Decellularization and Other Evolving Treatments of Urethral Strictures

Urethral strictures pose a significant clinical challenge, impacting millions of individuals worldwide and often requiring complex and invasive treatments. In recent years, there has been growing interest in developing novel therapeutic approaches to address urethral strictures, with a particular focus on regenerative medicine and tissue engineering techniques.

Among these emerging strategies, decellularization stands out as a promising option for urethral reconstruction, offering the potential for personalized and minimally invasive treatments.

Understanding Urethral Strictures

A urethral stricture occurs when the urethra — the tube that carries urine from the bladder out of the body — becomes narrow due to scar tissue or inflammation. This narrowing can obstruct the flow of urine and cause various symptoms, such as:¹

• Difficulty urinating
• Frequent urination
• Not emptying your bladder properly
• Urinary tract infections
• Dark or bloody urine
• Pain when urinating
• Pelvic pain
• Bloody semen
• Loss of bladder control

The causes of urethral strictures can vary, including:²

• Infections such as recurring urethritis
• Trauma from sexually transmitted infections or chronic inflammation
• Certain medical procedures like surgery or radiation in the pelvic region
• Benign prostatic hyperplasia
• Congenital strictures

Depending on the degree of narrowing and its location along the urethra, symptoms can range from mild to severe. 

Treatment may involve medications to reduce inflammation, dilation procedures to stretch the urethra, or surgical intervention to remove the scar tissue and widen the passage. In some cases, a healthcare professional may temporarily insert a urethral catheter to relieve the obstruction.²

Treating this condition can dramatically improve patients’ quality of life and prevent additional health complications.

“While not immediately life-threatening, urethral strictures lead to multiple health complications that impair quality of life and predispose to kidney dysfunction. Developing an effective and durable treatment would significantly impact lives and has the potential to decrease the cumulative healthcare costs of treating recurrent kidney stones, infections, and downstream kidney complications, especially of long-segment urethral strictures,” says Dr. Maria T. Millan, President and CEO of the California Institute for Regenerative Medicine (CIRM). [SOURCE: https://urology.ucsf.edu/news/all/202208/wake-forest-university-health-sciences-and-ucsf-urology-receive-grant-cirm] 

Decellularization as a Urethral Stricture Treatment

Decellularization is a promising approach to treating urethral strictures, offering potential advantages over traditional methods. In this process, the patient’s own cells are removed from a small piece of tissue, leaving behind the structural framework known as the extracellular matrix (ECM). This ECM provides a scaffold that the patient’s cells can populate when implanted, facilitating tissue regeneration.³

Decellularization can be applied to create a bioengineered graft or scaffold that is implanted to reconstruct the narrowed urethral segment. This approach aims to restore the natural architecture and function of the urethra while minimizing the risk of rejection of complications associated with synthetic materials.³

Decellularized urethral grafts have shown promising results in preclinical studies and early clinical trials, demonstrating good biocompatibility, tissue integration, and functional outcomes.⁴ By leveraging the patient’s own cells and natural tissue architecture, decellularized grafts can promote tissue regeneration and reduce the likelihood of structure recurrence compared to traditional treatments such as dilation or urethroplasty.

Risks, Disadvantages, and Potential Complications

While decellularization holds promise for treating urethral strictures, like any medical procedure, it’s not without risks and potential complications. One significant concern is the possibility of immune reactions or rejection of the decellularized graft by the patient’s body. Despite removing cellular components during decellularization, residual antigens or other immunogenic factors may still be present in the ECM scaffold, triggering an immune response. This reaction could lead to inflammation, fibrosis, graft failure, or even recurrent stricture formation.³

Another potential complication is the infection risk associated with decellularized graft implantation. Although the process aims to remove cellular material, it may not completely eliminate all microbial contaminants or pathogens. Inadequate sterilization of handling procedures could result in graft contamination and subsequent infection at the implantation site. This may pose a risk to the patient's health and compromise the treatment’s success.³

Additionally, there’s a concern regarding the mechanical properties and long-term durability of decellularized urethral grafts. While the ECM scaffold provides a structural framework for tissue regeneration, it may lack the mechanical strength and elasticity necessary to withstand the dynamic forces and pressures exerted on the urethra during urination and other activities. This could increase the risk of graft failure, erosion, or collapse over time, necessitating additional surgical interventions or alternative treatment approaches.⁴

This treatment can be costly, and finances cause substantial stress for approximately 57% of employees, leading them to put the necessary surgery on hold.⁵ Fortunately, many individuals have access to employer-provided health insurance, which can help cover a significant portion of the costs.

