Exploring better methods for treating urethral stricture caused by lichen sclerosus

Abstract

Lichen sclerosus (LS) is a chronic inflammatory dermatosis significantly associated with urethral stricture disease (USD), particularly affecting the genitalia in both sexes. While topical corticosteroids remain the first-line therapy for LS, their efficacy for deep urethral involvement is limited. Surgical intervention, primarily urethroplasty utilizing buccal mucosa grafts or lingual mucosa grafts, is often required for LS-associated USD but is associated with risks of recurrence and complications. This review explores the etiology, highlighting the roles of immune dysregulation, genetic factors, and the resulting fibrosis. Furthermore, we emphasize the emerging potential of urethral tissue engineering, which uses scaffolds seeded with progenitor or stem cells, as a promising approach for reconstructing complex LS-related strictures, although clinical translation remains limited. Future research should focus on optimizing tissue engineering solutions.

INTRODUCTION

Lichen sclerosus (LS) is a chronic inflammatory disease, and lichen sclerosus urethral stricture disease (LS USD) is a progressive and intractable disease. There are various potential etiological factors, such as autoimmunity, infection, and genetics, all of which are all inducers of this disease. In females, it is characterized by chronic and progressive dermatitis associated with vulvar thinning and inflammation, which are frequently accompanied by intense pain and itch.1 One study revealed that compared with other symptoms, sexual dysfunction is the most impaired factor when several measures are assessed in LS patients. In males, LS of the penis may induce dyspareunia, phimosis, and urethral strictures caused by scarring lesions in the glans penis, prepuce, and coronal sulcus.2 In reality, the exact etiology of LS in males and females is still unknown. The primary conditions to consider when distinguishing LS include lichen planus, lichen simplex chronicus, vitiligo, and various immunobullous disorders, such as mucous membrane pemphigoid and vulvar intraepithelial neoplasia. According to Campos-Juanatey et al.3, urethral stricture is a common complication of LS (approximately 15% of cases), and panurethral stricture is the most prevalent subtype. To date, there are many treatment options for LS and LS USD. Some conservative management strategies include topical corticosteroids (TCSs), topical calcineurin inhibitors, topical testosterone, topical androgens, CO₂ lasers, oral acitretin, ultraviolet radiation, platelet-rich plasma (PRP), and other hormonal treatments. Other therapies to treat LS include cryotherapy, photodynamic therapy, phototherapy, laser therapy, and systemic therapy. Among the known systemic therapies, oral retinoids and steroid-sparing immunosuppressants are included.4 If the LS involves the urethra and causes urethral stricture, surgical intervention should be performed. Some surgical treatments to solve LS USD include single-stage urethroplasty, two-stage urethroplasty, perineal urethrostomy, urinary diversion, and full-length urethral reconstruction.5 However, the complications and high recurrence rates of the abovementioned complications remain unsatisfactory. To address this issue, urethral tissue engineering has emerged as a promising approach for the repair of the urethra.

LS USD differs from typical urethral strictures because of its extensive involvement of the genital and perineal skin, resulting in cutaneous thinning, pallor, loss of elasticity, and scarring. Within the urethra, stricture formation represents a localized manifestation of this systemic disorder. LS-associated strictures are often not isolated or short; rather, they tend to be long-segment, multiple and may involve the urethral meatus. The skin and urethral plate affected by LS have poor blood supply, are fragile in texture, lack elasticity, and are in a state of continuous inflammation. These pathological features directly impact the feasibility of using local tissues for surgical reconstruction and adversely influence postoperative healing outcomes. Consequently, if surgical intervention merely addresses the stricture without managing or replacing the diseased tissue, the underlying disease progression continues, leading to stricture recurrence either at the original site or in adjacent regions. The recurrence rate in such cases is significantly higher than that in non-LS urethral stricture cases.

A critical surgical principle in managing LS-related strictures is to avoid the use of local flaps for reconstruction. Currently, oral mucosa is commonly used for urethroplasty. However, the limited availability of materials and complications in the donor area have brought new hope to tissue engineering technology for the treatment of urethral strictures caused by LS, especially for providing potential solutions for patients with complex, long-segment strictures and a lack of autologous tissue materials.

