Prophylactic adjuvant therapy for postoperative recurrence of urethral stricture: a narrative review

Introduction

Urethral stricture is a common organic disorder of the urinary system, typically characterized by the narrowing or occlusion of the urethral lumen, which leads to a reduction or interruption of urine flow. This condition can occur at any point along the urethra (1,2). Patients often present with symptoms such as dysuria, dyspareunia, and urinary retention (3), significantly impacting their quality of life. The causes of urethral stricture are complex and varied, including medical, idiopathic, congenital, traumatic, inflammatory, and infectious factors (4). The underlying pathophysiological mechanism involves fibrosis resulting from fibroblast proliferation and collagen deposition following tissue injury (5,6). Surgical treatment of urethral stricture is currently the mainstay; however, the high postoperative recurrence rate needs to be addressed (1).

Contemporary guidelines provide limited recommendations for adjunctive drug strategies and no integrated framework for emerging delivery platforms. A focused narrative synthesis is therefore timely to: (i) differentiate outcomes between direct vision internal urethrotomy (DVIU)/dilation and urethroplasty; (ii) clarify postoperative adjuvant options; and (iii) summarize delivery technologies with translational potential. This study aimed to summarize current evidence on postoperative pharmacological adjuvant therapies and emerging drug delivery systems that are designed to prevent recurrence following urethral stricture surgery, with explicit distinctions between endoscopic and reconstructive outcomes, between intraoperative intralesional use and postoperative adjuvant therapy, and between human-approved versus developmental strategies. This review primarily addresses adult male anterior urethral strictures unless otherwise specified; pediatric considerations are briefly noted. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-471/rc).

Methods

This review was conducted through a comprehensive literature search in PubMed, Scopus, and Web of Science up to March 19, 2025, focusing on studies evaluating pharmacological adjuvants and emerging drug delivery systems for urethral stricture management. Relevant preclinical and clinical data were critically appraised and synthesized to highlight current evidence, limitations, and future directions (Tables 1,2).

Current status of surgical treatment and recurrence of urethral strictures

Choice of surgical procedure and outcome

Surgery is the primary treatment for urethral strictures and typically involves endoluminal procedures and open urethral reconstruction (7). The choice of surgical approach should be based on a comprehensive assessment of the characteristics of the stenosis and the individual circumstances of the patient. Endoluminal procedures, such as DVIU and urethral dilation, are currently the most common and preferred initial treatment options among urologists worldwide (8-10). DVIU has been utilized since 1957 for the treatment of urethral strictures (11). According to relevant data, it offers advantages such as simplicity, directness, speed, and a short recovery time, along with a high overall first-time success rate of 70–80% within a short period (typically within six months) (12,13). Its optimal indications include short segments (<1.5 cm) of isolated medullary stenosis (14). The same holds true for medullary stenosis measuring 1.5–2 cm, which yields reasonable results (15). However, available evidence suggests that the therapeutic efficacy of DVIU is limited, with 5-year recurrence rates approaching 90% (13,16). Studies indicate that the long-term recurrence rate following a single DVIU is as high as 92%, and this rate increases significantly with repeated endoscopic treatments (17). Another study similarly confirms the high recurrence rate following the procedure, reporting a 30–60% recurrence rate within two years after the initial procedure. Furthermore, the recurrence rate significantly increases to 50–100% with repeat endoscopic interventions (18). Repeated endoscopic treatments may lead to increased fibrosis of the urethral corpus cavernosum, which in turn complicates the urethra and makes subsequent treatments more challenging (19). This can also impose physical, psychological, and financial burdens on the patient. In contrast, urethroplasty generally yields higher long-term patency and is considered the gold standard treatment option, with a 75–100% long-term success rate. However, 10–20% of patients experience recurrence within 10 years of surgery (20-22). For more complex stenoses, the failure rate can be as high as 60% (23). Recurrence is most concentrated within the first 6 months after surgery, reaching up to 75% (24), suggesting the need for early intervention after urethral stricture surgery to reduce the risk of recurrence. Urethral strictures in children are primarily caused by trauma (25). Compared to adult urethral strictures, pediatric urethral lumens are smaller, and the tissue is more fragile. A study involving urethroplasty on 23 patients with urethral strictures reported a 3-month follow-up success rate of 86.96%, with success rates at 5 and 10 years being 84% and 79%, respectively (26). Recurrence is defined as persistent postoperative urinary symptoms and unimproved urinary quality of life, accompanied by the inability to pass a flexible cystoscope through the urethra without applying force. An optimal follow-up strategy can assess anatomical and functional outcomes, protect urogenital health, and prevent additional burdens on patients (27). The success rate at six months post-DVIU varies (13). The 6-month postoperative period may be considered the short-term follow-up, while the 5-year period serves as the long-term follow-up (28). Overall, reports on pediatric patients are relatively scarce, but existing evidence indicates that recurrence risks and treatment principles are generally similar, requiring only adjustments based on anatomical structure and growth and development status.

