The future of anterior urethral strictures and urethroplasty in adult men: a narrative review

Introduction

Urethral strictures are common urological conditions that manifest as abnormal narrowing of the urethral lumen that impedes voiding function (1-3). Etiologies of urethral strictures in men have varied causes: blunt or penetrating traumatic injuries leading to spongiofibrosis or urethral epithelium disruption due to inflammatory, iatrogenic, or idiopathic causes (4). Patients with urethral strictures may present with lower urinary symptoms and obstructive voiding symptoms including hesitancy, poor stream, intermittent flow, post-void dribbling, the feeling of incomplete bladder emptying, and dysuria (5). Rarely, patients can present with renal failure if they are not treated in a timely fashion. Workup and diagnosis of a suspected stricture include retrograde urethrography, uroflowmetry, post-void residual, urethrocystoscopy, voiding cystourethrogram, urethral ultrasound cystourethroscopy, magnetic resonance imaging (MRI), or computed tomography (CT) urethrography with 3D reconstruction, which may be helpful for additional visualization and characterization (5-9).

Approach to treatment is contingent upon the stricture’s location, length, and underlying mechanism. Available treatment includes endoscopic management with dilation or direct visual internal urethrotomy (DVIU) with or without adjunct injections, urethral stents, or urethroplasty. Dilation can be safely accomplished with a S-curved coaxial dilator, designed to facilitate passage through the male urethra anatomy (10). Endoscopic procedures can be a first line treatment for short (<2 cm) strictures, but long-term success rates fluctuate from 35–70% (11). Another option is urethral stents, but they are no longer recommended due to complications including stent migration, encrustation, hyperplastic tissue reactions, and irritable voiding symptoms (5). Urethroplasty is widely-accepted for urethral strictures and can be performed with varied techniques (12,13). Anastomotic repair for isolated short urethral strictures can either be vessel-sparing or transecting (14). Substitution urethroplasty using tissue transfers can also be completed using either flaps from the penile skin or grafts from skin, bladder epithelium, rectal mucosa, or oral mucosa. Notably, buccal mucosa graft urethroplasty has success rates exceeding 80% (15,16). Buccal mucosa graft urethroplasty has been successful in both primary urethral strictures and rescue procedures following previous prostate surgeries or failed urethral repairs (17-21). Despite high success rates of urethroplasty, the variability in postoperative success definitions necessitates refinement to optimize patient-reported outcomes, reduce post-operative symptoms, and mitigate stricture recurrence (4,22-24).

Presently, the field is witnessing growing research aimed to revolutionize urethroplasty through novel techniques, biomaterials, and technological advancements. From tissue engineering to small molecules that promote urethral healing, emerging research may redefine urethral reconstruction. This narrative review article aims to elucidate such approaches and new findings. We present this article in accordance with the Narrative Review reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-23-246/rc).

Methods

To conduct this literature review, the first author searched “Urethroplasty” on PubMed on September 13, 2023, with the following terms: “Robotic”, “Endoscopic”, “Open”, “Tissue engineering”, “Reconstruction”, and “Future” (see Table 1). Because our review paper aims to highlight new innovations of urethroplasty, papers not published within the past 5 calendar years (before September 13, 2018) were excluded in our initial query. Responses/editorial comments, transgender, hypospadias, pediatric, female stricture, non-English, and unrelated papers were excluded from the review (see Figure 1). We focused our review on urethroplasty for urethral strictures and not for pelvic fracture urethral injuries.

Figure 1 CONSORT diagram for included articles.

Discussion

Endoscopic innovations

DVIU is a popular endoscopic procedure for urethral strictures due to its ease of performance and low complication rate. However, previous data from 76 patients revealed stricture-free rates after the first DVIU to be as low as 8% with a median time to recurrence of seven months (25). Stricture-free rates decrease with successive DVIUs and approach 0% with long-term follow-up. More recent data from the OPEN trial, a parallel-group, open-label, randomized trial of open urethroplasty versus endoscopic urethrotomy for recurrent urethral strictures in men, showed more encouraging results (26,27). A similar magnitude of symptom improvement was seen between the two groups after 2 years of follow-up with mean voiding symptom scores improving from 13.4 to 6 for the urethroplasty group (n=69) and from 12.2 to 6.4 for urethrotomy group (n=90). The urethroplasty group had fewer reinterventions, but urethrotomy was more cost-effective and should be still considered as a potential option for the management of urethral strictures. One solution to decrease stricture recurrence rates with DVIU is the addition of corticosteroid injections to inhibit scar formation (28,29). Others have trialed mitomycin C and found similar success in significantly reducing urethral stricture recurrence rates after DVIU (30,31).

