Biomaterials in the Urinary Tract: New Concepts

Transcription

1 Biomaterials in the Urinary Tract: New Concepts Ben H. Chew, MD, MSc, FRCSC Endourology & Laparoscopy Fellow The University of Western Ontario London, Canada 1. Ureteral Stent Encrustation 2. Stent-related Infection 3. Stent-related Pain 1

2 Definition: Stent 1. A device used to maintain a bodily cavity or orifice, or contour after skin grafting OR 2. A catheter, rod, or tube within a tubular structure to maintain lumenal patency or protect an anastomosis or graft. Steadman s Medical Dictionary Dorland s Medical Dictionary The Ancient Times 1000 BC: gold, silver, iron, wood, smeared with ghee (butter) catheters 300 BC Erastratus, Greece named catheter Egypt: Lead papyrus catheters 7 AD: strand of wool = siphon (Paul of Aegina) 1000 AD: Avicenna (Saracen philosopher) used soft and flexible materials for catheters : Charles T. Stent dental impression material of wax and gutta percha (latex relative) 1860: Natural rubber (Michele Troia), red rubber catheter Gibbons stent 1978 Finney: Double J Stent 2

3 The Ideal Stent 1. Biocompatible 2. Radiopaque 3. Relieve intra/extra luminal obstruction (rigid) 4. Resist encrustation and infection 5. Cause little discomfort No stent currently encompasses all these factors What is a Biomaterial? any substance, natural or synthetic, used in the treatment of a patient which, at some stage, interfaces with tissue Constant Urine Exposure Urethral Catheters Ureteral Stents Percutaneous Nephrostomy Urethral Stents Bladder / Ureteral Replacements No Exposure to Urine Testicular Prostheses Penile Prostheses Pubovaginal Slings Artificial Sphincters 3

4 Current Stent Biomaterials Synthetic polymer compounds currently used: Polyethylene Silicone Polyurethane Proprietary Silitek C flex Percuflex Encrustation, Biofilm Formation, Infection No biomaterial used in urinary tract able to completely withstand the effects of urinary environment Device related UTI / encrustation cause significant morbidity Major limiting factors for long-term use of biomaterials within urinary tract 4

5 Stent Related Problems Encrustation Infection Bothersome Symptoms STENT INDWELLING TIMES & ENCRUSTATION Polyurethane stents tested N=299 Stent indwelling times <6 weeks 6-12 weeks weeks >24 weeks Incidence of encrustation 6/65 (9.2%) 57/120 (47.5%) 55/79 (69.7%) 32/35 (91.5%) El-Faqih et al., J Urol

6 Infection / Encrustation Biofilm formation within hours on urinary materials 1. Organic conditioning film (proteins, lytes) 2. Bacteria adherence 3. Bacteria Exopolysaccharide matrix further growth 6

7 Pathophysiology of Encrustation: Urease-producing organisms Hydrolysis of urea Alkaline urine (NH 4+ ) Precipitation of Ca 2+ and Mg 2+ Crystallization of MgNH 4 PO 4 and calcium apatite Infected Urine Prevention and Management of Encrustation Biomaterials resistant to encrustation Prevention of colonization Modulation of urinary environment Prophylactic device replacement 7

8 Methods of Prevention of Encrustation Bulk material modification Silicone, Low surface energy (Tieszer et al, 1998) Surface Coatings Hydrogels Less platelet adhesion, low coefficient of friction Conflicting results Antibiotics Oral Ciprofloxacin adsorbs to stent surface (Reid et al, 2000) Prevention of colonization Silver nitrate (Multanen et al, 2002) Pentosan polysulfate 8X reduction in encrustation in rabbit model (Zupkas et al, 2000) Oxalate-degrading enzymes 42% reduction in encrustation in rabbit model (Walterson et al, J Endourol, 2003) Heparin Coated stents Hildebrandt et al, Biomaterials,

9 Methods of Prevention of Encrustation Alteration of Urinary Environment ph: difference in the solubility product between blockers and non-blockers (Choong et al, 2000) Ie. Catheter irrigation (Suby G) vs. oral acidification Alteration of Intestinal Microbial Flora Correlation between hyperoxaluria/oxalate stone disease and the absence of Oxalobacter formigenes (Sidhu et al, 1999) Prophylactic Device Replacement New Stent Technologies Biomaterials in other subspecialties Cardiology Orthopedics Dentistry Plastic Surgery Ophthalmology Cardiac Stents loaded with Paclitaxel, Sirolimus to prevent Re-stenosis Goal Therapeutic effect of stent AND Benefit of locally administered drug 9

10 Drug Eluting Stents: Engineering Stent Surface Elution of Drug Models for Evaluating Encrustation In vivo models Animal Rabbit (bladder implantation) Porcine (stent) In vitro models: (Tunney et al, 1997) 10

11 The Challenge What would be significant? Stent that would reliably reduce encrustation processes in high risk patients for 8 weeks: Pregnancy UTI Neurogenic bladder Diversions Infection Stones Anatomic Abnormalities Transplant Patient Diabetes Metabolic Stone Disease The Challenge What would be significant? Indwelling urethral catheter that reliably resides in the urinary tract without encrustation for 6-12 months Suprapubic catheter requiring changes every 2 years Urethral catheter / internal stent / nephrostomy tube with significantly decreased UTI incidence during 1-6 week time frame 11

12 Stent Related Problems Encrustation Infection Bothersome Symptoms The Scope of the Problem: Infection Limits long-term use 44-90% of retrieved stents had adherent pathogens (Reid et al, 1992, Paick et al, 2003) 50% of long-term indwelling foley catheters recurrent encrustation and blockage UTI: 8% to 30% of stented patients. 12