Although most investigations in this area remain at the preclinical or early clinical stages, tissue engineering has not yet become part of routine clinical practice. Considering the above factors, we aimed to explore special treatment methods for urethral strictures caused by LS compared with those for common urethral strictures and to explore new tissue engineering materials based on the etiology. This review systematically reviews existing research on the etiopathogenesis and various treatment approaches for LS and urethral stricture. This study explored the relationship between the LS and urethral stricture and concluded that future research should focus on developing new tissue engineering materials for urethral stricture caused by the LS.

EPIDEMIOLOGY

Accurate estimation of the LS incidence remains challenging because patients may have different clinical specialties. Not every physician can identify LS. Some patients may not go to the hospital to cure LS because some of them have no symptoms. LS can appear in male and female patients at any age, not only in adults but also in children. LS exhibits a bimodal age distribution: a primary peak in prepubertal females (mean age: 7.6 years) and a secondary peak in perimenopausal or postmenopausal females (mean age: 52.6 years).6 Prepubertal-onset cases constitute 94.6% of pediatric female cases (<18 years), in contrast with only 4.6% of adult female cases. Notably, the LS incidence among adult females is significantly greater during reproductive years than during postmenopausal periods.7

UPDATE ON LS ETIOPATHOGENESIS

Pathophysiology

The etiopathogenesis of LS remains incompletely understood. Emerging evidence implicates multifactorial interactions. Levy et al.8 reported that compared with controls, LS patients exhibit increased incidences of papillomavirus, varicella-zoster virus, and Epstein–Barr virus infections, suggesting potential viral triggers. Significant upregulation of the expression of cytotoxic T-cell markers (CD8⁺) and profibrotic chemokines (CCL-4) in LS-related urethral strictures indicates chronic immune activation. Autoantibodies against extracellular matrix protein 1 (ECM1), an 85 kDa glycoprotein, can serve as a potential basis for autoimmunity and may initiate matrix metallopeptidase 9/transforming growth factor beta (MMP9/TGF-β) cascades that drive fibroblast collagenogenesis.9 Cohen et al.10 performed a comparison between LS patients and non-LS patients and reported that organisms differed between the two kinds of patients. Specific bacterial genera, including Tissierellaceae, Sneathia, and Lactobacillus, were enriched in the urine of people with LS USD. Moreover, in terms of LS status, the abundances of Propionibacteriales and Fusobacteriales were greater in the LS group.11 Evidence indicates that compared with one-stage procedures, perineal urethrostomy has a higher revision rate and a lower overall success rate. On the basis of these findings, we speculate that the bacteria in the urine may inevitably be connected to the urethral stricture caused by LS.5,12 Several investigations have shown that the urinary tract possesses a unique microbiome, and more correlations should be identified to determine the function of bacteria in its pathophysiology.10 To determine whether dysbiosis can lead to inflammation, fibrosis, and carcinogenesis, further research is needed.13

Genetics

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence-specific manner. miRNAs have various expression patterns and play important roles in disease generation and development, and they help sustain intracellular environmental homeostasis and regulate diverse physiological processes.14 Accumulating evidence suggests that miR-142-5p might serve as a biomarker for LS treatment and diagnosis.15 Additionally, a study performed by Kohli et al.16 compared miRNA expression between LS and non-LS USD. Indeed, they reported that 27 miRNAs, including one of the most dysregulated miRNAs, miR-155-5p, were differentially expressed between the groups. This growing attention to miRNAs will urge scientists and doctors to discover new novel therapeutic targets to heal or control LS. For male LS, there is little evidence of a genetic predisposition, although this is implicated in women. While certain human leukocyte antigens (HLAs) have been linked to male LS, the same HLAs seem to confer protection against vulvar LS in females.17 Genetic studies on cohorts with LS have shown a strong correlation with HLAs and specific haplotypes. These include DQ7, DR12, DRB112, and DRB113, indicating a genetic predisposition associated with LS.18 LS does exhibit a greater familial predisposition, suggesting a genetic contribution to the condition.

