**5. Metal ureteral stents**

Metal ureteral stents were introduced by Pauer in 1992 (Pauer and Lugmayr 1992) and have been utilized in the treatment of malignant ureteric obstruction (Kulkarni and Bellamy 2001; Liatsikos, Karnabatidis et al. 2009; Masood, Papatsoris et al. 2010; Papatsoris and Buchholz 2010; Sountoulides, Kaplan et al. 2010), ureteral strictures (Daskalopoulos, Hatzidakis et al. 2001; Papatsoris and Buchholz 2010), and ureteropelvic junction obstruction (Barbalias, Liatsikos et al. 2002; Masood, Papatsoris et al. 2010; Benson, Taylor et al. 2011). Current

Biomaterials in Urology - Beyond Drug Eluting

and Degradable - A Rational Approach to Ureteral Stent Design 463

dependent upon the urine pH. In vitro experiments with artificial urine showed that the stents were stable at urine pH less than 7.0 for at least 30 days, while they dissolved completely within 48 hours at pH greater or equal to 7.0. The principle behind this stent is that it would remain stable at physiological urine pH of 5-6, but can be triggered to dissolve by medically altering urinary pH. Although very promising, this technology remains at an experimental stage and awaits animal trials. An additional factor that may need to be taken into consideration is the influence of encrustation protein deposition as it can form a platform for bacterial adherence and infection. The influence of encrustation and protein deposition must also be considered as it can form a platform for bacterial adherence, all of which may influence urine pH. Uropathogens in general are known to increase urine pH, and may have an effect *in vivo*. In addition to this, medically increasing the urinary pH may introduce an additional risk for infection as more alkaline pH favours bacterial survival and some increased stone formation (calcium phosphate and struvite stones). In addition, encrustation of the stent may also prevent May also prevent its exposure to the altered pH environment, environment and the altered pH, thus limiting its rate of decomposition. A spiral stent (Spirastent®, Urosurge Medical, Coralville, IA) is a polyurethane stent with metal helical ridges designed to prevent kinking and compression in chronically obstructed patients. In *in vitro* studies, this stent increased flow and theoretically increased the space between stent and ureter to facilitate passage of stone fragments.(Stoller, Schwartz et al. 2000) The spiral design has been incorporated into biodegradable materials for urethral stents.(Isotalo, Talja et al. 2002; Laaksovirta, Isotalo et al. 2002) Laaksovirta et al used a selfreinforced poly-L-lactic and poly-L-glycolic acid (SR-PLGA) copolymer spiral urethral stent (SpiroFlow stent, Bionx Implants Ltd, Tampere, Finland) following prostatic laser coagulation.(Laaksovirta, Isotalo et al. 2002) This stent degraded in 6–8 weeks and resisted encrustation at 4 weeks in artificial urine. After 8 weeks, the SpiroFlow® stent was significantly less encrusted than the metal urethral stents Prostakath® (Engineers and Doctors A/S, Copenhagen, Denmark) and Memokath® 028 (Engineers and Doctors A/S). SR-PLGA is the most commonly utilized material for prostatic stents, but it has also been developed as a ureteral stent and may be incorporated into new degradable, encrustation-

resistant ureteral stents in the future.(Olweny, Landman et al. 2002)

commercially available. (Lingeman, Preminger et al. 2003)

An alginate based ureteral stent was designed to stay in place for at least 48 hours after uncomplicated ureteroscopy.(Lingeman, Preminger et al. 2003; Lingeman, Schulsinger et al. 2003) Of 87 patients, 80.5% of patients retained their stents greater than 48 hours. Seventeen patients had early stent passage (earlier than 48 hours), but did not require any supplemental procedures to insert another stent. Although these results were promising, several patients (14) still had stent fragments remaining at 30 days, while 3 patients had stent fragments remaining after 90 days. All three of these patients underwent shockwave lithotripsy and two went on to have endoscopic ureteroscopy to remove the fragments from the kidney. Because of the lack of all stents to degrade by 3 months, this stent is no longer

The authors are currently involved in developing a new biodegradable stent (Poly-Med Inc., Anderson, SC) that dissolves within 1 to 4 weeks in a porcine model. The animals stented with degradable stents displayed less histologic inflammation than animals stented with control polyurethane biostable Double J stents (Chew, Lange et al. 2010). Weekly intravenous pyelograms displayed less hydronephrosis in the degradable stent group. All stents degraded by 4 weeks and degradation began after 1 week in a very controlled fashion

problems associated with metallic stents include biofilm formation, infection, migration, and tissue hyperplasia leading to luminal obstruction (Barbalias, Liatsikos et al. 2002; Wah, Irving et al. 2007; Liatsikos, Karnabatidis et al. 2009; Sountoulides, Kaplan et al. 2010).

