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... damage to the ureter is still a challenge for all urologists. Different proce- dures have been introduced to bridge ureteral defects, including ureteral substitutions with intestinal segments, transuretero-ureterostomy, bladder flaps and renal autotransplantation. 1 There are also reports for the application of artificial biomaterials in ureteral replacement; however, the results were sometimes not satis- factory. 2 Amniotic membrane (AM), which has been a qualified biomaterial in reconstructive surgeries in the field of ophthalmology, 3 promised to be a good candidate for recons- truction operation in urology practices. The AM has some properties, such as facilitation of epithelial cells migration, reinforcement of basal cellular adhesion and induction of epithelial differentiation. Its anti-inflammatory ability makes it a good choice for urologic reconstructive surgeries. 4 We evaluated the use of human AM for the reconstruction of ure- teral defects in a canine model in this study. This experimental study was carried out on seven mixed breed adult male dogs weighing about 15 kg. The graft was derived from hu- man placenta right after delivery. The speci- mens with meconioum contamination or chorio- amnionitis were discarded. After receiving the amniotic membrane in the laboratory, the following procedure was applied on all of the amniotic membranes: The chorion was sepa- rated from the amnion; This was washed two to three times in phosphate buffer solution (PBS) and antibiotic until no RBC was re- maining (clearing); membranes were cut in desirable sizes (3 cm x 1 cm); membranes were attached on the nitrocellulose membrane and soaked in 4% DMSO for 10 min, 8% DMSO for 10 min and 12% DMSO for 10 min (DMSO contains both antibiotics and anti- fungal agents); membranes were frozen in 12% DMSO in -70 о, and they were brought out of the freezer before being used for any procedures. Intramuscular ceftriaxone (25 mg/ kg) was injected 15 min before starting the operation; all the interventions were performed under anesthesia in a standard operating room. A complete, circumferential incision was made over the ureter and a 3 cm segment of the mid part of the ureter was removed. A 3 cm × 1 cm patch of AM was tabularized over a 6 French feeding tube and the margins were sutured. The new tube was used to bridge the defect by suturing the proximal and distal ends of the ureter by watertight interrupted sutures over a 5 Fr Double-J stent. Antibiotic therapy with Ampicilin (300 mg q 6h) was continued for one week after the procedure. After six weeks, the animals were sacrificed and the right kidney and ureter of each animal were re- moved and sent for pathological study. Two dogs died in the first week after the operation and the autopsy revealed urinary leakage from the site of anastomosis with subsequent uri- nary ascites. In another animal, the autopsy results showed a severely hydronephrotic kid- ney with a thin cortex (a bag of water) and dilation in the upper part of the ureter. The lumen of the reconstructed segment of the ureter was obstructed and the catheter was not detected in its place, migrating to the urinary bladder. The wall of the reconstructed segment was thick, hard and whitish. Histopathologic studies of the reconstructed segment contai- ning AM revealed infiltration of the inflam- matory cells and macrophages, causing severe acute and chronic inflammation with formation of granulation tissue (Figure 1). Areas of calcification and ossification in the outer wall were observed (Figure 2). In the four remai- ning animals, gross pathologic evaluation re- vealed mild pelvocaliectasis. The catheter was in the lumen, which was stenotic. The wall of the reconstructed segment was thick, hard and whitish. In microscopic evaluation, lympho- cytic and polymorphonuclear cell infiltration were detected in the renal parenchyma without glomerular or tubular damages. In the grafted segment, non-keratinizing stratified squamous metaplasia was detected along the ureter without any transitional epithelium (Figure 3). Lymphocytic and granulocytic infiltration asso- ciated with fibrosis was observed in the wall, but no specific ureteral layer (muscle layer and adventitia) was formed. The AM has several features that make it a source of stem cells. 5 Amniotic epithelial cells (AECs) do not ex- press HLA-A, HLA-B and HLA-DR on their surfaces. 6 They harbor HLA-G, which causes an immune tolerance by inhibition of natural killer cells and macrophages. 7 These findings may explain the reason as to why the AM is immunologically neutral, a characteristic that reduces the risk of rejection of the AM, while it is used as a biomedical scaffold. Some re- ports suggest that the AM can reduce inflam- mation. The stromal matrix of AM significantly suppresses the production of inflammatory cytokines. AM also contains natural inhibitors that can inhibit the matrix metalloproteinases produced by inflammatory cells. 8,9 The AM consists of an epithelial monolayer, a base- ment membrane and a stroma. The stroma is avascular and has several layers, each of which contain large amounts of glycoproteins, pepti- doglycans and collagen types I, III, IV and V. These large molecules play an important role in the attachment and migration of the host cells to the AM, which makes it a favorable substance to be used as a scaffold. 