Polymers as Ureteral Stents

Abstract

Ureteral stents find wide application in urology. The majority of patients with indwelling ureteral stents are at an increased risk of urinary tract infection. Stent encrustation and its associated complications lead to significant morbidity. This review critically evaluates various polymers that find their application as ureteral stents with regard to various issues such as encrustation, bacterial colonization, urinary tract infections, and related clinical issues. A complete literature survey was performed, and all the relevant articles were scrutinized thoroughly. We discuss issues of encrustation/biofilm formation, new approaches to their testing, polymers currently available for use, new biomaterials, coatings, and novel ureteral stent designs, thereby providing a complete update on recent advances in the development of stents. Finally, we discuss the future of biomaterial use in the urinary tract.

Introduction

Stents and their characteristics

Stents are commonly used during surgery for ureteral stones. The main advantages of stent placement are facilitation of stone fragments passage, prevention of ureteral obstruction, and prevention of delayed formation of ureteral stricture. The stent is held in place by its design. One design incorporates “pigtail” spiraling that holds the stent in place. The stents are available in various shapes and sizes to suit the patient's comfort/condition.¹

Silicone, which is regarded as the gold standard for stents, is the first-generation polymer that is used, but the high frictional coefficient make these stents unfit (Fig. 1). Silicone was later replaced by polyethylene, but this polymer is unstable in the urinary environment, which leads to early fracture. A third-generation polymer is polyurethane, which remains undisputed for its remarkable properties.

FIG. 1.

Historical development of stents.

The size, shape, and the material of the ureteral stent depend on the anatomy of the patient and the reason for stent placement. Most stents are 5 to 12 inches (12–30 cm) in length and 0.06 to 0.2 inches (1.5–6 mm) in diameter. One or both ends of the stent may be coiled (pigtail stent) to prevent migration. In some cases, a stent has a thread attached to it that aids in its removal.

Ureteral stents are designed to reduce early and late complications. Table 1 compares the specific advantage of the polymers that are commercially available as stents over other polymers. Some of the novel designs include tail stents, which are primarily aimed at reducing bladder irritability, and mesh stents, which are self-expanding, thereby retaining flow while minimizing irritability. Dual durometer stents are made up of a firm material at the renal end and a soft material at the other end. Examples of these stents include Sof-Curl^® (ACMI, Southborough, MA) and Polaris^® (Boston Scientific, Natick, MA) stents.

Table 1.

Comparison of Polymers That Are Commercially Available as Stents

Polymer	Commercial Name	Advantages	Disadvantages
Polyurethane	Tecoflex^®	Softens considerably within minutes that favor ease of insertion.	Severe encrustation of calcium oxalate monohydrate, protein and uric acid.
	Hydrothane^®	Exhibits rapid water absorption rate and good retention of mechanical properties when hydrated, elastomeric even when dehydrated.	Reorientation of the hydrophilic moieties could lead to the activation of complement system, not a suitable substrate for cell adhesion.
	ChronoFlex^®	Supports fibroblast adhesion, growth, and cell cycle.	Retains hydrophobic proteins, favoring formation of a stable conditioning layer.
	Percuflex^®	Stents of this material are soft and smooth, enhanced physical properties.	Not preferable in case of malignant extrinsic obstruction because small force could compress the stents.
	Sof-Flex^®	Provides low frictional surface.	Highly prone to oxalate and calcium carbonate encrustation.
Hydrogel + Urethane/silicone/polyvinyl chloride	Aquavene^®	Superior resistance to encrustation and intraluminal blockage.	No reported clinical data.
Styrene/ethylenebutylene/styrene block copolymers	C-Flex^®	Highly resistant to external compressive force	Efficient only in a protein free environment.
Polyester	Silitek^®	Higher resistance to extrinsic compression.	Higher bacterial adhesion.
Proprietary polymeric material	TUDS	Biodegradable, adequate drainage and prevents postoperative complications, of all patients' satisfaction.	Maintains patency only for 2 days.