Clear distinction: DVIU/dilation vs. urethroplasty recurrence rates

To clarify the results, Table 3 summarizes the recurrence rates by type of surgery and duration of follow-up. Representative citations are also included.

Variability in the choice of surgical procedure in different regions

Practice patterns vary by region and level of economic development. Survey data indicate that most urologists typically choose urethroplasty only after failed endoscopic treatment. For instance, a survey in China found that approximately 76.2% of surgeons resort to urethral reconstruction only when endoscopic procedures fail (29). This reluctance stems from the inherently more invasive nature of open urethroplasty, which requires specialized expertise and results in longer catheterization times for patients (30,31). Its relatively low cost-effectiveness also limits its status as the preferred treatment. International reports reveal significant differences among Europe, North America, and Asia regarding the preference for urethral reconstruction as a primary treatment option and the timing of referral (9,32). Notably, despite the generally high recurrence rate of urethral surgery, urethroplasty offers a high long-term patency rate and is therefore recommended as the standard treatment by international urological organizations (32). The American Urological Association (AUA) guidelines endorse urethroplasty as the gold standard for appropriate strictures, while allowing DVIU/dilatation for short, primary, favorable lesions (33). However, significant variations in clinical practice persist across regions. Western countries often recommend urethroplasty earlier, whereas in Asia and other developing nations, repeated urethral dilation remains common due to limitations in medical resources and technical expertise. Global surveys indicate that despite existing guidelines, 60–75% of urologists still use urethral dilation as a first-line treatment. This disparity highlights the critical need to promote standardized approaches to urethral stricture management worldwide.

Postoperative adjuvant drugs and mechanisms

The AUA 2023 Revised Guidelines recommend postoperative treatment with a paclitaxel drug-coated balloon (DCB) to significantly reduce the rate of recurrence after urethral stricture surgery. Comparative studies have also shown that patients who undergo intermittent self-urethral dilatation for three months may experience a higher recurrence rate than those who follow a continuous catheterization regimen lasting four months or more (AUA Guidelines: Conditional Recommendation, Level of Evidence C) (33). This marks the first time official guidelines have endorsed medication-assisted treatment for urethral strictures, indicating that such therapy after surgery can significantly improve prognosis. Adjunctive pharmacologic strategies can be categorized into intraoperative local therapies [e.g., mitomycin C (MMC), paclitaxel (PTX), steroid injections] and true postoperative adjuvant therapies [e.g., steroid-coated clean intermittent catheterization (CIC)] (34-37). To develop a more effective postoperative medication-assisted therapy system, several factors must be considered, including the antifibrotic mechanisms of the drugs, various routes of administration, locally effective maintenance concentrations, safety, and the diversity and individualization of patient factors. The following is a detailed review of several drug classes for which there is currently strong evidence, summarizing their strengths and weaknesses in Table 4.

MMC

Mechanisms of drug action

MMC is an alkylating antibiotic with antitumor properties, and its anti-fibrotic mechanism has been well elucidated. It inhibits scar formation by inducing DNA cross-linking, which blocks fibroblast proliferation, reduces type I collagen production, and promotes fibroblast apoptosis (38-40). In recent years, MMC has increasingly been used as an adjunctive therapeutic agent following urethral stricture surgery. An animal model study has provided significant evidence supporting its clinical application. MMC can notably reduce cell proliferation and DNA damage in urethral tissues while accelerating DNA repair (41). Furthermore, MMC has demonstrated superior efficacy in prevention compared to other antifibrotic drugs, such as triamcinolone acetonide (TA) (17). This reinforces the use of MMC in the treatment and prevention of urethral strictures.

