Introduction

We reported a clinical overview of the studies on the use of biological constructs for tissue-engineered repair of hypospadias or urethral stricture. We excluded studies in which tissue engineered biomaterial was used only in the laboratory or experimental animals, and in the absence of autologous cultured epithelial cells. The studies herein reported demonstrate a high degree of heterogeneity with respect to epithelial cells (from urethra, bladder, mouth), type of scaffold, etiology and site of urethral stricture, number of patients, followup length and outcomes.

Urethral or Oral Mucosa Stem Cells for Urethral Regeneration?

In our review, we found some research suggesting, as a source of stem cells for culture, the use of urethral mucosa, and others suggesting the use of oral mucosa. In 2016, some authors investigated the differences between urethral and oral stem cells for biological constructs in urethral regeneration.¹ In this study, 19 biopsies from urethra and 21 from oral mucosa were obtained from patients to determine whether urethra or oral mucosa can be equally useful for urethra engineering, making a comparison of clonogenic ability, proliferative potential and stem cell markers. The authors concluded that both tissues can be cultured and preserve their stem cells in vitro, suggesting that they can be equally useful for tissue engineering of the urethral tract, even if few limited differences appeared in oral mucosa vs urethra.¹

Urethral Reconstruction Using Urethral Mucosa Cells

In 1990, Romagnoli et al were the first authors reporting the use of tissue-engineered graft of cultured urethral epithelium to repair primary hypospadias.² A biopsy of urethral mucosa was taken from urethral meatus and treated with trypsin to produce a suspension of single cells, seeded in dishes and cultured. The cultured epithelium was extended into the penile shaft as first-stage urethroplasty and 10 days later was tubularized up to glans.² In 1993, the same authors described the manufacturing of cultured urethral mucosa cells mounted on polytetrafluoroethylene tube and used for one-stage anastomotic urethroplasty in 8 boys with hypospadias.³ The authors reported 2 complications and not the final long-term outcomes of these 8 patients, and the use of these techniques in a larger series of patients.

Urethral Reconstruction Using Muscle and Epithelial Cells from the Bladder

In 2011, Raya-Rivera et al reported urethral reconstruction using tissue-engineered bladder muscle and epithelial autologous cells in 5 boys with complex posterior urethral strictures.⁴ Bladder biopsies were taken, and primary cultures of smooth bladder muscle and urothelial cells were collected. Epithelial cells were seeded onto the luminal surface and muscle cells onto the outer surface of a tubular collagen scaffold, and a biodegradable mesh made of polyglycolic acid was tubularized and sized according to the stricture length, and sutured to the distal and proximal urethral ends in anastomotic repair. At a median followup of 71 months, the authors reported final success in all 5 patients.⁴ In 2012, Fossum et al reported urethral reconstruction in 6 patients with scrotal or perineal hypospadias using a transplant of cultured autologous urothelial bladder cells, harvested by bladder washing.⁵ With a median followup of 7.25 years, all patients were classified as a success with good cosmetic appearance and functional outcome. Neither of these groups reported the final long-term outcomes of these 11 patients and the use of these techniques in a larger series of patients.

Urethral Reconstruction Using Oral Mucosa Cells

In 2008, Bhargava et al reported the use of tissue-engineered graft of cultured oral mucosa cells in patients with urethral strictures.⁶ At a mean followup of 33.6 months, 1 patient required complete excision of the grafted area and 1 required partial graft excision for fibrosis and hyperproliferation of tissue, respectively. Furthermore, 3 patients required postoperative urethrotomy or dilation.⁶ The authors never reported the final long-term outcomes of these techniques in a larger series of patients.

In 2014, Lazzeri et al reported the preclinical and clinical data with regard to the safety of tissue-engineered oral mucosa graft (MukoCell®) for urethral reconstruction.⁷ Oral mucosa cells were cultured on the surface of a biocompatible scaffold. Preliminary reported clinical data on 70 patients showed no postoperative adverse events related to tissue engineered grafts.⁷ In 2015, these authors reported the legal framework, the manufacturing procedure, the pharmacology, pharmacokinetics, toxicology and clinical development of MukoCell.⁸ A total of 21 patients were included on the study, and at a median followup of 18 months, 17 cases (80.9%) were a success and 4 (19.1%) were failures. No expected or unexpected adverse reactions related to the MukoCell implant were reported.⁸ In 2017, these authors reported a multicenter, prospective, observational trial on the results of the use of MukoCell for urethral reconstruction in 99 patients with urethral strictures.⁹ The success rates ranged from 85.7% to 0% in case of high vs low experience in urethral surgery. In 2018, these authors reported the surgical techniques and long-term results for the implant of MukoCell in 38 patients.¹⁰ Out of 38 cases, 32 (84.2%) were classified as successes and 6 (15.8%) as failures.

Discussion and Conclusions

Our survey showed the limits and controversies in the use of biological constructs for urethral reconstruction as reported in the current literature. The use of urethral or bladder mucosa for manufacturing the tissue-engineered graft is not justified according to the data reported in the literature: small series of patients and no extensive followup increasing its use in a larger series of patients. The majority of these studies included only occasional and anecdotal reports of their techniques and outcomes.^2-5 The use of oral mucosa for manufacturing biological constructs represents the best choice according to the current data reported in the literature, collecting large series of patients with long-term followup. The clinical results are superior for safety but not for the efficacy of native oral mucosa in urethroplasty, and this represents a great limit on the use of these technologies, also according to the legal and financial problem in arranging these materials.