The Optilume (Urotonic, Plymouth, MN, USA) drug-coated balloon (DCB) is a more effective long term endoscopic treatment for urethral strictures (32). This method combines balloon dilation and paclitaxel drug delivery at the stricture. Paclitaxel is an antiproliferative, antimicrotubular agent that arrests the cell cycle to prevent new tissue formation and fibrotic scarring (33). The ROBUST III Study, a randomized, single-blind trial evaluating Optilume versus endoscopic management of recurrent anterior male urethral strictures found that the DCB is safe and superior to standard DVIU for strictures <3 cm in length (34). Anatomical success for Optilume was significantly higher than the control at six months (75% vs. 27%) with more durable symptom and urinary flow rate improvement. However, a limitation to the ROBUST III study was the lack of standardized endoscopic treatment for patients in the control group as they were treated by endoscopic serial dilation with urethral sounds, DVIU, balloon dilation, or a combination. Three-year results from the ROBUST I Study found sustained symptomatic improvement after treatment with Optilume for men with recurrent bulbar urethral strictures <2 cm in length (35). A cohort Markov model study conducted in England to estimate the costs saved over a five-year timeline of adopting Optilume versus current endoscopic methods estimated a cost saving of £2,502 per patient (36). Optilume may be a cost-saving and effective method to treating urethral strictures prior to more involved procedures such as urethroplasty. However, lengthy strictures are a limitation to this treatment. Longer term data is needed to study Optilume as a treatment modality.

The Memokath stent (Pnn Medical A/S, Kvistgaard, Denmark) is an older stent with a “memory-shape effect” feature. After endoscopic positioning, the stent is anchored by warm water. If desired, removal of the stent is facilitated by flushing cold water to soften the coils. The Memokath stent remains a subject of debate due to a wide spectrum of outcomes. Recent research has found that when compared to polymer-coated bulbar urethral stents for management of traumatic bulbar urethral rupture after primary realignment, the Memokath had comparable functional results but higher complication rates including more discomfort, granulation tissue formation, and post-void dribbling (37). Thus, using the Memokath stent for urethral management is nuanced and should be based on shared decision-making with patients.

Refinement of buccal graft urethroplasty

Urethroplasty is the gold standard treatment for urethral strictures. The most successful graft has been and remains buccal mucosa because it possesses the following characteristics: ease of accessibility and harvest, lack of hair, durability and viability in a moist environment, and the presence of a thin lamina propria to facilitate neovascularization (38). Compared to anastomotic urethroplasty for bulbar urethral strictures, studies suggest buccal mucosa grafting results in less penile complications and stricture recurrence (39,40).

Oral mucosal graft substitution urethroplasty can be categorized into single-stage and multi-staged procedures. Single-stage procedures can be subdivided into onlay augmentation, augmented anastomotic procedure, and tube augmentation (41). A single-stage dorsal inlay buccal graft urethroplasty, with or without using the “sliding-T” technique, can be used for fossa navicularis strictures, yielding satisfactory outcomes with minimal complications (42,43). If there is inadequate urethral tissue, a double-face urethroplasty can be completed with dorsal or ventral approaches with success rates ranging from 86–90% (44-46). Challenging lichen sclerosis urethral strictures can be managed through multi-stage buccal graft urethroplasty, typically in two stages (47). The initial stage involves the application of the buccal mucosa graft, followed by tubularization closure in the subsequent stage. High-risk and long strictures may indicate a graft plus flap substitution urethroplasty where a neourethral lumen is created using a buccal graft with additional coverage from gracilis muscle or fasciocutaneous penile flaps (48,49). In distal and primary strictures, a new streamlined “two-in-one” stage approach where graft tubularization can be performed in the same surgical procedure as the first stage of the classical approach, can be performed to reduce surgical burden on patients while maintaining outcomes (50). In addition to mitigating the frequency of surgical interventions required for buccal graft urethroplasty, a retrospective analysis involving 143 patients (87 inpatient and 56 outpatient) revealed that buccal graft urethroplasty can be safely performed in an ambulatory setting without increased rates of complications or compromising outcomes (51).