TUDS = temporary ureteral drainage stents.

Clinical complications with stents include irritative voiding symptoms, incontinence, hematuria, pyuria, urinary tract infections, encrustation, ureteral erosion or fistulization, malposition, and migration. Impediments in these foreign devices also include developmental abnormalities, physiologic malfunction, acquired barriers, and intrinsic or extrinsic physical obstruction.²

The length of the stent is very important to reduce clinical symptoms. A longer stent leads to an overlong intravesical segment and may induce irritative symptoms. A 22-cm stent is well suited for patients with a mean height of 161.9 cm.³ The characteristics of a good stent include ease of insertion and removal, resistant to encrustation and migration, biocompatible, highly radiopaque, affordable, biodurable, and optimal flow characteristics.

Long-term stent placement leads to encrustation, which occurs because of the deposition of salts on the inner and outer surface of the catheter, occluding the lumen. Normal acidic urine has salts dissolved in it that crystallize when the urine turns alkaline. This is attributed to the effects of the microorganism Proteus mirabilis.⁴ Encrustation can lead to urinary tract infection.⁵

Colonization of bacteria is another complication that impacts temporary and permanent body implants. This colonization begins with the deposition of the host conditioning film on the polymer surface followed by the attachment of microorganisms because of the production of exopolymer. This ultimately grows and multiplies, resulting in the base film being more favorable for anchorage of more organisms; a surface film, which is free floating, can arise and spread. Within 30 days, bacterial infection develops in nearly 100% of people who have a ureteral stent. This increases the morbidity rate to threefold.^6,7

Differences in the surface characteristics of the biomaterial, such as roughness, hydrophobicity, and charge, have been proposed as possible reasons why one biomaterial is less prone to bacterial adherence and encrustation when compared with another. Microscopic irregularities on the biomaterial surface encourage bacterial adherence and encrustation by acting as nucleation sites for crystal growth and later bacterial colonization.⁸

Late complications include stent fracture and breakage. The latter makes the removal process complicated and hinders further stent placement. Mechanical properties of the polymers are very important while selecting a material for a stent.

Polymers as Ureteral Stents

A variety of polymers are used and have been tested as ureteral stents. They include polyurethane (PU) and modified PU; silicone, polyisobutylene, self-reinforced polylacticacid, self-reinforced polyglycolic acid, polystyrene, Silitek^® (ACMI, Southborough, MA), and polymethylmethacrylate (PMMA)/poly(2-hydroxyethyl methacrylate) (PHEMA). PU, the most widely used polymer for stents, is described in detail below.

PU and Modified PU

PU

PU is a linear polymer that consists of urethane links with a backbone that contains carbamate groups (-NHCO₂). This linkage is produced by a chemical reaction between a diisocyanate and a polyol. PU stents are usually spiral supported by a built-in metal spiral wire to improve drainage. They are easy to form and have high drainage capacity.⁹ PU is more prone to encrustation than silicone, predominantly by calcium oxalate, struvite, and hydroxylapatite.^10,11

Common uropathogens adhere to this biomaterial surface, which leads to initiation and pathogenesis of infection. Hydrophobic Enterococcus faecalis adhere more and Escherichia coli less on PU than on silicone and Silitek. The medium surrounding the bacteria and the polymer surface have a greater impact on the adherence of bacterial cells.¹² Analysis of explanted stents from humans revealed that there was no causative link between the extent of formation of biofilm and encrustation; the amount of encrustation was associated with urolithiasis and not with the urinary calcium/magnesium levels. Also E faecalis was the most common pathogen associated in biofilm.¹³