Immune dysregulation and the inflammatory response

The specific mechanism through which LS leads to urethral stricture is still unknown and involves several factors, including autoimmune responses, inflammation, tissue fibrosis, and structural destruction. Immune system dysfunction and chronic inflammation are considered two primary pathological processes. Limited research has indicated a potential link between LS and certain autoimmune conditions, including thyroid disorders, vitiligo, and psoriasis.19 In the advanced stages of LS, the condition is characterized by a degenerated epidermis, featuring plug-like formations akin to comedones and a fissure within the stratum corneum. Additionally, there is an increase in dermal hardness, a decrease in and expansion of blood vessels in the dermis, and the disappearance of skin appendages.20 Autoantibodies targeting EMC1 might trigger the activation of MMP9, which subsequently activates TGF-β.9,21 TGF-β and bone morphogenetic protein 2 (BMP2) subsequently stimulate fibroblasts to produce collagen types I and III.22 Moreover, galectin-7 also promotes the synthesis of collagen types I and III.23 Excessive deposition and abnormal alignment of collagen are key factors in scar formation. The metabolism of ganglion collagen may contribute to the treatment and prevention of scars and could be a target for future treatments. DNA methylation (DNAme) deconvolution indicated a significant increase in T-cells and a decrease in fibroblasts in LS patients. DNA methylation in LS was significantly associated with immune and collagen pathways. Furthermore, CD99 signaling between T-cells and fibroblasts was markedly enhanced, as shown by cellular communication analysis. Therefore, targeting CD99 signaling presents a novel therapeutic opportunity for LS.24

CONSERVATIVE MANAGEMENTS

TCSs

TCSs are the first-line treatment for LS, effectively alleviating pruritus in most cases. A retrospective cohort study by Kohn et al.25 revealed that vulvar itching, lesions and architectural changes, or vulvar pain, burning, and discomfort were the primary presenting symptoms prompting initial medical consultation. Patients adhering to prescribed TCS regimens were more likely to demonstrate symptomatic and physical examination improvements. Notably, ultrahigh- and high-potency TCS formulations were significantly more effective at achieving substantial improvements. Furthermore, TCS treatment may also improve associated sexual dysfunction.25 However, a longer duration of topical corticosteroid treatment does not seem to improve the clearance of vulvar LS.26 Nevertheless, the impact of steroids is primarily localized to inflammation, which might be beneficial for external conditions such as LS affecting the glans penis or urethral meatus. However, exerting a steroidal influence in the more distant parts of the urethra becomes challenging.

Topical calcineurin inhibitors (TCIs)

TCIs, such as tacrolimus ointment and pimecrolimus cream, are effective for treating various immune-mediated dermatoses, including atopic dermatitis. Owing to their suppressive effect on the immune system, TCIs have been evaluated for treating various skin conditions that are mediated by the immune system, including vulvar LS. Significant clinical experience supports their efficacy in managing LS, particularly in terms of oral manifestations.27 TCIs are second-line treatments for LS if TCSs are ineffective and are typically applied twice daily.28 Comparative studies have shown that while both tacrolimus and clobetasol reduce LS symptoms and signs, clobetasol demonstrates significantly superior clinical efficacy (P < 0.05).29

Photodynamic therapy (PDT)

PDT is an emerging treatment for nonmalignant dermatological conditions. As a novel approach to treating LS, PDT shows promise for controlling chronic symptoms and reducing disease recurrence at early stages.30 A comparative study by Shi et al.31 evaluated the efficacy and adverse reactions of PDT versus TCSs in LS management. Patients were randomized into two groups: one receiving TCSs (corticosteroid group) and the other receiving PDT (PDT group). Compared with the corticosteroid group, the PDT group demonstrated a significantly higher complete response rate. At the 6-month follow-up, symptoms such as pruritus, burning sensation, and pain recurred or worsened more frequently and severely in the corticosteroid group than those in the PDT group. This evidence establishes PDT as a safe and effective therapeutic option for patients with relapsing or severe LS.31 Collectively, these findings indicate that PDT is an effective intervention for distressing symptoms and clinical lesions of vulvar LS.

