) 81–104. [4] J. Adamowicz, T. Kloskowski, J. Tworkiewicz, M. Pokrywczyńska, T. Drewa, Urine is a highly cytotoxic agent: does it influence stem cell therapies in urology? Transplant. Proc. 44 (2012) 1439–1441. [5] K. Juszczak, J. Kaszuba-Zwoińska, P. Chorobik, A. Ziomber, P.J. Thor, The effect of hyperosmolar stimuli and cyclophosphamide on the culture of normal rat urothelial cells in vitro, Cell. Mol. Biol. Lett. 17 (2012) 196–205.
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Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr
Bladder tissue engineering: A literature review☆,☆☆ Ornella Lam Van Ba, Shachar Aharony, Oleg Loutochin, Jacques Corcos ⁎ Department of Urology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
a r t i c l e
i n f o
Available online xxxx Keywords: Bladder Tissue engineering Scaffold Biomaterial Bladder reconstruction
a b s t r a c t Purpose of review: In bladder cancer and neuro-bladder, reconstruction of the bladder requires bowel segment grafting for augmentation cystoplasty or neo-bladder creation. However, even if currently considered as the gold standard, it is associated with potentially severe short- and long-term adverse effects. Thus, bladder tissue engineering is a promising approach to bladder reconstruction. Recent findings: In the last few years, progress has been made with the development of new biomaterials for bladder tissue replacement and in deciphering the role of stem cells as well as their contribution to bladder scaffold integration and tissue regeneration. Summary: This review of recently published articles allows us to forecast the characteristics of efficient and safe bladder biomaterials. However, several factors, such as native bladder traits, the specific involvement of urine, and bladder tissue replacement indications, have to be assessed with caution before including bladder tissue engineering in clinical trials. Many authors agree that these challenging techniques could deliver significant benefits with clinical application, reducing morbidity and global long-term costs. © 2014 Published by Elsevier B.V.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . Biomaterials . . . . . . . . . . . . . . . . . . 2.1. Biological scaffolds . . . . . . . . . . . . 2.1.1. Naturally derived biomaterials . . 2.1.2. Acellular tissue matrices . . . . . 2.2. Synthetic scaffolds . . . . . . . . . . . . 2.2.1. Synthetic polymers (poly-α-esters) 2.2.2. Silk-based materials . . . . . . . 2.3. Comparison between biomaterials . . . . 2.3.1. Collagen and acellular matrices . . 2.3.2. Synthetic matrices . . . . . . . . 3. Cell sources . . . . . . . . . . . . . . . . . . 3.1. Choice of cell sources . . . . . . . . . . 3.1.1. Autologous cells . . . . . . . . . 3.1.2. Stem cells . . . . . . . . . . . 3.1.3. Human cell reprogramming . . . 4. Clinical experience . . . . . . . . . . . . . . . 4.1. Unseeded acellular matrix studies . . . . . 4.2. Seeded matrix studies . . . . . . . . . . 4.3. General comments on clinical studies . . . 5. Conclusion . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: iPSC, induced pluripotent stem cells; MSCs, mesenchymal stromal cells; PGA, polyglycolic acid; SIS, small intestinal submucosa; VEGF, vascular endothelial growth factor. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Regenerative Medicine Strategies in Urology”. ☆☆ The authors state they have no conflicts of interest related to tissue engineering. ⁎ Corresponding author at: Department of Urology, Jewish General Hospital, McGill University, 3755 Côte-Sainte-Catherine Road, Montreal, QC H3T 1E2, Canada. E-mail address: [email protected] (J. Corcos).
http://dx.doi.org/10.1016/j.addr.2014.11.013 0169-409X/© 2014 Published by Elsevier B.V.