Overall, while decellularization has the potential to be a novel approach for treating urethral strictures, the potential risks and complications must be carefully considered to ensure the procedure's safety and efficacy.

Other Promising Treatments

Several other urethral stricture treatments offer potential alternatives.

Balloon Dilation

Balloon dilation is a minimally invasive procedure commonly used to treat urethral strictures by expanding the narrowed segment of the urethra using a balloon catheter.⁶ During the procedure, you insert a deflated balloon catheter into the urethra and position it at the stricture site under fluoroscopic guidance. Once in place, you inflate the balloon with saline or contrast media, exerting radial pressure on the surrounding tissue and stretching the narrowed area.

This is done slowly to prevent damaging blood vessels and surrounding tissue. This mechanical dilation disrupts the scar tissue or obstruction, restoring patency to the urethra and improving urinary flow.⁶

Balloon dilation offers several advantages over more invasive surgical techniques. Benefits include minimal trauma, shorter recovery times, and reduced risk of complications such as bleeding or infection. You can perform it on an outpatient basis under local anesthesia, making it a convenient option for many patients.

Its efficacy may vary depending on the severity and location of the stricture, with some individuals requiring multiple treatments or experiencing recurrence over time. However, some studies report success rates as high as 95%, with only 5% of patients experiencing complications.⁷

Nevertheless, balloon dilation remains a valuable therapeutic option for urethral strictures, particularly in cases where you deem surgical intervention unnecessary or inappropriate.

Urethroplasty

If balloon dilation fails, urethroplasty is often the next step. It’s considered the gold standard for treating urethral strictures, particularly those that are long or complex.

During urethroplasty, you surgically excise the narrowed section of the urethra and rejoin the healthy ends to widen the passage. In cases where the stricture is extensive or has recurred after previous treatments, tissue grafts may be used to augment the repair and provide additional support.⁸

You can perform this procedure using various surgical techniques, including end-to-end anastomosis, substitution with grafts — such as buccal mucosa or skin — or flap procedures. The chosen method depends on the location and characteristics of the stricture.⁹

While urethroplasty is a more invasive procedure compared to minimally invasive techniques like dilation or stenting, it offers several advantages. Benefits include higher success rates and lower recurrence rates.⁸ It provides a more definitive solution for urethral strictures, addressing the underlying pathology by reconstructing the urethra and restoring normal urinary function.⁷

Despite the complexity, advances in surgical techniques, imaging technology, and perioperative care have improved outcomes and reduced morbidity, making it an effective treatment option.⁸

Endoscopic Urethrotomy

Endoscopic urethrotomy is a minimally invasive procedure commonly used to treat urethral strictures by incising or cutting through the scar tissue to widen the narrowed area.¹⁰ During the procedure, you insert a specialized endoscope equipped with a cutting instrument into the urethra. This allows you to visualize the stricture and perform the incision under direct vision.

You can perform this as an outpatient procedure under local or general anesthesia. This offers the advantages of shorter recovery times and reduced risk of complications compared to more invasive surgical techniques.¹¹

While endoscopic urethrotomy can provide symptomatic relief and temporary improvement in urinary flow for some patients, it is associated with high stricture recurrence rates, particularly for longer or complex strictures.¹¹ Additionally, there’s a risk of complications such as bleeding, infection, or urethral perforation.

As such, this procedure is often considered a palliative or temporizing measure rather than a definitive treatment for urethral strictures. Some individuals require repeated procedures or eventually undergo more definitive surgical interventions like urethroplasty.