Metal stents were originally used for the relief of end-stage malignant disease, where the ureteral stricture ws either directly caused by the tumor or indirectly via pressure of a tumor on the ureter. Pauer and Lugmayr used metallic ureteral stents in 1996 (Pauer and Lugmayr 1996) to treat 54 malignant stenoses of the ureter in 40 patients via the implantation of a selfexpandable permanent endoluminal stent (SPES), the WallstentTM. During a follow-up period of 10.5 months, 51 ureters maintained adequate patency. Of these, 51% needed no further intervention, while 49% needed intervention to re-establish patency. In comparison insufficiency was noted at a mean 4.3 weeks in control patients with an indwelling Double-J catheter. One of the drawbacks of metal stents is, however, that they induce local urothelial hyperplasia, with ingrowth of tissue through the struts that may result in recurrent obstruction during long term placement. Recently, a nickel-cobalt-chromium-molybdenumalloy stent double pig-tailed stent (ResonanceTM Stent, Cook Urological, Spencer, IN, USA) has been developed to provide long-term urinary drainage in patients with malignant ureteric strictures (Blaschko, Deane et al. 2007; Wah, Irving et al. 2007; Lopez-Huertas, Polcari et al. 2010; Wang, Lee et al. 2010). The tight winding of this metal stent helps to maintain stent flexibility and movement, while resisting in-growth of tissue. In addition to this, the movement of the stent causes opening of the coils, allowing the fluid to access the lumen. In a study of 15 patients, this metal stent provided adequate long-term (up to 12 months) urinary drainage in patients with malignant ureteric obstruction without significant bulky pelvic disease. These stents were also found to have minimal encrustation (Wah, Irving et al. 2007). An *in vitro* study has shown that this metal stent provides its best drainage when the ureter is tightly compressed onto its outer surface which is likely due to the result of increased flow between the coils of the metal stent. It was this feature that makes the ResonanceTM stent useful in patients in which the ureter is obstructed due to malignancy (Blaschko, Deane et al. 2007; Liatsikos, Karnabatidis et al. 2009; Masood, Papatsoris et al. 2010; Sountoulides, Kaplan et al. 2010; Wang, Lee et al. 2010; Benson, Taylor et al. 2011).

#### **6. Biodegradable stents**

Despite the fact that the biocompatible materials and stent designs have improved over the years, they have one key disadvantage, which is the fact that they have to be removed via a separate procedure unless the retention suture is left on the stent. Avoiding a secondary procedure for ureteral stent removal would decrease patient morbidity and make this technology attractive. More recent research has focused on the design of stents that do not need to be removed and are biodegradable. The design of a biodegradable stent must take into consideration the biocompatibility properties of the material, as well as the degree of expansion and degradation rates, and most importantly it must be able to fulfill the basic requirement of a stent in that it must be able to guarantee urinary flow from the renal pelvis through the ureter and into the bladder for the desired period of time. Degradable materials also must retain their properties after sterilization and be able to withstand a long shelf-life before use. One of the challenges involved in designing a biodegradable stent is the control of the rate and direction of degradation. Schlick and Planz (Schlick and Planz 1997; Schlick and Planz 1998) designed a stent composed of plastic, the degradation of which was

problems associated with metallic stents include biofilm formation, infection, migration, and tissue hyperplasia leading to luminal obstruction (Barbalias, Liatsikos et al. 2002; Wah, Irving et al. 2007; Liatsikos, Karnabatidis et al. 2009; Sountoulides, Kaplan et al. 2010). Metal stents were originally used for the relief of end-stage malignant disease, where the ureteral stricture ws either directly caused by the tumor or indirectly via pressure of a tumor on the ureter. Pauer and Lugmayr used metallic ureteral stents in 1996 (Pauer and Lugmayr 1996) to treat 54 malignant stenoses of the ureter in 40 patients via the implantation of a selfexpandable permanent endoluminal stent (SPES), the WallstentTM. During a follow-up period of 10.5 months, 51 ureters maintained adequate patency. Of these, 51% needed no further intervention, while 49% needed intervention to re-establish patency. In comparison insufficiency was noted at a mean 4.3 weeks in control patients with an indwelling Double-J catheter. One of the drawbacks of metal stents is, however, that they induce local urothelial hyperplasia, with ingrowth of tissue through the struts that may result in recurrent obstruction during long term placement. Recently, a nickel-cobalt-chromium-molybdenumalloy stent double pig-tailed stent (ResonanceTM Stent, Cook Urological, Spencer, IN, USA) has been developed to provide long-term urinary drainage in patients with malignant ureteric strictures (Blaschko, Deane et al. 2007; Wah, Irving et al. 2007; Lopez-Huertas, Polcari et al. 2010; Wang, Lee et al. 2010). The tight winding of this metal stent helps to maintain stent flexibility and movement, while resisting in-growth of tissue. In addition to this, the movement of the stent causes opening of the coils, allowing the fluid to access the lumen. In a study of 15 patients, this metal stent provided adequate long-term (up to 12 months) urinary drainage in patients with malignant ureteric obstruction without significant bulky pelvic disease. These stents were also found to have minimal encrustation (Wah, Irving et al. 2007). An *in vitro* study has shown that this metal stent provides its best drainage when the ureter is tightly compressed onto its outer surface which is likely due to the result of increased flow between the coils of the metal stent. It was this feature that makes the ResonanceTM stent useful in patients in which the ureter is obstructed due to malignancy (Blaschko, Deane et al. 2007; Liatsikos, Karnabatidis et al. 2009; Masood, Papatsoris et al. 2010; Sountoulides, Kaplan et al. 2010; Wang, Lee et al. 2010; Benson, Taylor