Effectiveness of drug treatment

Several evidence-based clinical studies have systematically confirmed the efficacy of MMC, demonstrating its significant role in the treatment of urethral strictures and its ability to substantially reduce the rate of recurrent urethral strictures. Multiple randomized controlled trials (RCTs) have confirmed the efficacy of MMC-assisted therapy. For instance, a three-RCT study involving 311 patients demonstrated that MMC-assisted therapy reduces the risk of urethral stricture recurrence after urethrotomy by 59% [risk ratio: 0.41, 95% confidence interval (CI): 0.25–0.68] (42). A subsequent analysis of four RCTs involving 392 patients further demonstrated that MMC-assisted therapy can reduce the risk of recurrence by more than 70%. (odds ratio: 0.27, 95% CI 0.16–0.45, P<0.0001) (43), particularly in patients with anterior urethral strictures measuring ≤2 cm in length (44). Clinical efficacy data show that among 40 male patients with anterior urethral stricture, the recurrence rate after DVIU combined with MMC decreased from 50% to 10%, compared to DVIU alone. This difference was statistically significant (P=0.006) (45). Another study treated 103 patients with anterior urethral strictures by injecting the Vatsala-Santosh PGI triple injection solution (TA, MMC, and hyaluronidase) into the lesion following DVIU surgery. The results showed that this combined medication-assisted treatment achieved a first-time success rate of 80.6%, with a high success rate of 94.2% after a second surgery (46). Application of hydrogel carrier-based MMC for the treatment of anterior urethral strictures, even at drug concentrations significantly higher than those used in conventional experimental protocols, still achieves satisfactory therapeutic results (47). In the treatment of primary or secondary strictures of the posterior urethra, a local injection of MMC in combination with minimally invasive treatment can also achieve significant outcomes (48,49). The concern is that MMC, although one of the adjunctive medications supported by the highest level of evidence (50), however, it is also necessary to control the dosage. Studies have shown that MMC has a dose-dependent effect, that is high concentrations have an antiproliferative effect but are also associated with an increased risk of tissue toxicity (51,52). And due to the poor permeability of MMC in the urethral tissue, local overdose injection is avoided as much as possible. Controlled-dose injections in healthy urethral tissue can effectively prevent the risk of tissue necrosis and fistula formation due to overdose or local tissue fluid collection (53). Overall, while MMC demonstrates significant efficacy as an adjunctive therapy for urethral strictures, it also has limitations, including a narrow safety margin and a lack of consensus on the optimal dosage and administration methods. Future research should focus on dose standardization, carrier technology, and long-term safety.

PTX

Mechanisms of drug action

PTX is a diterpene chemotherapy drug that induces mitotic arrest and apoptosis by stabilizing microtubule structures (54-57). PTX can inhibit the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway, exerting an antifibrotic effect by reducing fibroblast proliferation and collagen deposition (58-61). Low-dose PTX also exhibits this effect (62), inhibiting the fibrotic process to achieve both treatment and prevention of recurrence. In clinical practice, to enhance the efficacy of antifibrotic drugs such as paclitaxel to maintain effective concentration and prolong the retention time in the local lesion, and to reduce the toxic effects on the patient (63). DCB is a paclitaxel-coated urethral dilation balloon that works by mechanical dilation combined with drug release to effectively prevent recurrence of urethral strictures (64).

