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Boston—Evolving from dream to reality in only a few years, tissue engineering is beginning to provide clinical options in urology. This is quite an accomplishment, said Anthony Atala, MD, of Harvard Medical School, given that 10 years ago keeping urothelial cells alive in the laboratory for more than a few weeks was difficult.
Atala, who spoke at the American Society of Andrology meeting last month, has contributed much to the success of the field. It was at Harvard under his direction that the first urologic application of cell-based tissue engineering—the injection of autologous cells for the correction of vesicoureteral reflux in children—took place.
In this treatment, investigators inject a bulking agent under the ureteral orifice that changes the angle of the ureter and narrows the lumen, thereby preventing retrograde urine flow into the kidney, Atala explained. The injected material, which consists of chondrocytes grown from a biopsy of the patient's ear and a hydrogel called alginate, eventually forms a permanent cartilaginous structure that holds the ureter in place.
The new procedure can be performed in a 15-minute outpatient operation, a notable improvement over the standard surgical treatment, which requires a 4-day hospital stay. With phase 1 trials having shown the safety of the new procedure, phase 2 and 3 trials are under way, and results should be available in about a year, Atala said.
The same procedure has been applied to the correction of urinary incontinence in adults, with the chondrocyte/hydrogel mixture injected into the bladder neck. Phase 1 trials have been completed for this application. Atala said he and colleagues are also investigating this method to inject smooth muscle cells mixed with hydrogels for use in plastic and reconstructive surgery.
A number of additional applications of tissue engineering technology are currently under study, said Atala. For example, his group has used tissue regeneration for urethral reconstruction. "One of the first applications we tried," he said, "was for hypospadias, in which the urethra is not developed all the way to the tip of the penis." In many pediatric patients with this condition, he explained, there is a lack of native urologic tissue for surgery. Grafts from nonurologic tissues can be used, but doing so may increase hospitalization time and morbidity. Atala's group uses a collagen scaffold seeded with the patient's own urothelial cells for urethral repair. More than 60 patients have had this surgery, he said, and at 3-year follow-up, there has been no incidence of stricture formation in any patient.
Last year Atala's laboratory demonstrated that they could engineer a functional bladder in dogs (Nat Biotechnol. 1999;17:149-155). From canine bladder biopsies, researchers obtained urothelial and smooth muscle cells, which they cultured and seeded onto spherical polymer scaffolds. They then transplanted the reconstructed bladder into the dog from which the biopsy was obtained, and Atala said evaluations showed that the neo-organs (as engineered body parts are called by their creators) were normal in terms of histology, elastic properties, and ability to retain urine.
So far, this procedure has not been carried out clinically, but about 2 years ago a patient underwent bladder augmentation using an engineered patch of tissue, said Atala. After a year of observation showed good results, a second patient underwent the procedure. There are now seven patients enrolled in a study.
Atala said he believes in proceeding slowly in bringing this new technology to the clinical setting, explaining, "whenever I've had control of a trial, I've done one patient first, waited a year, and then enrolled other patients."
Other tissue engineered devices that Atala hopes will soon enter clinical trials are autologous penile prostheses. Atala said that silicone prostheses are currently used in cases of traumatic injury or to correct ambiguous genitalia, but because silicone is not a biocompatible material, its use can sometimes be problematic.
By seeding biodegradable polymer rods with chondrocytes harvested from rabbit ears, his group created cartilage rods that were elastic and able to withstand compression in rabbits. Studies showed that the implants were well tolerated for the length of the 6-month study, and the animals were able to copulate, produce sperm, and impregnate their mates.
Encapsulated cells are another promising technology. Researchers in Atala's laboratory have shown that Leydig cells encapsulated in alginate/poly-L-lysine microspheres can secrete testosterone in culture and in rats. Atala said that in vivo, the protected covering allows nutrients to reach the cells and hormones to escape while preventing the relatively large host immune cells from attacking the cells.
These constructs may be useful in treating such conditions as androgen deficiency and prostate cancer. Atala's group is also applying this microencapsulation technique to ovarian cells for the release of progesterone and estrogen.
In spite of its promise, Atala stressed that it is important to recognize that tissue engineering is still a new field that will have its problems just like any other developing technology. Nevertheless, as work continues to yield such exciting results, he said, he is "guardedly excited."
Friedrich MJ. Tissue Engineering in the Genitourinary System. JAMA. 2000;283(19):2509. doi:10.1001/jama.283.19.2509-JMN0517-2-1
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