Recent advancements in minimally invasive techniques have presented promising approaches for substitution graft urethroplasty in the posterior urethra. Notably, single-port robotic posterior urethroplasty using buccal mucosa grafts has demonstrated durability, safety, and comparability to traditional open approaches in nine patients (52). Robotic surgery could also be combined with transabdominal and open transperineal approaches for complex anastomotic urethroplasties and allow adjunctive procedures such as prostatectomy or fistula repair (53). Distal and fossa navicularis urethral strictures have been treated by a transurethral buccal mucosa graft inlay urethroplasty technique with excellent intermediate term outcomes without the need for transection (54,55). A recent series demonstrated a novel minimally invasive endoscopic approach to buccal graft urethroplasty utilizing the RD 180 endoscopic suturing device as a pulley phenomenon and showed promising 6-month post-operative outcomes (56). In our own hands, we utilized a Collins needle to endoscopically fix a buccal graft into intraurethral position. By using a barbed Vicryl stitch via the endoscopic needle as a “sewing machine” (57), we have had success with two patients with posterior urethral stenosis. We anticipate technology to evolve in this space and allow endoscopic approaches that more closely resemble traditional open urethroplasty. Long-term data is needed to ascertain effectiveness and impacts on quality of life.

An alternative endoscopic method augmenting DVIU with endoscopic graft delivery and fixation using a liquid buccal mucosa graft was trialed in rabbits and demonstrated engraftment with improvement of urethral strictures on retrograde urethrograms and urethroscopy (58). A repeat trial with a robust randomized control study design found 67% (8/12) of rabbits exhibited engraftment compared to none (0/13) in the control group with 58% (7/12) of treated rabbits showing radiographic resolution or improvement of strictures compared to 38% (5/13) rabbits in the control group (59). Although statistical significance regarding stricture improvement was not attained in the randomized control trial, improvement in the majority of liquid buccal mucosa graft rabbits is promising.

Alternatives to the buccal mucosal graft

Bowel mucosa is an alternative for patients deemed unsuitable candidates for buccal mucosal graft urethroplasty. Using bowel mucosa offers several advantages including avoiding oral discomfort and future concerns related to limitations in speech and mastication and longer graft availability for more complex strictures. A case series of five patients, either with prior failed buccal mucosal graft urethroplasty or lack of healthy buccal tissue, exhibited promising short-term outcomes after undergoing rectal mucosal graft urethroplasty (60). In instances of more complex or lengthy strictures where oral mucosa graft length is insufficient for substitution, a transanal endoscopically harvested rectal mucosa graft can be utilized for successful urethroplasty (61,62). Robotic methods for rectal mucosa harvest using a single-port GelPOINT path transanal access platform have recently been described in several cases with preliminary results demonstrating no post-operative complications across nine patients (63-65). Bladder mucosa has also been trialed because of similar tissue characteristics, but the main limitation described has been the invasiveness of open harvesting. However, recent advancements in minimally invasive techniques has resulted in using an endoscopic Holmium Laser to harvest bladder mucosa with successful post operative uroflowmetry showing 21 mL/s and no bladder sequelae (66). Another alternative to the buccal mucosal graft is an everted saphenous vein graft (eSVG). In a prospective human study with seventeen patients who had long strictures and tobacco-exposed oral mucosa, eSVG urethroplasty demonstrated success in sixteen patients (67). Results from a prospective nonrandomized study comparing fifteen eSVGs and fifteen oral mucosa grafts appear comparable with the International Prostate Symptom Score (8.0 vs. 7.9), uroflowmetry (22.6 vs. 25.6 mL/s), and postoperative complications (68).