Effectiveness of drug treatment

The AUA guidelines first suggested that DCB therapy could be utilized in combination for short recurrent urethral strictures, providing a conditional recommendation with a level of evidence classified as B. Clinical evidence: several clinical studies have validated the effectiveness of DCB in treating urethral strictures. One study involving 43 patients treated with DCB revealed that 16 patients were untreated, 27 underwent endoscopic treatment, and 11 also received urethroplasty following endoscopic treatment. The balloon dilation was performed for an average duration of 8.4±2.7 minutes, with a postoperative follow-up period of 290.3±87.0 days. The postoperative post-void residual volume was measured at 33.4±90.6 mL, and only four cases required repeat intervention, resulting in a significantly lower rate of stricture recurrence (65). This was significantly lower than with conventional treatments, but this study had the limitations of a small sample size and high heterogeneity. Another larger prospective RCTs (n=127) demonstrated that, during the two-year follow-up period, the rate of no intervention in the DCB group reached 77.8%, which was significantly higher than that in the non-DCB group (23.6% at 1 year, P<0.001) (66). This is one of the main reasons why DCB is approved for use and recommended by the AUA guidelines. The data from these studies confirm that PTX reduces the recurrence rate of urethral stricture. Studies on recurrent urethral strictures have shown a functional success rate of 67% and an anatomical success rate of 74.6% after 6 months of treatment with DCB (67). In another application of DCB to male patients with recurrent medullary stenosis with a stenosis length of <2 cm, the patients’ quality of life, urinary flow rate, and residual urine output improved significantly during the 3-year follow-up period (64). The Markov model developed by Kelly et al. similarly supported this view, with results showing support for the use of DCB as an alternative to standard-of-care endoscopic management for the treatment of men with recurrent male anterior urethral strictures in England (68). VanDyke et al. conducted a multicenter study of patients after urethroplasty and showed that patients with a history of failed urethroplasty were equally successful in treating recurrent urethral strictures with DCB at short-term follow-up compared to patients without a history of urethroplasty (69). These findings suggest that DCB therapy is equally applicable to complex and recurrent stenosis cases. It is important to note that the neurotoxicity threshold for paclitaxel is 1,000 mg/m² (70), which may induce peripheral neuropathy (71). DCB is currently the only adjunctive treatment included in the guidelines. Existing evidence indicates that this therapy can reduce the recurrence rate of short-segment anterior stenosis; however, its long-term efficacy, applicability to complex stenotic lesions, and optimal patient selection criteria remain controversial.

Steroids

Mechanisms of drug action

Glucocorticoids are complex, fat-soluble steroid hormones produced by the adrenal cortex that possess potent anti-inflammatory and anti-fibrotic effects. Their antifibrotic properties primarily inhibit scarring by reducing collagen synthesis and suppressing fibroblast proliferation (12,72-74). As a result, glucocorticoids are considered a first-line treatment for both the treatment and prevention of scarring, owing to their significant anti-inflammatory and immunomodulatory properties, as well as their crucial role in scar management (75). Studies have demonstrated that the application of glucocorticoids to localized urethral scarring leads to prolonged and significantly reduced postoperative recurrence of urethral strictures (76,77). Consequently, glucocorticoids are increasingly recognized as an adjunctive treatment for urethral strictures. TA, a long-acting glucocorticoid agent, has been utilized in the management of urethral strictures (78), achieving notable success in treating skin disorders as well. Additionally, it exhibits unique advantages in the treatment of urethral strictures (79).

Effectiveness of drug treatment

Clinical evidence: TA stands out in a comparative trial of intra-lesional injections of various steroid treatments, as demonstrated by a multicenter RCT study (80). Since 1972, when Hebert first proposed the application of TA in the urethra (81), numerous studies have further confirmed its effectiveness in treating urethral strictures. In one study, 50 patients with anterior urethral strictures underwent DVIU, with some of them receiving TA injections at the urethrotomy site. The results indicated that the recurrence rate was reduced by nearly 30% in the DVIU combined with TA injection group compared to the DVIU group alone (82). Another study involving 60 male patients with urethral strictures who underwent CIC after DVIU, with TA ointment applied to the catheter versus a placebo control, demonstrated a 24.2% reduction in recurrence rate in the TA group compared to the placebo group (74). Compliance with CIC protocols varies, and discomfort or infection risks may limit their widespread adoption. This finding illustrates that different modes of administration remain effective. For complex posterior urethral strictures, a study involving 28 patients with recurrent posterior urethral strictures who underwent transurethral scar resection, along with intraoperative and postoperative TA injections, showed a 93% reduction in recurrence rate compared to the control group that did not receive TA (83). In another study of 45 patients with posterior urethral strictures, holmium laser dissection followed by TA-assisted therapy resulted in a high rate of subjective urinary improvement and a favorable prognosis (84). Although these findings demonstrate some consistency, most studies were single-center, had limited sample sizes, and featured insufficient follow-up periods, which limits the generalizability of their conclusions. It is important to emphasize that while TA is associated with higher patency rates and lower recurrence rates, potential side effects such as capillary dilation, delayed healing, and infection must also be taken into consideration (85). However, it is crucial to be aware of the side effects it may cause. Studies have shown that the combination of TA and 5-fluorouracil (5-FU) not only enhances the efficacy of the treatment but also reduces the drug’s toxicity compared to TA alone (86). Although current evidence suggests that TA may help reduce recurrence rates and extend remission periods, its clinical efficacy and safety require validation through large-scale RCTs due to limitations in sample size and methodological shortcomings.