Please cite this article as: O. Lam Van Ba, et al., Bladder tissue engineering: A literature review, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.11.013
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O. Lam Van Ba et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
1. Introduction
2.2. Synthetic scaffolds
Bladder tissue engineering is an important research axis in urology. To be optimal, it implies: i) a complete regeneration of the replaced bladder wall, including its particular histological aspects (i.e., urothelial, muscular and adventitial layers), to ensure good functional results, ii) a solid and rapid tissue reconstitution to prevent any complications, such as early urine leakage or bladder rupture and iii) a safe, long-term evolution, particularly in the context of oncological risks [1]. So far, when bladder replacement or augmentation is needed, the gold standard technique for bladder reconstruction is the implantation of bowel segments (gastric, small or large bowel tissue) for vesical reservoir restoration [2]. Important and serious reported adverse events of this technique, such as metabolic anomalies, vitamin deficiencies, intravesical mucus production, urinary tract infection, stone formation and even cancer, have led to develop research in bladder tissue engineering [2]. This research includes the development of unseeded and cell-seeded biomaterials [3]. Biomaterials appear to be brilliant options for restoring bladder anatomy and avoiding complications. However, the bladder is a complex organ particularly because of its specific storage and voiding functions, implying good compliance (elasticity) in association with volume and contractility variations. These functions are challenging to reproduce in bladder tissue engineering. Beyond the complexity of bladder physiology other important factors influence the success of bladder tissue engineering. First, among usual available biomaterials, cell-seeded matrix ones seem to be more effective in tissue regeneration. Therefore research on cell sourcing is booming. However, such biomaterials can be difficult to use for bladder replacement, as the major indication in bladder wall replacement stands for oncological diseases. Therefore the use of autologous cells, theoretically the best choice to induce tissue integration and regeneration, can not usually be possible for long-term safety reasons [1]. Second, urine toxicity can alter seeded matrix properties [4, 5]. Considering all these requirements, bladder tissue engineering is a promising but still challenging option to provide a safe alternative to gastrointestinal reconstructive techniques for bladder wall replacement. Despite extensive research, no ideal biomaterials have yet been designed. The purpose of this article is to provide an overview of recent advances made in the domain of biomaterials and cell sources for bladder tissue engineering along with the principal results of clinical trials.
They comprise several materials, such as polyvinyl sponges, Teflon, Vicryl (polyglycolic acid, PGA) matrices, silicone and silk derivatives [11]. The two most commonly either used or promising are described in the sections that follow.
2. Biomaterials Currently available biomaterials in bladder tissue engineering are classified as biological or synthetic [3].
2.1. Biological scaffolds Biological scaffolds are described in the two sections that follow.
2.1.1. Naturally derived biomaterials They can be made of i) collagen, a ubiquitous structural protein, or ii) of alginate, isolated from seaweed, which belong to a family of D-mannuronate and L-guluronate copolymers [3].
2.1.2. Acellular tissue matrices Usually extracted from pigs, they are made from different types of tissue, such as bladder submucosa, small intestine submucosa (SIS), derma, bladder and gallbladder [6–9]. Amniotic tissue has also been proposed [10].
2.2.1. Synthetic polymers (poly-α-esters) This includes poly (L-lactide), PGA, and poly (lactide-co-glycolic acid) [12]. They have the advantage of being non-toxic, possibly biodegradable and easy to process with modulation of their structure. So far they are the most commonly used synthetic biomaterials. 2.2.2. Silk-based materials They are produced by the domesticated silkworm Bombyx mori and are composed of 2 protein types: i) Sericin, an antigenic gum-like protein surrounding the silk fibers, and ii) Fibroin, the core filament of silk comprised of highly-organized b-sheet crystalline and semicrystalline regions responsible for silk's elasticity. Initially, silk components were used for sutures but silk matrices are now being considered as potential biomaterials in bladder tissue engineering thanks to their physical properties, including high structural strength and elasticity, processing plasticity, and tunable biodegradability [13–15]. Initial problems of biocompatibility were reported (type I allergic reactions) and are now explained by the presence of Sericin in virgin silk that induced hypersensitivity. Sericin has been removed from silk biomaterials and the tolerance of these latters now appears to be comparable to most other biomaterials [13]. Thus silk-based materials constitute a promising therapeutic option in synthetic biomaterials. 