Emerging new research and techniques in urethral tissue engineering

Novel tissue engineering technology may offer alternative approaches to urethroplasty when traditional methods fail (69-71) (see Table 2). Tissue engineering refers to the goal of assembling scaffolds, cells, and molecules into constructs that restore, maintain, or improve damaged tissues. In urology, there has been a focus on developing strategies for more precise tissue-engineered urethral reconstruction (84).

Scaffolds are engineered structures that guide implanted cells. Ideal urothelial scaffolds should facilitate cell colonization and offer structural support to prevent collapse, degradation, and immune responses within the urethra’s histological architecture. A natural scaffold option is an acellularized artery. Preclinical evidence showed that autologous adipose-derived stem cells seeded in an acellularized carotid arterial matrix can be used as a tubularized scaffold in urethral reconstruction in male canine models (72). Acellular tissue-engineered indigenous bovine pericardial patch, conventionally used in cardiovascular procedures, has also been trialed for single stage dorsal inlay urethroplasty in nine patients with a 88.9% success rate after a median follow-up of eight months (73,85). There have been over 80 preclinical studies on decellularized natural scaffolds for urethral reconstruction, but translation is still underway as animal models do not represent disease processes in humans (86,87).

Synthetic scaffolds are another option. A synthetic bilayer scaffold using an inner porous poly-D,L-lactide (PL) layer for cell proliferation and outer hydrophobic poly-e-caprolactone (PC) layer for protection from cytotoxic urine has been tested with allogenic mesenchymal stem cell seeding in rabbit models. Results from rabbits grafted with PL-PC or buccal mucosa revealed less fibrosis and inflammatory cell infiltration in the experimental PL-PC group (74). Another promising scaffold is a collagen type I-based matrix seeded with autologous urothelial cells that showed excellent stability, surgical manipulation, and integration into host tissue without signs of inflammation in eight minipigs (75). Cell-free scaffolds are another option to avoid the complicated and time-consuming process of primary cell isolation, potentially decreasing cost and donor site complications. A novel bilayer nanofibrous scaffold constructed to mimic natural extracellular matrix (ECM) was applied in rabbits for anterior urethral reconstruction and compared to rabbits repaired with small intestinal submucosa. After 6 months, urethrography and histological analysis revealed a larger urethral diameter in ECM-mimicking scaffolds (3.01±0.12 mm) compared to intestinal submucosa grafts (0.95±0.07 mm) (76). MatriStem (ACell, Inc., Columbia, MD, USA) is an ECM acellular matrix graft derived from porcine urinary bladders. Seven of eight patients who underwent staged urethral reconstruction with MatriStem ECM had adequate graft take (77). A separate case series of six patients described the feasibility of a novel cell-based endoscopic technique using buccal epithelium in a thermoreversible gelation polymer scaffold (78). The polymer scaffold used was composed of poly(N-isopropylacrylamide-co-n-butyl methacrylate) [poly(NIPAAm-co-BMA)] and polytheylene glycol, and its thermoresponsive property can be advantageously used to embed and culture cells when the temperature is increased. Symptomatic improvement was observed in all six patients, and urethroscopy at 6 months showed healthy mucosa. Four patients were voiding well at 3 years, and recurrence was seen in two patients at 18 and 24 months.

Autologous urothelial, epithelial progenitor, bone marrow stem, adipose-derived stem, and urine-derived stem cells have been harvested and cultured from patients for the purpose of seeding scaffolds to repair urethral defects (88,89). In particular, urine-derived stem cells are stem cells isolated from human urine that express a combination of pericyte and mesenchymal stem cell markers (90). In the context of tissue-engineered solutions, MukoCell has garnered attention as an oral mucosa graft cultured and grown from a tiny oral mucosa biopsy of 0.5 cm². Results from 99 patients in a multicenter, prospective, observational trial using MukoCell found no stricture recurrence in 67.3% [95% confidence interval (CI): 57.6–77.0%] of men at twelve months post-operative (79). A separate tertiary single-center reported an overall recurrence-free rate of 68.8% among 77 patients with anterior urethral strictures treated with MukoCell grafts after a median period of 38 months [interquartile range (IQR), 31–46 months] (80). Tissue-engineered oral mucosa graft using MukoCell (n=77) and native oral mucosa graft (n=76) had comparable success rates (78.9% vs. 68.8%) after a median follow-up of 53.5 months (IQR, 43–58 months) for native oral mucosal grafts and 52 months (IQR, 45–60 months) for MukoCell grafts (81). A separate retrospective multicenter study encompassing 38 patients demonstrated MukoCell graft success in 84.2% of cases after a median follow-up of 55 months (82). Tissue-engineered grafts grown from oral mucosa biopsies may significantly shorten surgical time and minimize oral complications by obviating the need for intraoperative mucosa harvesting.