Despite the fact that the biocompatible materials and stent designs have improved over the years, they have one key disadvantage, which is the fact that they have to be removed via a separate procedure unless the retention suture is left on the stent. Avoiding a secondary procedure for ureteral stent removal would decrease patient morbidity and make this technology attractive. More recent research has focused on the design of stents that do not need to be removed and are biodegradable. The design of a biodegradable stent must take into consideration the biocompatibility properties of the material, as well as the degree of expansion and degradation rates, and most importantly it must be able to fulfill the basic requirement of a stent in that it must be able to guarantee urinary flow from the renal pelvis through the ureter and into the bladder for the desired period of time. Degradable materials also must retain their properties after sterilization and be able to withstand a long shelf-life before use. One of the challenges involved in designing a biodegradable stent is the control of the rate and direction of degradation. Schlick and Planz (Schlick and Planz 1997; Schlick and Planz 1998) designed a stent composed of plastic, the degradation of which was

et al. 2011).

**6. Biodegradable stents** 

dependent upon the urine pH. In vitro experiments with artificial urine showed that the stents were stable at urine pH less than 7.0 for at least 30 days, while they dissolved completely within 48 hours at pH greater or equal to 7.0. The principle behind this stent is that it would remain stable at physiological urine pH of 5-6, but can be triggered to dissolve by medically altering urinary pH. Although very promising, this technology remains at an experimental stage and awaits animal trials. An additional factor that may need to be taken into consideration is the influence of encrustation protein deposition as it can form a platform for bacterial adherence and infection. The influence of encrustation and protein deposition must also be considered as it can form a platform for bacterial adherence, all of which may influence urine pH. Uropathogens in general are known to increase urine pH, and may have an effect *in vivo*. In addition to this, medically increasing the urinary pH may introduce an additional risk for infection as more alkaline pH favours bacterial survival and some increased stone formation (calcium phosphate and struvite stones). In addition, encrustation of the stent may also prevent May also prevent its exposure to the altered pH environment, environment and the altered pH, thus limiting its rate of decomposition.

A spiral stent (Spirastent®, Urosurge Medical, Coralville, IA) is a polyurethane stent with metal helical ridges designed to prevent kinking and compression in chronically obstructed patients. In *in vitro* studies, this stent increased flow and theoretically increased the space between stent and ureter to facilitate passage of stone fragments.(Stoller, Schwartz et al. 2000) The spiral design has been incorporated into biodegradable materials for urethral stents.(Isotalo, Talja et al. 2002; Laaksovirta, Isotalo et al. 2002) Laaksovirta et al used a selfreinforced poly-L-lactic and poly-L-glycolic acid (SR-PLGA) copolymer spiral urethral stent (SpiroFlow stent, Bionx Implants Ltd, Tampere, Finland) following prostatic laser coagulation.(Laaksovirta, Isotalo et al. 2002) This stent degraded in 6–8 weeks and resisted encrustation at 4 weeks in artificial urine. After 8 weeks, the SpiroFlow® stent was significantly less encrusted than the metal urethral stents Prostakath® (Engineers and Doctors A/S, Copenhagen, Denmark) and Memokath® 028 (Engineers and Doctors A/S). SR-PLGA is the most commonly utilized material for prostatic stents, but it has also been developed as a ureteral stent and may be incorporated into new degradable, encrustationresistant ureteral stents in the future.(Olweny, Landman et al. 2002)