10 AM has been used as a biological matrix in the urinary tract in different studies. AM was used as a scaffold in the urinary tract, 11 and as a favorable biological matrix for urothelial cell growth and proliferation. 12 In addition, AM can act as a favorable substance for induction of epithelialization. 13 Few studies have eva- luated the results of the application of AM as a scaffold in the ureteral defects. In our study, in 57% of the cases, the non-keratinized stratified squamous epithelium was observed and in none of the cases, a normal ureteric wall tissue was formed. In the histopathological study, the signs of acute and chronic inflammations were detected in the implanted segments, which might be subsequent to the healing process and also due to the toxic effects of urine. Urine is a noxious stimulus and the formation of stra- tified squamous epithelium is a defense me- chanism to protect the tissue against the urine. Long-term urinary catheter may be responsible for the development of squamous metaplasia in the urothelium. Although the AM is expec- ted to be immunologically neutral, its rejection repression property may be applicable within the same species, but not across the species as in the present study (human AM to canine ureter); therefore, the inflammation observed in the reconstructed segments can also be considered as a rejection phenomenon. We observed that AM did not act as a favorable scaffold when it was used as a bridge in long circumferential ureteral defects, a finding which was similar to the results of the study performed by Osman et al. 14 Koziac et al intro- duced the application of AM as an encou- raging method to repair long ureteral defects while being used as a patch graft. 15 Although the patency of the ureter was confirmed by radiological imaging, the histopathological changes in the used AM were not evaluated in the Koziac study. Infiltration of the inflam- matory cells with fibrous tissue formation and lack of any specific layer of the ureter in the implanted segments imply that the AM was not a favorable biomaterial in the recons- truction of long circumferential ureteral de- fects in our study. Further studies are neces- sary to evaluate the efficacy of AM as a patch graft versus full circumferential graft in the reconstruction of ureteral defects. ...
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Recently, tissue engineering has been proposed as an alternative to reconstruct or replace craniofacial defect in facial plastic and reconstructive surgery. The biomaterials are the most important component of tissue engineering. Generally, the biomaterials are defined as any material that is used to replace or restore function to a body tissue and...
Citations
... A study compared the effects of acellular hAM to synthetic poly-L-lactide-co-1-caprolactone on human urothelial cell viability, proliferation, and urothelial differentiation levels, with unfavorable results for the amnion [137]. Salehipour et al. evaluated its use in the reconstruction of long ureteral defects in dogs and speculated its efficacy as a patch graft versus a full circumferential graft in the reconstruction of ureteral defects [138]. ...
An important component of tissue engineering (TE) is the supporting matrix upon which cells and tissues grow, also known as the scaffold. Scaffolds must easily integrate with host tissue and provide an excellent environment for cell growth and differentiation. Human amniotic membrane (hAM) is considered as a surgical waste without ethical issue, so it is a highly abundant, cost-effective, and readily available biomaterial. It has biocompatibility, low immunogenicity, adequate mechanical properties (permeability, stability, elasticity, flexibility, resorbability), and good cell adhesion. It exerts anti-inflammatory, antifibrotic, and antimutagenic properties and pain-relieving effects. It is also a source of growth factors, cytokines, and hAM cells with stem cell properties. This important source for scaffolding material has been widely studied and used in various areas of tissue repair: corneal repair, chronic wound treatment, genital reconstruction, tendon repair, microvascular reconstruction, nerve repair, and intraoral reconstruction. Depending on the targeted application, hAM has been used as a simple scaffold or seeded with various types of cells that are able to grow and differentiate. Thus, this natural biomaterial offers a wide range of applications in TE applications. Here, we review hAM properties as a biocompatible and degradable scaffold. Its use strategies (i.e., alone or combined with cells, cell seeding) and its degradation rate are also presented.
... The complexity of surgery procedure, toxic effect of urine, and high level of minimum requirements for candidate constructs have hindered the advances in this area. Different strategies of preparation and application of tissue-engineered constructs for ureter tissue reconstruction have been studied so far (El-Hakim et al., 2005;Wolfe et al., 2011;Zhao et al., 2012Zhao et al., , 2016Salehipour et al., 2013;de Jonge P. K. et al., 2018;Janke et al., 2019). As urinary diversion tissue engineering holds relatively similar requirements and problems to the ureter, the reconstructive approaches are quite comparable. ...