2.3. Comparison between biomaterials Bladder tissue engineering is a recent research area with abundant literature reports comparing several biomaterials in experimental studies. These investigations mostly focused on feasibility design, with short follow-up and contrasting results on acellular and synthetic [12,16–19]. Few studies contained a control group utilizing techniques for gastrointestinal tissue replacement, which generally limited the interpretation of their results [12,20]. A recent review, focusing on animal models in experiments on tissue engineering for urinary diversion, revealed that each animal model had its own specificity which limited the extrapolation of the results to humans [21]. For example, because of the chemical composition of their urine, rabbits implanted with exogenous bladder material may develop bladder stones more often than any other animal species [22,23]. Thus, specific aspects of each animal model need to be considered before drawing conclusions about biomaterials tested. Despite the potential limitations mentioned above, we listed below the potential advantages/disadvantages of each biomaterial. 2.3.1. Collagen and acellular matrices As compared with synthetic biomaterials, we feel that acellular matrices exhibit the following advantages: i) Good biodegradability. This is a well-recognized property of acellular matrices as demonstrated in a study employing a radioactive tracer on SIS scaffolds implanted in dog bladders: 3 months after implantation of initially “100% traced” SIS scaffolds, only 10% of the original 14C radioactive tracer could be found, indicating good biodegradability [24]. ii) Good potential of biocompatibility [3]. iii) Persistence of growth factors embedded in scaffolds despite decellularization. Decellularization is aimed at obtaining optimized acellular scaffolds to avoid remnant cellularity that could induce immunological responses [25]. Preservation of structural proteins and growth factors constitute an additional challenging requirement of decellularization techniques. Indeed, although some authors have demonstrated the feasibility of being conservative [26–28], others have reported that acellular matrices, such as SIS, though they did contain growth factors, were unable to provide optimal tissue integration
Please cite this article as: O. Lam Van Ba, et al., Bladder tissue engineering: A literature review, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.11.013
O. Lam Van Ba et al. / Advanced Drug Delivery Reviews xxx (2014) xxx–xxx
and regeneration [20,29–34]. As a consequence, this can induce a scar tissue, which prevents bladder contractility in scaffolds, producing non-optimal functional results. Among the disadvantages of acellular matrices possible lack of modulation in the healing process or initial hypoxia within implanted scaffolds should be noticed [1,35,36]. Indeed, the establishment of vascularization in implanted biomaterials in vivo is difficult, particularly in large tissue grafts. Non-optimal blood supply reduces oxygen and nutrient diffusion, resulting in tissue necrosis. To overcome this phenomenon, efforts are being made to incorporate additional growth factors in these scaffolds. Thus, in vitro and in vivo studies tended to demonstrate the benefit of artificial growth factor adjuncts to optimize bladder tissue regeneration [37–40]. However, these promising techniques are still experimental, non-physiological, and difficult to perform. The choice of growth factors, concentration and timing of growth factor delivery need to be investigated [41]. Eventual complications, such as overgrowth, fibrosis and even cases of cancer relapses have to be considered. Thus, it has been shown that over-expression of growth factors, such as vascular endothelial growth factor (VEGF), VEGF Receptor-1 and VEGF Receptor-2, was associated with disease stage and recurrence of bladder cancer. Moreover, platelet-derived growth factor receptor beta has been reported to be significantly increased in patients with non-invasive bladder tumor relapse. It is even considered as a non-invasive biomarker for the prediction of nonmuscle invasive bladder cancer recurrence [1,30,42,43]. 2.3.2. Synthetic matrices In our opinion, the advantage of synthetic biomaterial processing resides in the possibility of completely interfering with the physical properties of scaffolds, giving them more consistent and predictable physical behavior. Among available processing techniques, electrospinning is a simple technique that generates nano-fibrous structures while simultaneously providing macroscopic control over scaffold formation and architecture [44]. However, as compared with biological biomaterials, the lack of biological recognition and activity of synthetic biomaterial is a limitation that needs to be mentioned [3]. Given the contrasting findings of biological and synthetic scaffold implantation some authors have hypothesized that cell adjunction could improve bladder tissue regeneration and functional outcomes in bladder tissue engineering. It has enlarged research into potential cell sources available for this purpose [45]. 