Urethras constructed from a tubular scaffold seeded with cells harvested from the patient's own bladder are fully functional 6 years after use in reconstructive surgery. This is the latest tissue engineering breakthrough to emerge from the Wake Forest Institute for Regenerative Medicine in North Carolina, USA.

Director of the institute, Anthony Atala, and colleagues have long been at the forefront of cell-based therapeutics for urological application, most notably in the field of bladder bioengineering. Other recent milestones have included generation of functional autologous penile and vaginal tissue in rabbits. Now, an all-important leap from animal model to human has been made, with successful implantation of lab-grown urethras in five boys with complex posterior defects. “We are definitely a step further in demonstrating that the results that have been reported in animals can be translated to the clinic”, Karl-Dietrich Sievert—author of a Comment on Atala and colleagues' Lancet paper—told Bloomberg Businessweek.

The five study participants were patients at the Federico Gomez Children's Hospital in Mexico City. Aged between 10 and 14 years, their complex posterior urethral defects (ranging in length from 4 cm to 6 cm) were the result of either a motor vehicle accident or saddle trauma. Three of the boys were urethroplasty-naive, whereas two had failed previous repairs (one a tubularized buccal mucosa graft, the other a tubularized foreskin graft).

Credit: © Nature Publishing Group

A 1 cm2 bladder biopsy from each boy was collected by lead author Atlantida Raya-Rivera via a 3 cm suprapubic transverse incision. This biopsy tissue served as the source for primary cultures of smooth muscle and urothelial cells. After between 3 and 6 weeks of in vitro expansion, cells were seeded onto tubes of biodegradable polyglycolic acid mesh—urothelial cells on the luminal surface and muscle cells on the outer surface. The dimensions of each mesh scaffold were matched to the defect size of each individual.

Surgical implantation of the sterilized neourethras via a perineal inverted semicircular incision proceeded without complications. No fistulae or urinary tract infections developed during a median follow-up period of 71 months. Anastomotic narrowing requiring transurethral incision developed in the first patient to undergo surgery. This temporary complication developed following removal of his catheter at 2 weeks. Narrowing did not develop in the subsequent four patients, for whom the period of postoperative catheterization was extended to 4 weeks.

Wide caliber urethras, without strictures or diverticula, were evident on voiding cystourethrograms 1 year after surgery. At last follow-up, mean end maximum flow rate was 25 ml/s. All boys are continent, and satisfied with the outcomes of the procedure.

The results show “that these [autologous tissue-engineered urethras] are actually able to work in the long term, and that they're able to grow with the patient” Atala told Bloomberg Businessweek. Further, serial biopsies revealed the architecture and histology of the engineered urethras to be free of aberrations, with layers of pure epithelia and smooth muscle being distinguishable just 3 months after implantation.

In his Comment, Sievert (Eberhard-Karls University, Tübingen, Germany) suggests that developing a noninvasive means of harvesting the source tissue for cell culture—for example, via bladder wash—would make this landmark procedure an even-more attractive option for reconstructive urethroplasty. He also cautions that “the tissue-engineered cell-seeded urethral tubes ... must still prove to be cost effective”. According to Atala, it cost about US$5,000 to create a urethra over a period of 4–7 weeks at the Metropolitan Autonomous University in Mexico City. He told Bloomberg Businessweek that, compared to current surgical options which have a high rate of failure, use of neourethras would actually save money over time, as fewer revision procedures would be required.

Another issue that needs to be clarified is the applicability of these preliminary findings to adult patients, and to patients with anterior—as opposed to posterior—urethral defects. Sievert opines that researchers who undertake to expand the indications for this technology should “accept the challenge of [Atala and his colleagues]” by aiming for “a 100% success rate as the gold standard”.

Currently working on engineering of more than 30 different tissues and organs, Atala feels that these latest results could pave the way for creation of other tube-like structures, such as replacement arteries (Bloomberg Businessweek). Chris Mason from University College London summed up the wide-ranging potential of the Lancet study when he told BBC News that “when an organ or tissue is irreparably damaged or traumatically destroyed, no amount of drugs or mechanical devices will restore the patient back to normal. If the goal is cure, then cell-based therapies are the answer.”