... Since ureter injuries are usually acute and require immediate management, surgeons need a graft ready for implantation, so most of the research in this field are dedicated to design a off-the-shelf grafts. Natural scaffolds, such as SIS, amniotic membrane, and decellularized ureter, were the most used materials, which have been employed for reconstruction of the ureter in dog, pig, rabbit, and rat models (Xie et al., 2000;Osman et al., 2004;Salehipour et al., 2013). In addition, collagen sponge (Tachibana et al., 1985;, Gore-Tex (Baltaci et al., 1998), and electrospun PLCL (Kloskowski et al., 2014) scaffold were tested, as bare scaffolds, for ureter tissue regeneration. ...
Functional disorders and injuries of urinary bladder, urethra, and ureter may necessitate the application of urologic reconstructive surgeries to recover normal urine passage, prevent progressive damages of these organs and upstream structures, and improve the quality of life of patients. Reconstructive surgeries are generally very invasive procedures that utilize autologous tissues. In addition to imperfect functional outcomes, these procedures are associated with significant complications owing to long-term contact of urine with unspecific tissues, donor site morbidity, and lack of sufficient tissue for vast reconstructions. Thanks to the extensive advancements in tissue engineering strategies, reconstruction of the diseased urologic organs through tissue engineering have provided promising vistas during the last two decades. Several biomaterials and fabrication methods have been utilized for reconstruction of the urinary tract in animal models and human subjects; however, limited success has been reported, which inspires the application of new methods and biomaterials. Electrospinning is the primary method for the production of nanofibers from a broad array of natural and synthetic biomaterials. The biomimetic structure of electrospun scaffolds provides an ECM-like matrix that can modulate cells’ function. In addition, electrospinning is a versatile technique for the incorporation of drugs, biomolecules, and living cells into the constructed scaffolds. This method can also be integrated with other fabrication procedures to achieve hybrid smart constructs with improved performance. Herein, we reviewed the application and outcomes of electrospun scaffolds in tissue engineering of bladder, urethra, and ureter. First, we presented the current status of tissue engineering in each organ, then reviewed electrospun scaffolds from the simplest to the most intricate designs, and summarized the outcomes of preclinical (animal) studies in this area.
... More recently, Iigma and others demonstrated that transplantation of preserved human amniotic membrane could successfully be used for bladder augmentation in rats, with resulting regeneration of a number of tissues in the bladder being demonstrated as early as 3 months postoperatively (26). Salehipour et al. have evaluated the use of human amniotic membrane in the reconstruction of long ureteral defects in dogs (27). In this study, the use of human amniotic membrane for the reconstruction of ureteral defects in a canine model was studied. ...
To examine the rationale and applications of amniotic tissue augmentation in urological surgery. Published literature in English-language was reviewed for basic science and clinical use of amniotic or amnion-chorionic tissue in genitourinary tissues. Basic science and animal studies support the likely benefit of clinical applications of amnion-derived tissues in a variety of urologic interventions. The broad number of properties found in amniotic membrane, coupled with its immunologically privileged status presents a number of future applications in the urological surgical realm. These applications are in their clinical infancy and suggest that further studies are warranted to investigate the use of these products in a systematic fashion.
... 15 AMs have been applied successfully in the reconstruction of long ureteral strictures in humans. 16,17 On the basis of these reviews above, we used decellularized human amniotic scaffolds (dHAS) seeded with canine bone marrow MSCs (BMSCs) and/or EPCs to repair long segment of circumferential urethral defect in model dogs, screen their repair effects, and provide reference data for clinical treatment of long segment of circumferential urethral defect cases of large animals and humans. ...
The treatment options for patients with a urethral defect are limited by the availability of autologous tissues. We hypothesized that transplantation of decellularized human amniotic scaffolds (dHAS) seeded with allogeneic bone marrow mesenchymal cells (BMSCs) and/or endothelial progenitor cells (EPCs) may serve as a promising repair strategy for long segment of circumferential urethral defect. To verify the hypothesis, with urinary catheterization, a 3-cm segment of whole urethra in 25 male mongrel dogs was excised and replaced by dHAS seeded with allogeneic BMSCs and/or EPCs. Postoperative observation and ascending urethrogram found that dHAS+BMSCs+EPCs and dHAS+EPCs groups demonstrated unhindered urination and capacious urethral caliber, which were similar to the normal group, while urethrostenosis was revealed in dHAS+BMSCs, dHAS and sham operated group, with the shortest narrow section in dHAS+BMSCs group and the longest in sham operated group. Urethral anatomy check and histological analyses showed that new urethral mucosa composed of stratified columnar epithelium completely covered on the inner surface of the graft site in dHAS+BMSCs+EPCs and dHAS+EPCs groups, but the middle epithelium was thin in dHAS+EPCs group, while incompletely covered in dHAS+BMSCs, dHAS and sham operated groups, and there were monolayer epithelial cells at the urethrostenosis in dHAS+BMSCs and dHAS groups. In addition, abundant new vessel and blood sinus showed at submucosa in dHAS+BMSCs+EPCs and dHAS+EPCs groups, instead of the scar tissue of collagen deposition and structural distortion at the urethrostenosis in dHAS+BMSCs, dHAS and sham operated groups. This study demonstrates that dHAS seeded with BMSCs+EPCs or EPCs can successfully repair a 3-cm circumferential urethral defect in model dogs, but the former works best. This technology may provide some references for human clinical trials on long segment of circumferential urethral defect repair.