3. Cell sources Several studies have reported that seeded scaffolds provided better bladder tissue integration and urodynamic outcomes than unseeded ones [46–51]. As compared with other organs tissue engineering, the choice of bladder cell sources must be modulated according to the initial indication of bladder wall replacement. 3.1. Choice of cell sources 3.1.1. Autologous cells Theoretically, autologous cells are the best choice for the induction of tissue integration and regeneration. They also don't present the risk of inducing immunological responses. However, the use of autologous bladder cell may not constitute the best choice of cell sources for the following reasons. First, most indications of urinary diversion are oncological diseases [52]. Therefore, there exists a significant risk of cancer recurrence from autologous bladder cells in patients treated for invasive or non-invasive muscle bladder tumors [1]. Similarly, even if progress has been made recently in harvesting cells from urine, they may also be of tumoral origin. Urothelial tumors can develop simultaneously and spread to the urinary tract [53–56]. Second, non-oncological indications are mainly neurological bladder, which may contain abnormal bladder cells. Indeed, some authors reported that in vitro neuropathic bladder cells (smooth muscle and urothelial cells) had a lower
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contractility potential, with reduced proliferation and differentiation capacity [57,58]. In contrast, other authors did not evidence any phenotypic or functional differences between muscle cells obtained from urodynamically normal or neurogenic bladders when seeded on bladder scaffolds implanted in athymic mice [59]. In this context, mesenchymal stromal cells (MSCs) seem to be a good option as cell sources in bladder tissue engineering. 3.1.2. Stem cells MSCs are non-hematopoietic, multi-potent stem cells that have the ability to proliferate and differentiate in vitro and in vivo into various cell types [1,60,61]. They were reported to also have a paracrine effect, which could enhance tissue regeneration and angiogenesis even more efficiently than adjunction of pro-angiogenesis growth factors [62]. MSCs refer to amniotic fluid, bone marrow, adipose, hair follicle stem cells. The most frequently used are bone marrow derived MSCs [1]. MSCs were tested in various indications, particularly in hematooncology with promising results [1,60,61]. They were recently proposed for bladder tissue engineering [45]. Unlike embryonic stem cells, they don't present a risk of rejection. However, like embryonic stem cells, MSCs stem cells exhibit a theoretical potential risk of tumor induction, which must be considered when transplanting adult stem cells [63, 64]. At last as MSCs stem cells are not autologous bladder cells they are more prone to be altered by urine toxicity [4,5]. This can strongly influence the success of tissue regeneration. However, MSCs do not seem to be influenced by neurological initial pathology and it has been demonstrated that the use of multiple cell sources co-transplanted could enhance bladder tissue regeneration [65]. 3.1.3. Human cell reprogramming This is another source of stem cells for seeding into scaffolds to enhance tissue regeneration. Thanks to gene transcription techniques, cells are reprogrammed in pluripotent stem cells [66–68]. This has been successful reported in urology tissue with the constitution of prostate-induced pluripotent stem cells (iPSC) and urinary tract-iPSC. These cells were derived from parental stromal cells, the origin of which was confirmed by DNA fingerprinting. Their ability for sustained self-renewal and pluripotent differentiation (prostate, bladder and ureter) has been confirmed [69]. However, the risk of malignancies induced by these reprogrammed cells cannot be excluded. Research is ongoing with new protocols, including virus-free and transgene-free reprogramming as well as xeno-free approaches [70]. Alternative approaches have been proposed via vector-free human iPSC generation through episomal factor delivery as well as feeder- and albumin-free culture [71]. 4. Clinical experience So far, gastrointestinal techniques are considered the gold standard for bladder enlargement or replacement. In neurological indications, they were associated in the long-term with significant improvements in bladder capacity and decreased maximal detrusor pressure [72]. However, several adverse effects were reported such as metabolic acidosis, intra-vesical mucus production, urinary tract infection, stone formation and even cancer [2]. Bladder tissue engineering could represent an alternative, but still remains an area of research that has not been formally validated in current clinical practice. Few studies have examined this therapeutic option in humans and only for cases of neurogenic bladder related either to myelomeningocele or to spinal cord injury. The main results of these studies are summarized in Table 1. No study has assessed biomaterials in patients with oncological indications. Indeed, radical cystectomy is the recommended surgical treatment for localized invasive bladder muscle cancer. It involves whole organ replacement, which has not yet been designed in experimental studies.