Other investigations have explored alternative cell reservoirs. A recent in vitro study uncovered the potential of human amniotic epithelial cells derived from a single placenta in suppressing the migration of urethral stricture fibroblast cells derived from six patients undergoing urethroplasty (83). Gene expression analyses were completed, and amniotic epithelial cells were found to significantly reduce 55% of urethral stricture fibroblast cells’ expression of alpha-smooth muscle actin, a biomarker highly expressed in urethral fibrous tissue and correlated with increased collagen production. Additional studies are necessary to evaluate these antifibrotic effects.

Advancements in urethral healing knowledge

Exploring the postoperative inflammation pathways and molecular mechanisms governing urethral healing and stricture development are crucial in advancing therapies. Lichen sclerosis urethral strictures are especially difficult to treat, often with high rates of recurrence. Tissue microarray immunohistochemistry performed on urethral tissue from patients treated for lichen sclerosis with successful reconstruction (n=31) or recurrent stricture (n=19) revealed that recurrent strictures surprisingly expressed lower levels of several inflammatory markers (C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor-α), had a lower Ki-67 mitotic index, and displayed higher vascular endothelial growth factor levels (91). The authors hypothesized that recurrent strictures may have expressed lower levels of inflammatory markers due to prolonged disease duration burnout or suppression from exogenous steroid exposure. Nonetheless, additional studies are warranted to clarify these molecular pathways. A study applying nanofibers expressing anti-inflammatory peptides to small intestinal submucosa substitution urethroplasty in rats found enhanced healing process, increased angiogenesis, and earlier complete urethral healing (92). Another study looking at neutrophil-lymphocyte ratios in 512 patients who underwent DVIU over an eight year period found a significant difference between the non-recurrence and recurrence groups (2.02±0.87 vs. 3.66±2.3) (93). Under histopathology, ectopic germinal centers with B cells, T cells, and follicular dendritic cell networks were found in 8% (6/45) of urethral resection specimens for bulbar urethral stricture, but there was no correlation found between the degree of fibrosis and the abundance of immune cells (94).

The urinary tract microbiome may open a new paradigm in understanding the inflammatory nature of urethral strictures. A comparison in urinary microbiome from urine samples from men with lichen sclerosis urethral stricture disease (n=22) and without strictures (n=76) found a higher mean sample diversity richness in samples from men with strictures (25.9) versus men without strictures (16.8) (95). Urine samples from men with lichen sclerosis strictures had a unique bacterial profile enriched with Bacillales, Bacteroidales, and Pasteurellales bacteria. Another study found significant differences in alpha diversity (species diversity on a local scale) between pre-operative urine samples of patients with lichen sclerosis (n=26) and non-lichen sclerosis (n=33) urethral stricture disease (96). Interestingly, there was no significant difference in alpha diversity between the two groups post-operatively.

Limitations

This narrative review paper has several limitations. Because the authors utilized PubMed as the main search engine, studies present on other search engines were not captured in the initial query. In addition, this review excluded urethroplasty papers on transgender, hypospadias, pediatric, female, and pelvic fracture urethral injury patients, which may have prevented the discussion of urethroplasty advancements in these populations. Lastly, our query only included papers published within 5 calendar years from the initial query date, which may have excluded new advancements that have not been published after the query date.

Conclusions

In recent years, research in urethral reconstruction has contributed to new advancements in minimally invasive approaches, novel grafts, and the understanding of urethral disease pathophysiology. Further research is needed to improve patient care, quality of life, and treatment efficacy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-23-246/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-23-246/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-23-246/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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