SURGERIES

Despite significant advances in surgical techniques, urethral reconstruction continues to pose substantial clinical challenges in urology. The field currently lacks universally accepted consensus guidelines to cure urethral stricture caused by LS, with no standardized protocols achieving widespread endorsement.32

Urethroplasty

Dorsal onlay urethroplasty currently represents the primary surgical approach for urethral stricture in patients with LS. When graft materials are selected, oral mucosa constitutes the preferred tissue source. Buccal mucosal grafts (BMGs) remain the gold standard because of their favorable characteristics, such as infection resistance, the absence of hair follicles, and a thick epithelium, which help mitigate graft contracture, while a thin, highly vascular lamina propria facilitates graft integration. Emerging evidence supports lingual mucosal grafts (LMGs) as a clinically comparable alternative to BMGs, demonstrating equivalent efficacy in contemporary urethroplasty outcomes. We generally do not use skin for urethroplasty in LS patients. LS-affected skin and the urethral plate are poorly vascularized, friable, and non-elastic because of chronic inflammation. These pathological changes undermine their suitability as local flaps for reconstruction and negatively affect surgical outcomes.

The ventrolateral tongue surface represents the optimal harvest site for LMGs in urethroplasty. While this approach minimizes functional impairment, potential transient complications include lingual numbness, dysarthria, and dysgeusia. The overall urethroplasty success rate when LMGs were used reached 82.7%. Two principal techniques are employed: unilateral dorsal onlay augmentation urethroplasty and dorsal patch graft urethroplasty. Postoperative complications may include stricture recurrence, iatrogenic strictures, and urethral fistulas.33 A prospective study by Hussein et al.34 confirmed that dorsal onlay urethroplasty with LMGs provides durable reconstruction for LS-associated urethral strictures, with 88.2% patency maintained at the 5-year follow-up. Failures predominantly occur within the 1^st postoperative year, after which graft stability increases significantly. LMGs harvesting is associated with minor, self-limiting oral morbidity and no documented long-term functional deficits.

BMG urethroplasty remains a viable surgical option for LS-associated urethral strictures. A cohort study (n=625) by Kurtzman et al.35 reported an initial stricture recurrence rate of 10% posturethroplasty. This percentage increased significantly to 18% at the 24-month follow-up, confirming that compared with non-LS patients, LS patients have substantially higher recurrence rates.35 Further large-scale studies with extended follow-up periods are needed to establish definitive therapeutic outcomes.

Remarkable evidence of intestinal mucosa grafts in urethral strictures has been reported. Xu et al.36 explored the use of a colonic mucosa graft for urethral stricture, which was feasible, with success in 30 of 35 people. Recently, Palmer et al.37 explored novel techniques for the acquisition of rectal mucosa grafts via transanal endoscopic microsurgery, with a success rate of 75%. During the follow-up period of the colorectal surgery, no complications occurred, and all the patients had normal bowel function.37 Repair means included ventral or dorsal onlay and 2-stage repair. Harvesting a rectal mucosa graft through the transanal approach for urethroplasty is a secure method of reconstruction when a graft from the buccal mucosa cannot be obtained or is deemed inappropriate.

Perineal urethrostomy

Perineal urethrostomy is typically utilized for patients who have other health issues or are dealing with extensive and complicated anterior urethral strictures. Although studies have shown that this procedure has a high rate of success after surgery, it is not commonly the first choice for treatment. Peterson et al.38 reported that longer strictures resulting from LS are more suitable for perineal urethrostomy than for staged reconstruction.