Please cite this article as: O. Lam Van Ba, et al., Bladder tissue engineering: A literature review, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.11.013
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Study Population -n - Inclusion criteria - Age (mean, years) - Follow-up (months) Surgical procedure
Main results
Histological results
Side effects
Atala et al. [34]
Caione et al. [32]
Schaefer et al. [33]
Joseph et al. [74]
Zhang and Liao [73]
7 Myelomeningocele 11 (4–19) 46 (22–61) Cell-seeded matrix Autologous urothelial & smooth muscle cells Size: 70 to 150 cm2 Group a, n = 3: De-cellularized BSM matrix, no omental wrap Group b, n = 1: De-cellularized BSM matrix, omental wrap group Group c, n = 3: Composite decellularized BSM/PGA matrix, omental wrap group Mean BC Compliance
5 Post-complete exstrophy repair surgery 10.4 (8–17) 19.1 (max 48) Non-seeded SIS matrix (Surgisis®) Size: 20 cm2
6 Microbladder of mixed etiologya 9.8 (6.5–15.4) 24.4 (4.6–33.5) Non-seeded SIS matrix (Surgisis®) Size: 70 cm2
10 Myelomeningocele 8.2 (3–16) 36.0 Cell-seeded PGA matrix Autologous urothelial & smooth muscle cells Size: Non available, adapted to morphometric criteria
8 Mixed etiology b 25.4 (14–54) 12.0 (11–36) Non-seeded SIS matrix (Surgisis®) Size: 70 cm2 if BC N100 ml 140 cm2 if BC b100 ml
BC and compliance +30% (p b 0.05) at 6 and 18 months from surgery
BC and compliance Increase of BC: yes/no: 66.7% (n = 4) Estimated improvement of compliance: No significant improvement at 36 yes/no: 0% (n = 6) Months 0% (n = 0)
Tri-layered structure: 100% (n = 5) i.e. normal transitional mucosa and sero-muscular layer containing smooth muscle fascicles, small nerve trunks and vessels within abundant type-3 collagen but muscle/collagen ratio in the regenerative bladder wall decreased compared with controls (native bladder) at 6 and 18 months (p b0.05) 2 non-febrile urinary tract infection: 40% (n = 2)
Complete conversion of SIS: 100% (n = 6) and: - Normal & distinct urothelial lining achievement: 33.3% (n = 2) - Squamous epithelial lining: 66.6% (n = 4)
Non available
Struvite bladder stone: 33.3% (n = 2) Bladder rupture: 16.7% (n = 1)
No adverse effect (n = 0) Bladder Rupture: 30.0%(n = 3) Bowel Obstruction: 30.0%(n = 3) Shunt malfunction: 10.0%(n = 1) Pelvic abscess: 10.0%(n = 1)
+15% −30% Group a +67% +22% Group b +279% +58% Group c Tri-layered structure: 100% (n = 7) i.e. urothelial cell-lined lumen surrounded by submucosa and muscle
Urinary tract infection: 14.2% (n = 1)
BC: Bladder, capacity; BSM: Bladder sub-mucosa; PGA: Polyglycolic acid; SIS: Small intestinal submucosa; Compliance: Δ Volume/Δ Detrusor Pressure. a Cloacal exstrophy repair (1 patient). Iatrogenic micro-bladder (1 patient). Spina bifida (2 patients). Bladder exstrophy repair (2 patients). b Myelomeningocele (6 patients). Spinal cord injury (2 patients).
BC, Compliance at 12 months BC: +126% (p b 0.05) Compliance: +515% (p b 0.01)
Double layer structure: (n = 3) i.e. inner layer: multilayered transitional epithelium outer layer: abundant connective tissue, fibroblast & small amount of muscular fibers
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Please cite this article as: O. Lam Van Ba, et al., Bladder tissue engineering: A literature review, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/ 10.1016/j.addr.2014.11.013
Table 1 Published studies assessing augmentation cystoplasty with exogenous biomaterial in human patients.