The Potential of Regenerative Medicine and Tissue Engineering

Regenerative medicine and tissue engineering can transform urethral stricture management by offering innovative solutions promoting tissue regeneration and functional restoration. These approaches use the body’s natural healing mechanisms and advanced biotechnologies to develop personalized and minimally invasive treatments.³

Regenerative medicine uses stem cells, growth factors, and biomaterial scaffolds to stimulate tissue repair and regeneration in the urethra. This addresses the underlying pathology of narrowing and promoting long-term durability.⁷

Tissue engineering techniques provide bioengineered grafts or scaffolds that mimic the structure and function of natural urethral tissue. When implanted, these constructs facilitate tissue integration and regeneration, offering a more durable and biocompatible solution for stricture repair.³

Looking to the Future

Developing and refining decellularization techniques hold great promise for advancing urethral stricture treatment. Continued research efforts aim to optimize decellularized grafts’ compatibility, mechanical properties, and long-term durability, further improving patient outcomes.

Additionally, advancements in tissue engineering and regenerative medicine will likely lead to the development of novel therapies that leverage biomaterials, stem cells, and growth factors to promote tissue regeneration and functional restoration in the urethra. These innovative approaches have the potential to revolutionize urethral stricture treatment. They offer personalized and minimally invasive solutions that address the underlying pathology while minimizing the risk of complication and recurrence.

Ongoing clinical trials and translational research initiatives explore the safety and efficacy of emerging treatments, including regenerative medicine approaches and other minimally invasive interventions. Collaborative efforts are essential for accelerating the translation of promising therapies from the laboratory to clinical practice. These innovations will improve the outcomes and quality of life of patients with this condition.

The Promise of Regenerative Medicine

Decellularization and other evolving treatments hold tremendous promise for improving the management of urethral strictures. They offer innovative solutions that address the underlying pathology while reducing the risk of complications and recurrence. While there has been significant progress in the development and application of these therapies, challenges remain. Nevertheless, with continued research efforts and collaborative initiatives, the future looks brighter for individuals affected by this condition.

References

1. 1. Urethral stricture: Medlineplus medical encyclopedia. MedlinePlus. July 4, 2022. Accessed April 24, 2024. https://medlineplus.gov/ency/article/001271.htm. 
2. Abdeen BM, Leslie SW, Badreldin AM. Urethral Strictures. [Updated 2023 Nov 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK564297/
3. Fang W, Yang M, Jin Y, et al. Injectable decellularized extracellular matrix-based bio-ink with excellent biocompatibility for scarless urethra repair. Gels. 2023;9(11):913. doi:10.3390/gels9110913 
4. Jin Y, Zhao W, Yang M, et al. Cell-based therapy for urethral regeneration: A narrative review and Future Perspectives. Biomedicines. 2023;11(9):2366. doi:10.3390/biomedicines11092366
5. 1. The most popular employee benefits to offer in 2024. The Difference Card. March 12, 2024. Accessed April 24, 2024. https://www.differencecard.com/blog/the-most-popular-benefits-to-offer-in-2024/.
6.  Li X, Xu C, Ji X, et alBalloon dilation for the treatment of male urethral strictures: a systematic review and meta-analysisBMJ Open 2024;14:e071923. doi: 10.1136/bmjopen-2023-071923
7. Lu, H., Zheng, C., Liang, B. et al. Analysis of long-term effect of ureteral balloon dilatation combined with internal and external drainage tube in the treatment of benign ureteral stricture. BMC Urol 22, 4 (2022). https://doi.org/10.1186/s12894-022-00952-6
8. Kulkarni S, Joshi PM, Bhadranavar S. Advances in urethroplasty. Medical Journal Armed Forces India. 2023;79(1):6-12. doi:10.1016/j.mjafi.2022.12.002
9. Hoare DT, Doiron RC, Rourke KF. The evolution of urethral stricture and urethroplasty practice over 15 years: A single-center, single-surgeon 1319 urethroplasty analysis. Canadian Urological Association Journal. 2022;16(8). doi:10.5489/cuaj.7795
10. Singh J. Therapeutic adjuncts in the endoscopic management of urethral stricture disease: Past, present, and future. Frontiers in Urology. 2024;4. doi:10.3389/fruro.2024.1342941
11. Patrice AK, N’Diamoi A, Fatoumata O, et al. Endoscopic internal urethrotomy (EIU) for the treatment of ureteral stenosis: A review of 233 cases. Open Journal of Urology. 2021;11(07):264-272. doi:10.4236/oju.2021.117024