TISSUE ENGINEERING

The surgical treatment of urethral strictures through substitution urethroplasty, which involves the use of grafts or flaps to address narrowing of the urethra, continues to be among the most difficult procedures in the field of urology. It is often linked to complications, recurrence of stenosis, and a diminished quality of life for patients. Nevertheless, the use of flaps or grafts may not always be feasible because of the suboptimal condition of the graft bed or when the patient suffers from LS.12 The application of tissue engineering, which utilizes a variety types of cells and scaffolding materials, presents a hopeful new approach for the repair and replacement of tissues. When urethral reconstruction fails to meet these requirements, we can solve this problem through tissue engineering. The management of long segments or multiple recurrent complex strictures for patients with extremely long strictures (>10 cm) or severe urethral fibrosis after multiple surgeries has very limited available autologous tissues, resulting in significantly reduced surgical success rates. With respect to tissue engineering, grafts of any length and shape can be constructed, providing new hope for the most complex cases. Although oral mucosa is currently the preferred option, it is not the urothelium and may have long-term metabolic and structural mismatch problems. Therefore, tissue engineering offers a solution by constructing grafts with greater histological similarity. For example, autologous urothelial cells can be used to seed urothelial cells onto the scaffold to form true urethral tissue. Restenosis rates still exist, especially in high-risk patients, such as those with LS strictures, for whom the failure rate is relatively high. The main cause of failure is the necrosis and fibrosis of the graft due to poor blood supply. In tissue engineering, host blood vessels are actively recruited to grow into the scaffold through the loading of growth factors and angiogenic factors such as vascular endothelial growth factor (VEGF). Recognizing the urgent demand for innovative and efficacious materials to address extensive and intricate urethral defects, the field of urethral tissue engineering is currently a priority area of investigation. The majority of approaches to construct the urethra involve dual elements: a structural framework known as a scaffold and cellular components that act as a shield against fluid seepage. When urethral substitutes are being constructed, many challenges still need to be overcome. The cells in the scaffold could not be washed away with urine. They must be biocompatible to prevent scarring, infection, and stenosis. During the erection process, they must be able to stretch to maintain the patient’s postoperative sexual function. They must be watertight to prevent urine from leaking into the structure. Therefore, we should select the appropriate scaffold and cells to construct the urethra.

Selection of scaffolds

Scaffolds are designed constructs that serve as supportive matrices for anchoring transplanted cells or recipient tissues, thereby promoting tissue regeneration. An optimal scaffold should create a conducive environment for cell attachment and offer sufficient strength and stiffness to avoid deformation before the new tissue is fully formed. Furthermore, it should be designed to degrade and be reabsorbed by the body over time without causing significant immunological reactions, toxicity, or foreign body responses.39 After the cells have integrated into the scaffold, whether through external seeding or migration from surrounding tissues. These cells need to properly align and differentiate in accordance with the specific histological structure of the urethra. This structure is characterized by urothelium or urothelium-like stratified and (or) pseudostratified columnar epithelium on the inner surface and fibromuscular tissue within the urethral wall.40 The present investigations in the field of urethral reconstruction are predominantly concentrated on two types of scaffolding materials: natural materials and synthetic polymers.

Natural scaffolds for urethral reconstruction can be categorized into two types: one type consisting of acellular tissue matrices that are obtained through the mechanical and biochemical process of decellularizing donor tissues, and the other type involving bioengineered constructs that are made by combining natural substances such as collagen and elastin.41 In the context of urethral repair, commonly utilized acellular matrices include porcine xenografts such as small intestinal submucosa (SIS) and bladder acellular matrix (BAM).42

Decellularized scaffolds offer the benefit of preserving the natural histological architecture and biochemical properties of the original ECM, including essential components such as collagens, elastin, laminins, and a variety of growth factors and bioactive molecules.43 In addition to decellularized patches, scaffolds can be crafted from natural materials to mimic the ECM of the targeted tissue. Collagen is a popular choice for decellularized scaffolds, but other substances, such as alginate and silk, are also utilized.44

To increase cell seeding efficiency and viability, bioactive agents such as specific growth factors can be integrated into the scaffold. Examples include VEGF,45 epidermal growth factor (EGF),46 basic fibroblast growth factor (bFGF),47 and nerve growth factor (NGF).46 These compounds can be incorporated through various methods, such as covalent bonding, passive entrapment, or other chemical integration techniques, depending on the desired characteristics, including the final concentration and the rate of release.