An alginate based ureteral stent was designed to stay in place for at least 48 hours after uncomplicated ureteroscopy.(Lingeman, Preminger et al. 2003; Lingeman, Schulsinger et al. 2003) Of 87 patients, 80.5% of patients retained their stents greater than 48 hours. Seventeen patients had early stent passage (earlier than 48 hours), but did not require any supplemental procedures to insert another stent. Although these results were promising, several patients (14) still had stent fragments remaining at 30 days, while 3 patients had stent fragments remaining after 90 days. All three of these patients underwent shockwave lithotripsy and two went on to have endoscopic ureteroscopy to remove the fragments from the kidney. Because of the lack of all stents to degrade by 3 months, this stent is no longer commercially available. (Lingeman, Preminger et al. 2003)

The authors are currently involved in developing a new biodegradable stent (Poly-Med Inc., Anderson, SC) that dissolves within 1 to 4 weeks in a porcine model. The animals stented with degradable stents displayed less histologic inflammation than animals stented with control polyurethane biostable Double J stents (Chew, Lange et al. 2010). Weekly intravenous pyelograms displayed less hydronephrosis in the degradable stent group. All stents degraded by 4 weeks and degradation began after 1 week in a very controlled fashion

Biomaterials in Urology - Beyond Drug Eluting

effective across a broader patient range.

involving these stents are warranted.

**8. Drug eluting stents** 

and Degradable - A Rational Approach to Ureteral Stent Design 465

also been observed for ureteral stents. Riedl *et al*. (Riedl, Witkowski et al. 2002) used heaprin-coated and uncoated polyurethane ureteral stents and inserted them into obstructed ureters with indwelling times between 2 and 6 weeks. Electron microscopy showed that the uncoated control stents were covered with amorphous anorganic deposits and bacterial biofilms as early as 2 weeks following stent insertion, while the heparin-coated stents remeined unaffected by encrustation following 6 weeks of indwelling time. Cauda *et al*. (Cauda, Cauda et al. 2008) performed a long term study involving patients with bilateral ureteral obstructions treated via the insertion of a heparin-coated stent into one ureter, and an uncoated control stent into the other ureter. Overall, the uncoated control stents were found to be encrusted with amorphous, crystalline inorganic deposits and bacterial biofilm as early as 1 month post-insertion, while the heparin-coated stents remained visibly free of encrustation as long as 10 months post-insertion. Biofilm encrustation was evident only on the external surface of the coated stent after 1 year of being in place. Heparin coated ureteral stents (Radiance Stent, Cook Urological) were tested in an *in vitro* model of infected urine and did not display any reduction in bacterial adherence compared to control stents (Lange, Elwood et al. 2009). These preliminary results are somewhat promising, but clinical trials involving a larger number of patients are needed to ensure that heparin coating of stents is

The most serious complications of long term stenting involve infection triggered by bacterial adherance and biofilm formation on the surfaces of stents as well as patient discomfort due to stent placement. Much research has gone into the prevention of infection, and the most promising results have come from drug eluting stents. Triclosan is an antimicrobial used in many products including soap, surgical scrub, toothpaste, and mouthwash. It inhibits the highly conserved bacterial enoyl-ACP reductase, which is responsible for fatty acid synthesis and cell growth. Cadieux *et al*. reported that, compared to control stents, triclosanloaded stents implanted in rabbit bladders infected with *Proteus mirabilis* were associated with significantly fewer urinary tract infections.(Cadieux, Chew et al. 2006) Chew *et al.* have shown that bacterial adherence to triclosan eluting stents is markedly reduced compared to regular stents.(Chew, Cadieux et al. 2006) These studies indicate that human clinical trials

Ureteral stents may also be loaded with pharmaceuticals to aid patient comfort, and to prevent encrustation. Irritative and painful stent symptoms have traditionally been managed with oral medications such as anticholinergics and analgesics, or even by stent removal. Drug-eluting stents release a medication that acts locally on the bladder to decrease irritation and pain. In an attempt to determine which medication might improve stent-related symptoms, Beiko *et al*. intravesically instilled 3 different medications into the bladder of 40 patients who received a ureteral stent at the time of shockwave lithotripsy.(Beiko, Watterson et al. 2004) Intravesical ketorolac significantly reduced flank pain scores following stent insertion compared to lidocaine or oxybutynin following SWL. A ketorolac-eluting ureteral stent was designed and shown to produce the highest levels of ketorolac in the ureteral tissues in an porcine model (Chew, Davoudi et al. 2010). The levels of ketorolac in the ureter were 11 fold of that found in the serum thereby reducing potential systemic side effects while delivering medication directly to the target area. The stent was biocompatible and systemic levels of ketorolac were negligible. A double-blinded prospective randomized controlled trial comparing ketorolac-eluting ureteral stents to

and no animal had a distal obstructed ureter Due to retained stent pieces. Properties such as stent softness from these biodegradable stents may improve patient comfort. Clinical studies will be necessary to determine if biodegradable stents are more comfortable.