13 Triclosan Prevents bacterial fatty acid synthesis: bactericidal Found in: Mouthwashes Toothpastes Soaps Surgical scrubs Cutting boards Children s toys J&J Vicryl Plus suture Gram +/- organisms Antimicrobial in Foley Catheters Stickler inflated foley catheter balloons with triclosan in an in vitro bladder model infected with Proteus mirabilis (Lancet 361:1435, 2003) Control catheters blocked (encrusted) within 24 hrs, Triclosan inflated catheters remained patent x 7 days Triclosan prevented Proteus from urinary ph and the ensuing encrustation 13

14 Triclosan Loaded Ureteral Stents Hypothesis: Triclosan loaded ureteral stents would decrease the amount of encrustation and bacterial growth in rabbit bladders infected with Proteus mirabilis Optima Percuflex + Triclosan 14

15 Methods 45 male New Zealand White rabbits Controls: Bard Optima, Boston Sci Percuflex Plus Transurethral insertion of stent curls Bladder emptied and 1 x 10 6 CFUs Proteus mirabilis inserted Urine collected on days 1, 3 and 7 for C&S. Animals sacrificed at day 7. Stent encrustation, bladder pathology Stent Encrustation Encrustation (mg/cm 2 stent) Percuflex Optima Triclosan 15

16 Urine Culture Results Urine Culture 1.0E E+07 P=0.001 P= P=0.008 P= P=0.001 P. mirabilis 296 CFUs/ml 1.0E E E+04 * * ** ** Percuflex Optima Triclosan * 1.0E E+02 Day 1 Day 3 Day 7/8 16

17 1.0E+06 Stent Bacterial Growth 7.8E E E+04 P. mirabilis 296 CFUs/cm 2 stent 1.0E E+03 * ** Percuflex Optima Triclosan 1.0E+02 P= P= E+01 Day 7/8 1.4E+01 Bladder Pathology P= Pathology Grade (0-4) * Percuflex Optima Triclosan 17

18 Conclusion In an infected rabbit model, Triclosan stents have : less bacterial growth in urine culture less bacterial growth on the stent Less inflammation Encrustation? Potential treatment for obstructive pyelonephritis or prevention of stent-related UTI Further studies needed Triumph Stent (Boston Scientific) Stent Related Problems Encrustation Infection Bothersome Symptoms 18

19 Ureteral Stent Symptoms > 80% of patients experience symptoms: Dysuria Frequency, urgency Gross hematuria Flank pain Pelvic pain Infection Encrustation Blockage Joshi, J Urol, 2003 Easier Stent Removal? 19

20 Novel Prostatic Stents Urovalve No scope necessary Continent No external device?lower infection rate Change q 28 days Phillip J. Davis, Rafael S. Wurzel, GU Engineering (AUA), May 2004 Dissolvable Stents TUDS (Temporary Ureteral Drainage Stent) (Boston Scientific) Not all dissolved, some dissolved early Obstructed and required ureteroscopy Lingeman J Endo 17:169, Lingeman J Urol 169:1682,

21 Spiral Stent Stoller BJU Int 85:628, Stent Designs Tail stent Dunn J Endo 14:195, 2000 Liatsikos Urology 59:15,

22 Dual Durometer Stents Polaris (Boston Scientific) Sof-Curl (ACMI) 6: Firm durometer (kidney) 1: Soft durometer (bladder) Current treatment of stent symptoms: Analgesics Anticholinergics Early device removal Avoid stent use 22

23 Treating Stent Related Pain: A Novel Approach Local drug delivery Directly into urinary tract Various potential agents Effects of local drug delivery on urinary tract pain receptors unknown?possibility of receptor down-regulation Which drug? How to screen? Expensive to load into stents Hypothesis Intravesical instillation of: 1. Oxybutynin or 2. Lidocaine or 3. Ketorolac will be safe and effective in reducing ureteral stent symptoms. Methods: Human Screening Patients stented prior to ESWL Intravesical instillation of above 3 or saline 23

24 Results 46 patients recruited Oxybutynin: 10 Ketorolac: 10 Lidocaine: 10 Normal saline (control): 10 Not enrolled: 4 2-unable to stent, 1 GA, 1 obese - no SWL Dropout: 2 1-demanded early stent removal, 1 confused 24

25 Intravesical Indwelling Times Ketorolac NS Lidocaine NS Oxybutynin NS Saline NS Time to First Void (min) VAS Score Flank Pain at Rest Saline Ditropan Xylocaine Toradol 1 0 P<0.01 P= hr 2 hr 4 hr 24 hr 7 day 25

26 Criticisms Low numbers Retention times: minutes absorption? Validated questionnaire Different anesthesiologists Most given propofol, fentanyl, midazolam Conclusion Intravesical oxybutynin, lidocaine, and ketorolac are safe intravesical agents Ketorolac decreases flank pain in the first 1-2 hours after stent insertion Foundation for future studies of drugloaded stents to reduce stent-related symptoms (ketorolac-loaded stents) 26

27 Future Materials Small intestinal submucosa (SIS) Urethra, bladder (Landman et al, 2004) ureteral defects? Tissue engineering (cell culture)-atala Single cell to 1 cm 2 to 4000 m 2 in 8 wks. Bladders, ureteral defects? 27

28 Biomaterials Conclusion No perfect stent material New combination polymers promising Drug-eluting technology: the future Local gene therapy: Cancer Rx Nature: Clinical Practice Urology (Nov 2004) 28