Pirfenidone

Mechanisms of drug action

Pirfenidone (PFD) is a small-molecule drug with anti-fibrotic and anti-inflammatory properties. Its primary mechanism of action involves inhibiting TGF-β expression and the downstream activation of fibroblasts, thereby blocking fibroblast proliferation and collagen synthesis (87-90). Additionally, it modulates macrophage polarization, reduces nuclear factor-κB (NF-κB) activation, and decreases the production of pro-inflammatory cytokines (91,92).

Effectiveness of drug treatment

Evidence supporting the use of PFD in urethral strictures is currently limited to preclinical models and remains sparse. A study examined the effects of PFD on a urethral stricture model in rats. Thirty male Sprague-Dawley (SD) rats were selected and randomly divided into three groups: a PFD group, a model group, and a sham operation group. The results indicated that the degree of stenosis in the PFD group was less severe than that in the model group. Masson staining revealed that the PFD group exhibited fewer collagen fibers and was effective in inhibiting the expression of TGF-β1 and α-smooth muscle actin (α-SMA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) results demonstrated that PFD was able to suppress gene expression of inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the injured tissues (P<0.05 or <0.01) (91). In rat models, PFD reduced the severity of stenosis, collagen deposition, and the expression of TGF-β1 and α-SMA, while simultaneously downregulating inflammatory mediators. The anti-inflammatory effects of PFD can be summarized as follows: PFD synergistically modulates inflammatory responses through multiple mechanisms, including the inhibition of pro-inflammatory cytokines (e.g., TNF-α, IL-6), modulation of macrophage polarization (reducing the M1 phenotype and partially restoring M2 function), inhibition of T-cell overproliferation and pro-inflammatory factor release, blockade of NF-κB signaling pathway activation, and reduction of mitochondrial damage associated with neutrophil chemotaxis and apoptosis. Inhibits mitochondrial damage associated with neutrophil chemotaxis and apoptosis, thus achieving tissue protection in acute and chronic inflammation and fibrosis (92). Although PFD has been approved for the treatment of pulmonary fibrosis, its application in urethral strictures has not yet been evaluated in human clinical trials. Adverse effects reported in other indications include gastrointestinal discomfort and skin reactions; however, overall tolerability remains acceptable (93). PFD has demonstrated promising anti-fibrotic activity in animal models, but clinical data for urethral strictures are still lacking. Translational studies are necessary to assess their safety, dosage, and efficacy in humans.

Limitations of medication-assisted therapy

The adjuvant therapeutic effect of postoperative drugs is obvious in current treatment protocols, and their excellent ability to fight fibrosis and prevent scar formation can clearly improve the prognosis of patients. However, the problems that need to be faced are the side effects of drug toxicity to the human body, whether the drug can be effectively applied, and how to optimize the mode of administration. MMC has a dose-dependent property, and a high concentration of the dose may lead to tissue necrosis, fistula formation, and other hazards. At the same time, due to the low permeability of the urethral tissues, the ability to grasp the dose of the local injection is particularly important. PTX achieves local application in the form of DCB. Although the dose of local administration is low, the risk of long-term neurotoxicity still exists, and most of the relevant clinical evidence comes from short-term studies with small samples, short follow-up times, and high heterogeneity. The application of DCB is relatively expensive, and this status quo is not suitable for application in basic hospitals. The effect of TA alone to reduce the risk of recurrence is limited, and it is prone to the risks of capillary dilatation, delayed wound healing, and local tissue atrophy. and local tissue atrophy, among other risks. It is challenging to control the effective dosage when administering the drug, and repeated injections may increase the risk of infection and damage to surrounding tissue. Most of the current data on PFDs have been derived from animal models, and there is a lack of evidence from human clinical trials. Oral administration does not facilitate effective dosing in the urethra and is often associated with gastrointestinal side effects. All four drugs exhibit common limitations: a lack of long-term safety evidence, difficulty in controlling effective drug dosage, and challenges in combining drugs safely. Therefore, there is a pressing need to expand long-term follow-up research trials to clarify the threshold at which these drugs exert toxic effects and to minimize potential harm. Due to the flushing effect of urine, it is difficult for drugs to remain in the urethra for extended periods, resulting in an inability to deliver an effective dose sufficient to significantly reduce the rate of stricture recurrence. To address this issue, researchers have developed an innovative drug delivery method. This new approach utilizes a drug carrier to precisely target the controlled delivery of medication at the site of the urethral stricture, thereby prolonging the retention time of the drug and significantly reducing the recurrence rate.

