Tissue-Engineered Autologous Bladders: New Possibilities for Cystoplasty

Bradley P. Kropp; Joseph B. Zwischenberger

Disclosures

Nat Clin Pract Urol. 2006;3(11):588-589. 

In This Article

Synopsis and Commentary

Synopsis

Background: The use of gastrointestinal segments as donor tissue for cystoplasty is associated with a range of complications, including metabolic disturbances, urolithiasis, increased mucus production, and malignant disease. Nevertheless, it remains the gold standard, despite efforts to identify a suitable alternative. Recent advances in tissue engineering using selective cell transplantation offer potential for the manufacture of new, functional bladder tissue, which might provide a better alternative to bowel tissue for cystoplasty.
Objective: To investigate the use of autologous engineered bladder tissue in children requiring cystoplasty.
Design: Patients aged 4-19 years with high-pressure or poorly compliant bladders due to myelomeningocele were identified as candidates for cystoplasty and included in this study. All had frequent urinary leakage (up to every 30 min), despite maximum pharmacologic intervention and frequent intermittent catheterization.
Intervention: All patients underwent bladder biopsy. Urothelial and muscle cells obtained from the biopsy were separately expanded in culture. When sufficient cells had been produced, they were seeded on a biodegradable, bladder-shaped scaffold made of collagen, or a composite of collagen and polyglycolic acid, tailored to the size requirement of the patient. These autologous engineered bladder constructs were used for reconstruction and implanted either with or without an omental wrap about 7-8 weeks after the initial biopsy. Serial serum analyses, renal ultrasounds, voiding cystograms and urodynamic testing were performed postoperatively.
Outcome measures: The main outcome measure was improved functionality of the diseased bladder, assessed by intravesicular pressures, compliance, and continence.
Results: Seven patients were included in this study. Mean follow-up time was 46 months (range 22-61 months). The mean decrease in postoperative bladder leak-point pressure at capacity ranged from 12%, in the collagen engineered bladders without omental wrap, to 56%, in the composite engineered bladders with an omental wrap. Similarly, the composite engineered bladders with an omental wrap showed the greatest increase in volume and compliance (1.58-fold and 2.79-fold, respectively). The greatest increase in maximum average daytime dry interval was also seen in patients who received the composite engineered bladder with omental wrap (range 3-7h). Renal function remained normal and no metabolic consequences were reported. There was no evidence of urinary calculi formation and mucus formation was normal. Biopsy of the engineered bladders showed the expected tri-layer structure of a urothelial cell-lined lumen surrounded by submucosa and muscle, and all bladder tissue components were present.
Conclusion: The authors concluded that tissue-engineering techniques using autologous cells seeded on collagen-polyglycolic acid scaffolds can be used to create bladders that improve functional parameters in patients requiring cystoplasty. Wrapping the engineered bladder in omentum further improved results. More studies are required before this procedure can be widely used.

Commentary

Tissue-engineered urologic organs might be the future of urologic reconstruction. Despite decades of research, investigators continue to search for optimal materials, better surgical techniques, and an improved understanding of the mechanisms of tissue regeneration. The recent report in The Lancet by Atala et al. represents an initial effort to apply urological tissue engineering to human bladder reconstruction. There are, however, a number of questions raised regarding the use of materials, adequate preclinical data, and clinical trial outcome determination.

A major hurdle in the field of tissue engineering is identifying appropriate materials for tissue replacement. The material used in one underpowered, preclinical trial[1] was a composite of polyglycolic acid (PGA) and polylactic-coglycolic acid. This is not the same as the collagen-PGA matrix used in this human trial. Indeed, Sherwood Medical, the company that supplied the clinical material, apparently no longer exists. No preclinical data were reported on the collagen-PGA matrices used in this study. As this was the first use of a collagen-PGA matrix for urologic organ reconstruction, a full description of the material preparation, and the decision process concerning the choice of materials, should have been provided.

Given that preoperative data related to continence and age-expected bladder capacity were not reported, the authors' interpretation of the final results is speculative. Furthermore, the authors did not explain why the omental wrap used in preclinical testing[2] was not used on the first three patients. Did the authors conduct other preclinical trials demonstrating that omentum was not necessary? Other concerns about this trial include the lack of standardized operative techniques and scaffold material, the length of follow-up, and the failure to establish ethical clinical trials in humans.

The use of pelvic 3D CT imaging in the last three patients demonstrates that the authors understand the importance of age-expected bladder capacity in assessing the outcome of bladder-augmentation surgery, yet they do not report their data using this methodology. Importantly, of the nine patients who underwent this procedure, only one seemed to have a significantly increased bladder capacity. Furthermore, it was not explained why this patient's 438 ml bladder needed to be augmented in the first place.

Contrary to the authors' interpretation, postoperative urodynamic studies showed bladder compliance to be poor in all but one patient. Additionally, standard urodynamic results should include a subtracted detrusor pressure; reporting leak-point pressure in augmentation results is not germane. The authors also failed to explain why all follow-up biopsies demonstrated phenotypically normal tri-layered bladder structure, yet the clinical results showed that function did not follow form. It is unusual for grade 2 reflux to cause hydronephrosis-this does not seem a plausible explanation for the hydronephrosis-and the grade of hydronephrosis was not reported.

Finally, the close association of the senior author with Reprogenesis Inc, the company that held the license to the technology used in this study, should have been disclosed.

Atala and colleagues have focused attention on an important 'next step' in the integration of tissue engineering into clinical practice. The presented data are provocative and beg further preclinical testing in prospective, randomized, multicenter trials.

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