Purpose Chondroitin sulfate, which is less expensive and more inert than heparinoids, hyaluronan or pentosan polysulfate, has been introduced to restore the barrier function lost due to epithelial dysfunction in interstitial cystitis (IC). The binding of chondroitin sulfate to damaged bladder as a function of the range of pH seen in urine, its efficacy in restoring the bladder's permeability barrier, and the capacity of damaged bladder to bind chondroitin sulfate have not been determined previously. Methods Binding of chondroitin sulfate to bladder urothelium was investigated quantitatively using chondroitin sulfate highly labeled with Texas Red and quantitative fluorescence microscopy in a mouse model of acid damage of the urothelium. The efficacy of restoring the barrier function was determined using passage of intravesically instilled 86Rb, a potassium ion mimetic, through the urothelium into the bloodstream in a rat model of bladder damage. The binding capacity of acid-damaged bladder was determined by fluorometry. Results Chondroitin sulfate bound tightly and exclusively to the mouse bladder surface that had been damaged by acid but showed only minimal binding to undamaged bladder. There was no systematic variation with pH. The model showed some variability in the degree of damage induced. In rats, chondroitin sulfate instillation restored permeability to 86Rb to control levels. Binding was saturable at 0.67 ± 0.13 mg/cm2 of bladder surface. Conclusions Chondroitin sulfate binds preferentially to damaged urothelium and restores the impermeability barrier. This suggests that the GAG layer is a major contributor to the impermeability of bladder urothelium. As determined by the binding capacity, the dose applied to humans in Canada (400 mg per instillation) is sufficient to obtain maximum efficacy.

What's known on the subject? and What does the study add? Urinary bladder tissue can be produced by several regenerative techniques although consistent regeneration remains elusive and no single protocol is superior to the others. Small intestinal submucosa has been used as substrate for regeneration in several models and allows for full‐thickness bladder regeneration. Nanotechnology has been applied to impart specific physical and biological properties onto biological substrates. Nanoparticles composed of PLGA can be modified by the addition of hyaluronic acid and can be added to SIS. This modified SIS demonstrates a potential improvement in biological activity as suggested by more consistent smooth muscle regeneration in a canine model of bladder regeneration. This study demonstrates both the feasibilty and potential of synthetically‐modified natural biomaterials. OBJECTIVE • To determine if hyaluronic acid (HA) can be incorporated into porcine small intestinal submucosa (SIS) through poly (lactide‐co‐glycolide‐acid) (PLGA) nanoparticles to improve the consistency of the naturally derived biomaterial and promote bladder tissue regeneration. METHODS • Beagle dogs were subjected to 40% partial cystectomy followed by bladder augmentation with commercial SIS or HA‐PLGA‐modified SIS. • Urodynamic testing was performed before and after augmentation to assess bladder volume. • A scoring system was created to evaluate gross and histological presentations of regenerative bladders. RESULTS • All dogs showed full‐thickness bladder regeneration. • Histological assessment showed improved smooth muscle regeneration in the HA‐PLGA‐modified SIS group. • For both groups of dogs, urodynamics and graft measurements showed an approximate 40% reduction in bladder capacity and graft size from pre‐augmentation to post‐regeneration measurements. • Application of the scoring system and statistical analysis failed to show a significant difference between the groups. CONCLUSIONS • SIS can be modified through the addition of HA‐PLGA nanoparticles. The modified grafts showed evidence of improved smooth muscle regeneration on histological assessment, although this difference was not evident on a novel grading scale. • The volume loss and graft shrinkage experienced are consistent with previous models of SIS bladder regeneration at the 10‐week time point. • Additional research into the delivery of HA and the long‐term benefits of HA on bladder regeneration is needed to determine the full benefit of HA‐PLGA‐modified SIS. In addition, a more objective biochemical characterization will be needed to evaluate the quality of regeneration.

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