Scaffolds utilized in urethral reconstruction often consist of biodegradable polymers, such as polylactic acid (PLA), polylactic coglycolic acid (PLGA), poly-L-lactide-co-ε-caprolactone (PLCL), and polyglycolic acid (PGA). Numerous synthetic scaffolds have received the US Food and Drug Administration (FDA) approval and have been employed in surgical procedures for many years.48,49 To prevent fibrosis and stenosis around the scaffold, promote cell transplantation and proliferation, and minimize the foreign body reaction against the scaffold, natural materials such as collagens, elastin, laminin β1 chain, or growth factors can be incorporated into the synthetic matrix.50

Selection of cells

Urothelial cells were obtained through surgical biopsies of the bladder and subsequently cultured. They were then seeded, either alone or in combination with other cell types, primarily smooth muscle cells (SMCs), to increase the graft’s viability and integration.51 Isolating autologous urothelial cells from urine or bladder washes is a noninvasive approach that has been successfully employed in tissue engineering.52,53

Autologous epithelial progenitor cells derived from the oral mucosa and the foreskin which possess certain benefits, such as being readily accessible, having a low risk of immune rejection, and having the ability to develop into a robust epithelial layer that can withstand moist conditions.54 However, this approach is not feasible for patients with LS. Keratinocytes derived from the oral cavity, specifically from the buccal or lingual mucosa, have been widely studied for their use in urethral reconstruction because of their ability to form a thick epithelium and their ease of harvest.55

In the field of regenerative medicine, including reconstructive urology, stem cells have garnered significant attention. Stem cells are less specialized than progenitor cells and are defined by their two core attributes: the ability to self-renew and their pluripotency.56 They hold promise as a viable cell source for urethral reconstruction because of their potential proangiogenic effects, anti-fibrotic actions, and immunosuppressive capabilities. In theory, with the right growth factors, adult stem cells can differentiate into any cell lineage, making them a versatile tool for tissue regeneration in urethral repair.57

Bone marrow stem cells in reconstructive urology possess several advantages, including low immunogenicity and high levels of various growth factors, such as hepatocyte growth factor (HGF), platelet-derived growth factor-homodimer polypeptide of B chain (PDGFB), TGF-β1, and VEGF. For instance, HGF is known to promote cell growth, survival, and motility, whereas PDGFB is important for angiogenesis and wound healing. TGF-β1 is involved in the regulation of cell growth, differentiation, and other functions, and VEGF is essential for the development of the vascular and lymphatic systems. Owing to their potential to differentiate into various cell types, including urothelium and SMCs, stem cells offer a promising cell source for urethral reconstruction, leveraging their regenerative capabilities to increase graft survival and integration.58

In contrast to adipose-derived stem cells (ADSCs), urothelial-derived stem cells (UDSCs) exhibit enhanced proliferative and colony-forming capabilities, robust expression of stem cell markers such as CD44, SSEA4 (a pluripotency marker), and CD73. Additionally, UDSCs have been observed to exert a suppressive effect on the immune system, as observed under both coculture and isolated culture conditions.59 Furthermore, compared with ADSCs, UDSCs have superior potential for differentiation into myogenic, neurogenic, and endothelial lineages and tend to differentiate more readily into adipocytes, chondrocytes, and osteocytes.60

ADSCs can be readily harvested in substantial amounts through liposuction. Urothelial cells can be effectively derived from ADSCs through various methods: in vitro, by employing coculture techniques or specific induction media, and in vivo, by means of xenograft implantation.61