Emerging routes of drug delivery

Drug delivery system with biodegradable stent

Biodegradable stents have demonstrated significant potential for urethral reconstruction, offering a minimally invasive and safe treatment option for urethral strictures. These stents restore the normal structure of the urethra while promoting tissue regeneration and vascularization (94). Polylactic acid-hydroxyacetic acid copolymers (PLGA) are widely utilized biodegradable materials known for their excellent biocompatibility, controlled degradation, slow drug release, and protection against drug or gene degradation. PLGA can be hydrolyzed and gradually broken down into intermediate chemical entities, ultimately converting into simple organic acids that are absorbed by the human body (95-98). As a result, PLGA has become one of the most popular polymers for drug delivery due to its advantages and safety profile. It facilitates controlled release, ensuring that the desired drug dosage is effective while allowing for precise localized delivery to specific tissues and cells, thereby reducing the drug’s toxicity (99). PLGAs can be structurally designed and synthetically modulated to achieve precise control over the material’s physicochemical properties, thereby meeting the requirements for the release of specific bioactive payloads or for constructing an ideal scaffold matrix. Through chemical modification with other polymers or bioconjugation techniques involving functional molecules, PLGA materials can be endowed with specific functional properties (100). Evidence from animal studies: a study was conducted that combined the pharmacological properties of rapamycin with the mechanical support of a stent to the urethra (tubular organ) by combining the pharmacological effects of rapamycin and the mechanical support of the stent to the urethra (tubular organ) in a rabbit model of urethral stenosis. Observations were made throughout the study. The results indicated that rapamycin effectively prevented electrocoagulation-induced urethral stricture in rabbits. This effect may be attributed to the inhibition of TGF-β1 and Smad3 expression, as well as the promotion of matrix metalloproteinase-1 (MMP1) expression in urethral tissues by rapamycin (101,102). Therefore, the incorporation of drugs such as rapamycin could modulate the degradation time and therapeutic efficacy of PLGA scaffolds. Additionally, PLGA nanospheres modified with bladder decellularized matrix graft scaffolds demonstrated an efficient drug delivery capacity, allowing for the slow release of vascular endothelial growth factor (VEGF). This slow release helps to reduce postoperative restenosis, collagen deposition, and scar formation, while promoting angiogenesis in the repaired tissues (103). Meanwhile, the PLGA-based nano platform (PLGA NPF), known for its high drug-carrying efficiency, hydrophilic surface, negative charge, and electrostatic interactions, can effectively deliver antibiotics into the deeper layers of biofilms, thereby eliminating microbial biofilms (104). It is important to emphasize that PLGA composite stents possess mechanical and functional properties comparable to those of natural urethral tissue and can be replaced by neoplastic uroepithelium and urethral mucosa after degradation, resulting in effective functional recovery (105). Human data on drug-eluting biodegradable urethral stents are currently limited to small-scale feasibility or pilot studies, with no large RCTs available as of the literature cutoff date. Biodegradable scaffolds have shown promising tissue regeneration effects in preclinical models. Researchers must carefully design well-structured clinical trials to facilitate clinical translation and address this gap. Future research should focus on degradation byproducts, local inflammatory responses, and mechanical compatibility with urethral tissue.