... Other authors have evaluated different experimental techniques of ureteral reconstruction using free peritoneal grafts or patches [8,[19][20][21][22][23][24][25]. Thüroff and colleagues used a patch to envelop renal pelvis and ureter in case of extended perihilar inflammation or stenosis of the proximal ureter due to scarring. ...
Objective
To evaluate the feasibility and functional outcomes in porcine models of a novel robotic surgical technique for the treatment of complex ureteral injuries and strictures.
Materials and methods
Six pigs underwent robotic ureteral reconstruction using a long tabularized peritoneal flap and followed for 6–9 weeks after the surgery. Ureteral flap vascularity, intra-renal pressure, patency of the conduct, endoscopic aspect of the flap, renal function and histopathology were evaluated.
Results
All animals successfully underwent ureteral reconstruction using a tubularized peritoneal flap. Median operative time was 223 min (162–360). Flap tubularization suture took 31 min (19–47), and proximal anastomosis took 20 min (15–38). Bladder mobilization with psoas hitch and distal anastomosis took 9 min (7–12) and 23 min (13–46), respectively. On follow-up, significant shrinkage of the ureteral flap in both length and width was observed. Antegrade pyelograms confirmed dilation and tortuosity of the proximal ureter, dilation of the renal pelvis, and major and minor calyxes without any definitive strictures. Microscopically, focal urothelial lining was seen in the neoureter. Creatinine level was significantly higher at the end of the follow-up period (p = 0.003).
Conclusions
Robot-assisted ureteral reconstruction using a tubularized peritoneum flap is technically feasible and reproducible. The flap sustained abundant vascular supply after different intervals of follow-up and the peritoneal mesenchymal cells differentiated into urothelium and myofibroblasts. Further studies are needed to address the issue of functional obstruction to improve long-term renal function outcomes.
... Most early studies in ureteral tissue engineering used bare scaffolds, and almost all of them resulted in fibrosis, which may indicate the necessity of cell seeding [14-19, 21-24, 33]. This is supported by previous [27] Mice (F) PLLA, Collagen hADSC -S, T hUC Fu et al. [28] Mice (M) PLLA, Collagen hUC 1.0-1.5 S, T hUC Zhang et al. [29] Dogs (F) Autologous graft No 3.0 P, T UC, SMC, V Salehipour et al. [30] Dogs statements that cell seeding is required for large defects (>1.0 cm from the wound edge) to promote tissue regeneration and to prevent scar formation [34]. In most recent studies, cell seeding or pre-implantation of the scaffolds was explored to improve regeneration [27][28][29]31••, 32••]. ...
... The results, however, were not optimal in ureteral tissue engineering. Recently, Salehipour et al. [30] used amniotic membrane (AM), which is known for its anti-inflammatory properties, as a biomaterial to reconstruct long ureteral defects. In dogs, a 3.0-cm segment of the ureter was replaced by tubularized decellularized AM. ...
... In recent ureteral replacement animal studies, rabbits [31••, 32••], dogs [29,30], and in our case, pigs (unpublished) were used, while subcutaneous implantation studies were performed in rats [26] or mice [27,28]. The pig is the preferred model because the abdominal anatomy of pigs and humans is similar [52,53]. ...
Reconstruction of long ureteral defects often warrants the use of graft tissue and extensive surgical procedures to maintain the safe transport of urine from the kidneys to the urinary bladder. Complication risks, graft failure-related morbidity, and the lack of suitable tissue are major concerns. Tissue engineering might offer an alternative treatment approach in these cases, but ureteral tissue engineering is still an underreported topic in current literature. In this review, the most recent published data regarding ureteral tissue engineering are presented and evaluated, with a focus on cell sources, implantation strategies, and (bio)materials.