DISCUSSION

Several studies have explored the use of skin flaps and oral mucosa grafts for the correction of urethral strictures that cannot be managed through excision and reanastomosis. Nonetheless, these methods are not always viable because of the suboptimal condition of the graft bed or when patients suffer from LS. Current therapeutic options for urethral strictures, particularly complex panurethral cases, remain clinically limited. Iterative interventions for recurrent strictures impose substantial economic and psychological burdens on patients.62 There is an evident demand for innovative and efficacious materials to address extensive and intricate urethral structures, making tissue engineering of the urethra a highly prioritized field of research.63

LS, a chronic inflammatory skin condition that predominantly affects the genital areas, can complicate urethral reconstruction because of the increased collagen secretion activity of fibroblasts in affected skin, which can exacerbate urethral narrowing. This condition is more common in women and is associated with other autoimmune diseases. The standard treatment for LS involves the use of potent TCSs, and in some cases, oral medications or surgery may be necessary.

In the context of urethral stricture treatment, various surgical approaches exist, including catheterization, dilation, urethroplasty, endoscopic urethrotomy, and the use of implanted stents or long-term catheters. However, these methods may have their own set of complications and risks, such as infection, bladder irritation, and urinary tract infections.

Tissue engineering offers a promising alternative for urethral reconstruction. It relies on the use of cells, biomaterials that act as scaffolds, and environmental parameters such as growth factors. Different cell sources, including progenitor cells and stem cells, have been explored for use in urethral tissue engineering. For instance, autologous urothelial cells, epidermal cells, oral keratinocytes, and smooth muscle cells have been investigated for their potential use in urethral reconstruction. Biomaterials such as acellular tissue matrices and synthetic polymers are also being studied for their applicability in urethral reconstructive surgery. Despite the potential of tissue engineering in preclinical studies, its clinical translation has been limited. Only a few clinical studies have been reported, and they have shown mixed results. Multiple studies have concluded that SIS has limited efficacy as a reconstructive material, with consistent reports of complications and stricture formation in experimental animals. Compared with cell-seeded, untreated SIS scaffolds, a modified SIS scaffold seeded with urothelial cells or autologous UDSCs produces better urethroplasty outcomes.64,65 While tissue-engineered constructs demonstrate initial efficacy in short-term studies, longer-term trials are nevertheless critical to validate their durability and translational potential for clinical use.

Biological scaffolds and synthetic scaffolds are currently the two most widely used types of scaffolds. Natural biological materials are more commonly used in clinical research and applications because of their excellent biocompatibility and bioactivity. Stem cells are the core of tissue engineering and are responsible for the formation of new functional tissues. An ideal cell source should be easily accessible, have a strong expansion capacity, and have low immunogenicity. Using a patient’s own cells, such as urothelial cells, can completely avoid immune rejection and ethical issues, making it the preferred strategy for clinical translation. Stem cells have strong self-renewal and multidirectional differentiation potential, which is an ideal solution to the problem of insufficient autologous cells and sample collection trauma. Currently, animal experiments using tissue engineering materials have been conducted, and in the future, we will attempt to load UDSCs on the scaffolds, hoping to open up a new path for urethral reconstruction.

Various tissue engineering materials have been used for urethral reconstruction after urethral stricture. However, to date, there remains a lack of specific materials that target this underlying cause and are available for clinical use in the management of urethral stricture caused by LS. More targeted tissue engineering urethras are needed. We discuss the potential basis of LS and the current mainstream trend in the treatment of urethral stricture. Whether various factors can be combined to repair the damaged urethra in the future may constitute a mainstream research direction. Further research is needed to fill the gap in this field and further advance preclinical studies so that a treatment for urethral stricture caused by LS can be applied in clinical practice as soon as possible.

In conclusion, while tissue engineering holds great promise for addressing the challenges associated with urethral reconstruction, particularly in cases complicated by LS, more controlled preclinical and clinical studies are needed to determine its efficacy and to improve the translation of these techniques into routine clinical practice.

AUTHOR CONTRIBUTIONS

JQA drafted the manuscript. JWW provided conception of the design of the review, interpretation of included studies, and critical revision of the manuscript. Both authors read and approved the final manuscript.

COMPETING INTERESTS

Both authors declare no competing interests.