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4.1. Unseeded acellular matrix studies The first study using unseeded acellular matrix (SIS, Surgisis®) in human for neurological bladder augmentation cystoplasty was published by Caione et al. in 2012 [32]. In a pediatric population of 5 patients suffering from extrophy–epispadias complex disease, with poor bladder capacity and compliance (Δ Volume/Δ Detrusor Pressure) after complete extrophy repair a non-seeded SIS scaffold, representing 70–90% of the native bladder surface, was implanted. After 6 months of follow-up although scaffold degradation was complete the new tissue contained few smooth muscle fiber. These disappointing histological results were confirmed by functional tests, which showed a low increase of bladder capacity and compliance at 6 and 18 months respectively [32]. Schaefer et al.'s pilot study conducted in 6 pediatric patients found similar incomplete histological results, failed to evidence any improvement of compliance but found an increase in bladder capacity in 4 patients and reported serious adverse complications during follow-up (1 bladder rupture and 2 struvite bladder stones) [33]. As compared with Caione's study [32], same non-seeded SIS scaffolds were implanted for bladder augmentation, but were of larger size. These two pilot results suggest that acellular matrices had contrasted histological and functional outcomes when used in augmentation cystoplasty indication [32,33]. However another study conducted in a heterogeneous adult population of neurological bladder (6 myelomeningocele and 2 spinal cord injury cases) found on contrary promising results [73]. At 12-month, Zhang and Liao [73] reported significant urodynamic improvements and continence was achieved in 75% (n = 6) of patients with clean intermittent catheterization. As compared with the studies of Schaefer [33] and Caione [32], patients were adult and SIS matrices were similar but much larger [32,33,73]. We feel that these results need to be cautiously interpreted because of the small sample size, of the fact that histological analysis was possible in only 3 patients all of them exhibiting sub-optimal smooth muscle fibbers concentrations. New studies are needed, enrolling larger number of patients with more homogeneous clinical indications. Use of seeded matrices could provide better results.
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bowel obstruction (n = 3) and bladder rupture (n = 3), occurred in 36.4% (n = 4) patients were noticed [74]. 4.3. General comments on clinical studies Only two studies reported significant improvements in urodynamic results [73]. Thus, it appears that bladder tissue engineering, whether using seeded or unseeded matrices, only induces partial and incomplete bladder tissue regeneration. This phenomenon is associated with poor clinical and urodynamic results. Several factors could explain the failure of these studies as follows: i) Small graft size. Positive studies by Atala et al. [34] and Zhang and Liao [73] used large graft sizes between 70 and 150 cm2. Graft size in other studies was either smaller or not reported [32,33,74]. ii) Use of autologous bladder cells in a context of neurogenic bladder disease where their efficiency to induce bladder tissue regeneration is still being debated [57–59]. iii) A too brief period of or even an absence of bladder cycling in post-operative management. Indeed, data suggest that early exposure to bladder cycles (filling/emptying) could improve the graft healing process in a SIS or BSM dog bladder augmentation model study, comparing short-term versus long-term catheterization after surgery [75]. Beyond the problematic of effectiveness of bladder tissue engineering, issues concerning it safety must be underlined. Indeed, serious adverse effects have been reported in at least 2 of 5 human studies. The short follow-up (maximal follow-up 46 months) seems rather brief to detect long-term adverse effects. In order to reduce patient's discomfort and morbidity of the follow-up (endoscopy and bladder biopsy), a radiological by magnetic resonance imaging rather than an histological follow-up could be performed and represent a promising alternative. Experimental studies in animals showed that it could be possible to evaluating directly — or via incorporated iron oxide particles into collagen scaffolds parameters such as cell growth, distribution or scaffold viability as well as its composition and its degradation [76–79]. However, while these techniques present good sensitivity, they need to improve in specificity. 5. Conclusion
4.2. Seeded matrix studies The very first study using biomaterials for neurologic bladder in humans was performed by Atala et al. in 2006 and used seeded matrices with autologous cells [34]. It included 7 pediatric patients with myelomeningocele with high bladder pressure and poorly compliant bladder. At first seeded cells were harvested from bladder dome biopsy specimens and cultivated for a 7-week period with seeding on acellular or composite matrices. Matrix size for implantation was as large as in the study of Zhang and Liao [73] and adapted to patient age and analyzed by pelvic computerized tomography. After a follow-up of 46 months, histological and cystoscopic analyses revealed normal bladder aspects in all patients suggesting optimal tissue regeneration. In addition, good functional outcomes were also reported with decreased leak point pressure at capacity and increased bladder capacity as well as bladder compliance in the omental wrap composite matrix group but not in simple bladder submucosae seeded–non-covered matrix group (3 patients). No serious adverse effects were reported during a mean follow-up of 46 months. One patient required re-operative cystoplasty 4 years after the initial surgery for increasing bladder pressure. These results, which need to be interpreted in the context of a non-controlled pilot study, could suggest that seeded matrix may be effective, but only when a composite matrix is used. Using a synthetic PGA matrix seeded with autologous urothelial cells, Joseph et al. did not evidence any improvements in bladder capacity and compliance (0%) in 11 pediatric patients with myelomeningocele followed up 36-month. In addition, serious adverse effects, such as
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