RECONSTRUCTIVE UROLOGY

Terminal urothelium differentiation of engineered neoureter after in vivo maturation in the “omental bioreactor”
Baumert H, Mansouri D, Fromont G, Hekmati M, Simon P, Massoud W, Molinié V, Malavaud B
Department of Urology, Paris Saint Joseph Hospital Trust, Paris, France
Eur Urol. 2007; 52: 1492-8

• Objective: Long ureteric defects may theoretically be repaired with the use of tissue-engineered neoureter. However, attempts to construct such a neoureter in animal models have failed because of major inflammatory response. Avoidance of such inflammation requires a well-differentiated urothelium. We investigated whether omental maturation of a seeded construct in a pig model could achieve terminal differentiation of the urothelium to allow construction of a stricture-free neoureter.
• Material and Method: Bladder biopsies were taken to allow urothelial and smooth muscle cell cultures. These cultured cells were used to seed small intestinal submucosa (SIS) matrix. After 2 wk of cell growth, the in vitro SIS-seeded construct was shaped around a silicone drain and wrapped by the omentum to obtain neoureters. These neoureters were left in the omentum without any contact with urine, and then harvested 3 wk later for histologic and immunohistochemical studies.
• Results: Before implantation, the in vitro constructs were composed of a mono- or bilayer of undifferentiated urothelium overlying a monolayer of smooth muscle cells. After 3 wk of omental maturation, these constructs were vascularized and comprised a terminally differentiated multilayered urothelium with umbrella cells over connective tissue and smooth muscle cells, with no evidence of fibrosis or inflammation.
• Conclusion: We obtained, for the first time, with this model of in vivo maturation in the omentum, a mature neoureter composed of a well-differentiated multilayered urothelium.
  
  
• Editorial Comment
  The anatomy and structure of the ureter is still not completely understood. Because of its embryonic development the blood supply restricts the reconstructive possibilities. Over a decade researchers look into the option to find a better substitute of a ureter than the common used ilium interpronat (1). With the improvement of Mitrofanoff the diameter of the segment was adjusted but still complications are seen although the needed length of ileum was significantly reduced and the resorption reduced (2).
  Baumert et al. (3) present impressively a “sandwich model” with differentiated urothelium and a single layer of smooth muscle cells on SIS® different to others (4).
  During the recent years researchers presented remarkable results demonstrating the progress tissue engineering (5). One important lesson, even known in the reconstructive surgery prior, was the need of the optimized nutrition of the in vitro created tissue. Atala et al. reported an optimized outcome of the clinical used in vitro pre-seeded scaffold for bladder reconstruction with an omental flap wrapping (6).
  On the one hand the presented indication of a neo-ureter using an omentum flap makes the created ureter even more maneuverable compared to the possible “short” mesenterium of the ileum interpronat. On the other hand, Dahms et al. (7) published 10 years ago the ureter replacement by an acellular matrix, which was regenerated by urothelium and smooth muscle cells and functional, but in the following study in the rodent as well in the large animal model the created ureter shrunk after the stent removal although the prior seen urothelium lining was present (data not published). Some might argue that the presented approach will prevent the shrinking but as the author state it needs to be proven. Because others have made similar experiences - probably only a minority is published - it should be considered to report the outcome of an extended follow-up after the stent removal and as a replacement for a ureter.

References
1. Goodwin WE, Winter CC, Turner RD: Replacement of the ureter by small intestine: clinical application and results of the ileal ureter. Trans Am Assoc Genitourin Surg. 1958; 50: 56-68.
2. Woodhouse CR, Malone PR, Cumming J, Reilly TM: The Mitrofanoff principle for continent urinary diversion. Br J Urol. 1989; 63: 53-7.
3. Baumert H, Mansouri D, Fromont G, Hekmati M, Simon P, Massoud W, et al.: Terminal urothelium differentiation of engineered neoureter after in vivo maturation in the “omental bioreactor”. Eur Urol. 2007; 52: 1492-8.
4. Feil G, Christ-Adler M, Maurer S, Corvin S, Rennekampff HO, Krug J, et al.: Investigations of urothelial cells seeded on commercially available small intestine submucosa. Eur Urol. 2006; 50: 1330-7.
5. Sievert KD, Amend B, Stenzl A: Tissue engineering for the lower urinary tract: a review of a state of the art approach. Eur Urol. 2007; 52: 1580-9.
6. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB: Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006; 367: 1241-6.
7. Dahms SE, Piechota HJ, Nunes L, Dahiya R, Lue TF, Tanagho EA: Free ureteral replacement in rats: regeneration of ureteral wall components in the acellular matrix graft. Urology. 1997; 50: 818-25.

Dr. Karl-Dietrich Sievert &
Dr. Arnulf Stenzl
Department of Urology
Eberhard-Karls-University Tuebingen
Tuebingen, Germany
E-mail: arnulf.stenzl@med.uni-tuebingen.de