Elsevier

The Lancet

Volume 367, Issue 9518, 15–21 April 2006, Pages 1241-1246
The Lancet

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Tissue-engineered autologous bladders for patients needing cystoplasty

https://doi.org/10.1016/S0140-6736(06)68438-9Get rights and content

Summary

Background

Patients with end-stage bladder disease can be treated with cystoplasty using gastrointestinal segments. The presence of such segments in the urinary tract has been associated with many complications. We explored an alternative approach using autologous engineered bladder tissues for reconstruction.

Methods

Seven patients with myelomeningocele, aged 4–19 years, with high-pressure or poorly compliant bladders, were identified as candidates for cystoplasty. A bladder biopsy was obtained from each patient. Urothelial and muscle cells were grown in culture, and seeded on a biodegradable bladder-shaped scaffold made of collagen, or a composite of collagen and polyglycolic acid. About 7 weeks after the biopsy, the autologous engineered bladder constructs were used for reconstruction and implanted either with or without an omental wrap. Serial urodynamics, cystograms, ultrasounds, bladder biopsies, and serum analyses were done.

Results

Follow-up range was 22–61 months (mean 46 months). Post-operatively, the mean bladder leak point pressure decrease at capacity, and the volume and compliance increase was greatest in the composite engineered bladders with an omental wrap (56%, 1·58-fold, and 2·79-fold, respectively). Bowel function returned promptly after surgery. No metabolic consequences were noted, urinary calculi did not form, mucus production was normal, and renal function was preserved. The engineered bladder biopsies showed an adequate structural architecture and phenotype.

Conclusions

Engineered bladder tissues, created with autologous cells seeded on collagen-polyglycolic acid scaffolds, and wrapped in omentum after implantation, can be used in patients who need cystoplasty.

Introduction

A range of injuries can lead to damage or loss of the bladder, necessitating eventual replacement or repair of the organ. Children with congenital anomalies such as bladder exstrophy, myelomeningocele, or posterior urethral valves, can develop high-pressure and hypertonic low-compliant bladders.1, 2, 3 These patients often need cystoplasty when drug treatment fails.

Gastrointestinal segments are frequently used as donor tissues for cystoplasty. However, when such tissues are incorporated into the urinary tract, several complications can ensue, such as metabolic disturbances, urolithiasis, increased mucous production, and malignant disease.4, 5

Because of the these problems, many investigators over the past 100 years have attempted to use alternative methods, materials, and tissues for replacement or repair of the bladder. The first application of a free tissue graft for bladder replacement was reported by Neuhof in 1917, when fascia was used to augment bladders in dogs.6 Since that first report, several other materials have been used for free grafts experimentally and clinically, including skin, bladder submucosa, omentum, dura, peritoneum, placenta, seromuscular grafts, and small intestinal submucosa.7, 8, 9, 10, 11, 12 Synthetic materials that have been tried in experimental and clinical settings include polyvinyl sponge, tetrafluoroethylene (Teflon), gelatin sponge, collagen matrices, vicryl matrices, resin-sprayed paper, and silicone.13, 14, 15, 16, 17, 18 These attempts have usually failed because of mechanical, structural, functional, or biocompatibility problems. Usually, permanent synthetic materials succumb to mechanical failure, and urinary stone formation and use of degradable materials lead to fibroblast deposition, scarring, graft contracture, and a reduced reservoir volume over time. Evidently, bladder tissue, with its elastic properties and urothelial permeability, cannot be easily replaced. Therefore, the use of bowel tissue remains the gold standard more than a century after it was proposed, despite associated problems, since no better alternative is available. Anastomoses between two sets of urological tissue are preferable functionally, but the limited amount of autologous urological tissues for reconstruction generally precludes this option. Engineering bladder tissue with selective cell transplantation might provide a means to create functional new tissues.19

Cell-based approaches to engineer bladder tissue have been reported,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and bioengineering has allowed creation of functional neo-bladder tissues in several animal models.28, 32, 33, 34, 35 In dogs, successful transplantation of autologous bladders with bioengineering techniques has been reported.36, 37 Our approach in the dog experiments used autologous cells, thus avoiding rejection, wherein a biopsy of tissue is obtained from the host, the cells are dissociated and expanded in vitro, attached to a biodegradable matrix, and reimplanted into the same host. After implantation, histological evidence showed that the engineered bladders continued to develop until they appeared normal anatomically and functionally. Another study21 showed that engineered muscle formed from cells of normal and diseased bladders showed similar phenotypic and functional properties, suggesting that cells from unhealthy bladders have the potential to be engineered into normal tissues. Encouraged by these results, we aimed to engineer human bladder tissues by seeding autologous cells on matrices, and to implant these constructs in patients with end-stage bladder disease requiring cystoplasty.

Section snippets

Study design and patients

The study was approved by the institutional review board and oral informed consent was obtained from the patients' legal guardians. All bladder tissue processing was done at a cell-processing facility approved by the US Food and Drug Administration. Our clinical experience was gathered over 3 years, with up to 5 years of follow-up. The planned slow accrual of patients and long-term follow-up allowed us to modify the protocol whenever improvements were needed. Based on our initial preclinical

Results

Primary cultures of urothelial and smooth muscle cells were routinely expanded and passaged. There was no incidence of cessation of growth or abnormal changes in morphology. The cells were in culture for about 6 weeks for all patients.

All patients tolerated the augmentation cystoplasty procedure. The duration of hospital stay ranged from 23 to 34 days with a mean of 28·5 days (SD 3·8). Postoperatively, one patient had a urinary yeast infection, which was managed appropriately. No other

Discussion

We engineered human bladder tissues for patients with end-stage bladder disease by isolating autologous bladder urothelial and muscle cells, expanding the cells in vitro, and attaching them to biodegradable three-dimensional matrices.

The goal of the study was to improve the functionality of diseased bladders by decreasing the intravesical pressures, and improving bladder compliance and continence. Patients with a poorly compliant bladder may incur renal damage over time; thus, avoiding any

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