Hydrogel drug delivery system

Hydrogel is a biomaterial characterized by its hydrophilic properties, which stem from its high-water absorption capacity, excellent environmental responsiveness, and structural stability (106,107). This makes it an ideal drug carrier. Hydrogel has not only been widely utilized in various biomedical fields but has also demonstrated unique potential in the treatment of urethral strictures. Traditional drug delivery methods are often hindered by low bioavailability, short retention times, and poor patient compliance (108,109). Therefore, efficient and safe drug delivery is particularly crucial for patients with stenosis. Continuous innovations in novel drug delivery systems utilizing hydrogels are providing new avenues for both patients and healthcare providers. Hydrogels facilitate in situ assembly and programmed degradation in response to disease triggers, thanks to their chemical and physical versatility (110). The adhesive properties of the mucous membrane help the drug maintain an effective concentration in a continuous urine washout environment. This not only improves the drug’s bioavailability but also reduces complications, ensuring the safety and efficacy of the treatment (109,111). Preclinical studies have confirmed, for example, that chitosan-based hydrogel systems have been utilized to achieve long-lasting sustained release for over 10 days in bladder cancer treatment through electrostatic adsorption to the bladder mucosa (112). The development of smart hydrogel technology can be enhanced by responding to various environmental stimuli (113). The release of drugs is regulated by factors such as pH, temperature, magnetism, and specific biomolecules, which further improve therapeutic precision. For instance, temperature-sensitive chitosan hydrogels allow for weekly dosing in ophthalmology (114), while magnetic filipin protein hydrogels enable precisely targeted controlled drug release through external magnetic field modulation (115). These mechanisms also provide innovative approaches for localized drug-controlled release in the urethra. At the tissue repair level, hydrogels not only facilitate controlled drug release but also mimic the properties of the extracellular matrix, creating bioactive scaffolds that promote urethral tissue regeneration and repair (116). For instance, the simultaneous inflammation modulation exhibited by quercetin composite hydrogel in spinal cord injury (117) suggests its potential application in inhibiting urethral scar formation. In terms of clinical translation, advancements in polymer chemistry and manufacturing technologies over the past three decades have propelled the development of injectable and non-injectable hydrogel products (118). Notably, there have been multiple success stories in the treatment of diseases affecting the urinary system (119). Additionally, the bladder mucosal adsorption system utilizing PTX and chitosan nanoparticles has shown promise (112). The success of a 44-hour-long-lasting analgesia achieved by a bupivacaine temperature-sensitive hydrogel (120) demonstrated feasibility in postoperative management. Current reports have revealed that hydrogels can serve as controlled-release carriers for anti-fibrotic drugs. Additionally, feasibility studies in urology involving small sample sizes have demonstrated their translational potential. However, direct clinical evidence supporting hydrogel-mediated anti-fibrotic therapies for urethral strictures remains limited. Large-scale, early-phase human trials are needed to further validate their anti-fibrotic efficacy.

Conclusion of emerging drug delivery platforms

Emerging drug delivery systems present innovative therapeutic strategies for achieving sustained local release of anti-fibrotic drugs, addressing the limitations of traditional intra-lesional injections. However, current evidence is primarily derived from animal models and is limited by small sample sizes, short follow-up durations, risks of scaffold displacement, high costs, and lack of regulatory approval. Future research should focus on rigorously designed clinical trials to assess the safety, feasibility, and therapeutic efficacy of these delivery methods in urethral stricture surgery. Until robust human data are available, conclusions regarding their clinical value should be interpreted with caution.

Conclusions

The current clinical application of postoperative adjuvant medications and emerging drug delivery systems for urethral strictures has significantly reduced the rate of stricture recurrence and holds promise for future prevention of postoperative recurrences. However, the existing evidence primarily comes from studies with small sample sizes and short-term follow-up periods, resulting in a low overall level of evidence that makes it difficult to establish unified clinical recommendations.

Based on current evidence, the most promising approaches include: (I) combining localized delivery systems with anti-fibrotic drugs to enhance efficacy while minimizing systemic adverse effects; (II) combining different drugs (e.g., TA with 5-FU) to reduce toxicity and enhance therapeutic outcomes; (III) implementing personalized treatment strategies by, selecting optimal drugs and administration methods based on the location of stenotic segments and their histological characteristics.

The primary gaps that remain include: (I) a lack of multicenter, large-scale, long-term follow-up RCTs to validate efficacy and safety; (II) no consensus on the optimal drug concentration, timing, and frequency of administration; (III) the high cost of novel carrier materials, which limits their promotion and adoption in primary care hospitals.

Future research should focus on optimizing drug dosages and delivery methods, developing affordable novel carrier materials, and establishing a systematic, evidence-based adjunctive drug therapy system. Only through these approaches can the long-term risk of urethral stricture recurrence be genuinely reduced, thereby improving patients’ overall prognosis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-471/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-471/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82260141), and Young Talents Project of the “Technology + Healthcare” Joint Program (No. GZ2024YLJ124).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-471/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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