Abstract
We describe a novel infection-responsive coating for urinary catheters that provides a clear visual early warning of Proteus mirabilis infection and subsequent blockage. The crystalline biofilms of P. mirabilis can cause serious complications for patients undergoing long-term bladder catheterisation. Healthy urine is around pH 6, bacterial urease increases urine pH leading to the precipitation of calcium and magnesium deposits from the urine, resulting in dense crystalline biofilms on the catheter surface that blocks urine flow. The coating is a dual layered system in which the lower poly(vinyl alcohol) layer contains the self-quenching dye carboxyfluorescein. This is capped by an upper layer of the pH responsive polymer poly(methyl methacrylate-co-methacrylic acid) (Eudragit S100®). Elevation of urinary pH (>pH 7) dissolves the Eudragit layer, releasing the dye to provide a clear visual warning of impending blockage. Evaluation of prototype coatings using a clinically relevant in vitro bladder model system demonstrated that coatings provide up to 12h advanced warning of blockage, and are stable both in the absence of infection, and in the presence of species that do not cause catheter blockage. At the present time, there are no effective methods to control these infections or provide warning of impending catheter blockage.
Highlights
IntroductionUrease enzyme (Scheme 1) generates ammonia, elevating urinary pH, and leading to the precipitation of calcium phosphate and magnesium–ammonium phosphate from urine to form crystals of carbonate apatite [Ca10(PO4)6CO3], and struvite (MgNH4PO4 Á 6H2O), respectively (Stickler et al, 1993; Griffith et al, 1976; Holling et al, 2014a, 2014b)
It has been estimated that $ 100 million indwelling urinary catheters (IUC) are sold annually worldwide (Saint et al, 2000)
The problem of catheter associated urinary tract infections (CAUTIs) is pronounced in patients who are managed long-term with urethral catheterisation, where IUC are in place for weeks or months at a time
Summary
Urease enzyme (Scheme 1) generates ammonia, elevating urinary pH, and leading to the precipitation of calcium phosphate and magnesium–ammonium phosphate from urine to form crystals of carbonate apatite [Ca10(PO4)6CO3], and struvite (MgNH4PO4 Á 6H2O), respectively (Stickler et al, 1993; Griffith et al, 1976; Holling et al, 2014a, 2014b) These crystals subsequently become incorporated into the developing biofilms, which further stabilises and enhances their growth (Stickler et al, 1993; Holling et al, 2014a, 2014b). Elevation of urinary pH upon P. mirabilis infection (via the urease-catalysed hydrolysis of urea) causes dissolution of the upper EUDRAGITsS 100 layer, releasing the carboxyfluorescein contained in the lower hydrogel matrix to provide a clear visual signal throughout the catheter drainage system that blockage is imminent, and intervention is required
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