... It has been demonstrated that AM exhibits excellent properties of reducing inflammation, scarring, and the risk of rejection [8], as well as facilitating the migration, localization, and proliferation of epithelial cells, which largely depend on the function of the basement layer [9]. Amniotic membranes have been applied successfully in the reconstruction of long ureteral strictures in humans [10,11]. ...
... However, the use of human AM is relatively infrequent due to the shortage of tissue sources. AM xenografts prepared from non-human donors can dramatically expand AM sources for clinical use, but few studies have achieved satisfactory results using AM xenotransplantation in urethral reconstruction, probably due to anti-xenoresponses [11,12]. To overcome this limitation, we separated the basement layer of AM to obtain denuded human amniotic scaffold (dHAS), then engrafted primary rabbit urethral epithelial cells on the surface of dHAS to minimize potential xenograft rejection and maximize the biocompatibility of human AM. ...
Background
Mitigating urethral injury remains a great challenge for urologists due to lack of ideal biomaterials for urethroplasty. The application of amniotic membrane (AM) over other synthetic materials makes it a better potential source for urethral reconstruction. We separated the basement layer of AM to obtain denuded human amniotic scaffold (dHAS) and then inoculated primary rabbit urethral epithelial cells on the surface of dHAS to determine whether this strategy minimizes potential rejection and maximizes the biocompatibility of human AM.
Material/Methods
After the successful acquisition of dHAS from AM, cell-seeded dHAS were prepared and characterized. Both cell-seeded dHAS and acellular dHAS were subcutaneously implanted. Immune responses were compared by histological evaluation and CD4+ cell and CD8+ cell infiltrations. Then they were applied as urethroplastic materials in the rabbit models of urethral injury to fully explore the feasibility and efficacy of tissue-engineered dHAS xenografts in urethral substitution application.
Results
Mild inflammatory infiltration was observed in cell-seeded dHAS grafts, as revealed by fewer accumulations of CD4+ cells and CD8+ cells (or neutrophils or other immune cells). Urethral defects of rabbits in the urethroplastic group with dHAS implantation (n=6) were completely resolved in 1 month, while there were 1 infection and 1 fistula in the control group with acellular dHAS patches (n=6). Histopathological analysis revealed mild immune response in the cell-seeded dHAS group (P<0.05).
Conclusions
Tissue-engineered dHAS minimizes potential rejection and maximizes the biocompatibility of AM, which makes it a potential ideal xenograft for urethral reconstruction.
Objectives:
This study aimed to evaluate the efficacy of penile girth enhancement (PGE) using amniotic membrane (AM) as a graft in a rabbit model. Additionally, quantitative histological data of the structure of the penis were obtained by stereological studies.
Methods:
This study was conducted at the Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. In this study, 20 adult male rabbits of similar age and weight were allocated to two groups: sham surgery and surgery+AM. Both groups underwent surgery in which a longitudinal I-shaped midline incision was made in the tunica albuginea on the dorsal surface of the penis. The surgery+AM group underwent PGE using AM as a graft. The penile length and mid circumference were measured using a vernier caliper before and two months after the surgery.
Results:
The mean total volume and diameter of the penis significantly increased in the surgery+AM group (P <0.03 and P <0.04, respectively). On stereological evaluation, a significant increase in the mean volumes of the tunica albuginea and corpora cavernosa was observed in the surgery+AM group compared to the sham group (P <0.01 and P <0.03, respectively). Additionally, the mean volume densities of the collagen bundles, muscle fibres, cavernous sinuses, and the total number of fibroblasts and smooth muscle cells increased in the surgery+AM group compared to the sham group (P <0.05 each). No infections, bleeding or other complications were observed.
Conclusion:
The use of AM as a graft is a method that shows promising results for material use in penile enhancement. Thus, it may be considered for PGE in the future.
Polymers and scaffolds are the most significant tools in regenerative medicine. Urogenital disorders are an important group of diseases that greatly affect the patient's life expectancy and quality. Reconstruction of urogenital defects is one of the current challenges in regenerative medicine. Regenerative medicine, as well as tissue engineering, may offer suitable approaches while the tools needed are appropriate materials and cells. Autologous urothelial cells obtained from biopsy, bone marrow‐derived stem cells, adipose stem cells and urine‐derived stem cells that expressed mesenchymal cell markers are the cells that mainly used. In addition, two main types of biomaterials mainly exist; synthetic polymers and composite scaffolds that are biodegradable polymers with controllable properties and naturally derived biomaterials such as extracellular matrix components and acellular tissue matrices. In this review, we present and evaluate the most appropriate and suitable scaffolds (naturally derived and synthetic polymers) and cells applied in urogenital reconstruction.
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