Indwelling time for the encrusted stent was shorter and the incidence of encrustation was significantly higher in patients who were stone formers when compared with patients without urolithiasis.¹⁴ In vivo and in vitro mechanical studies revealed no significant changes in the ultimate tensile strength of the explanted stents when compared with the fresh ones.¹⁵ This indicates that stents explanted from patients did not show any greater tendency for fracture. Moreover, in situ fractures are observed near the drainage hole, which suggests that removal of holes could reduce the incidence of stent fracture. It was also clinically concluded that significant urine flow occurs around rather than through the hollow, vented stents, which suggests restriction of these holes to reduce incidence of fracture.¹⁶

Pure PU causes a long-lasting change in renal pelvic dynamics and also has a deleterious effect on renal function.¹⁷ Good mechanical properties, biocompatibility, neither migration nor early fractures enable them to be widely used as ureteral stents. They are prone to encrustation and bacterial adhesion, forcing their early removal. Other early clinical issues concerning PU stents include discomfort, irritative bladder symptoms, hematuria, bacteriuria, fever, and flank pain. Fragmentation, breakage, encrustation, and fracture of PU stents are late complications.¹⁸ This necessitates modification of the polymer so that it increases the indwelling time and reduces bacterial adhesion and salt encrustation.

Improving PU

Two different approaches to reducing bacterial adherence and encrustation include coating and blending the polymer. Each of these methods is described below.

Coatings

Hyaluronic acid

Hyaluronic acid is a type of glycosaminoglycan that is an inhibitor of nucleation, growth, and aggregation of salts and hence is used as a coating on PU. A plasma-activated surface modification of PU with hyaluronic acid leads to less encrustation than silicone coating. The latter is a long-term biomaterial that is widely regarded as the gold standard.^19,20 Plasma treatment leads to a covalent bond between hyaluronic acid ester and the polymer. This modification has a greater propensity toward hydration, reduced protein adsorption, and decreased bacterial and cell adhesion.²¹ Although a hyaluronic-acid–coated stent is more biocompatible with improved properties proved in vitro, there are no available reports that deal with its clinical trials to validate its efficacy.

Hydrogel

A hydrogel system consists of a hydrophobic macromer with an unsaturated group and a hydrophilic polymer (polysaccharide with a hydroxyl group) that is formed by the free radical polymerization of the unsaturated and the hydroxyl groups. Hydrogel-coated stents do not reduce bacterial adhesion/colonization, whereas antibiotic-treated stents exhibit high antimicrobial activity and for a longer period. The performance depends on the type of bacterium and the antibiotic used in vitro.²²

Adherence of hydrophobic E faecalis was greater and E coli was less on hydrogel-coated than the uncoated polymer.¹² Encrustation of calcium and magnesium salts was enhanced by crystalline biofilm of P mirabilis because it increases the alkalinity of the urine. The mean time of blockage of the stent is about 34 hours.²³

Immunoglobulin G that is released from PU hydrogel coating reduces bacterial adhesion effectively by facilitating the phagocytic activity of cellular immune components, monocytes, and neutrophils.²⁴ High radiographic visibility and ease of insertion even in the case of high-grade obstruction are the clinical advantages of this stent.²⁵

Sequential interpenetrating polymer networks (sIPNs).

sIPNs are sequential interpenetrating polymer networks that are prepared by immersing PU film in a solution of methylmethacrylate (MMA) and azobisisobutyronitrile. This is aimed at impregnating a polymeric component or a matrix with a releasable active component that exhibits antimicrobial activity. The mechanical properties of this sIPN depend on the concentration of PMMA. PMMA makes the stent rigid, which increases the extrinsic compression of the ureter and hence leads to blockage. PU/PMMA polymer network also affects the mechanical properties of the original PU.²⁶ Clinical efficacy of this stent has not been reported to date.

Heparin

Heparin, a highly sulfated glycosaminoglycan, is more widely used as an anticoagulant has the highest negative charge density among all known biologic molecules. Three different approaches could be adopted for coating a surface with heparin: Heparin that is physically adsorbed is effective only for a short period, because it may get leached out; heparin that is incorporated into the polymer may not be released at the desired rate and time to be effective. The third method is covalent bonding, which is more effective than the other two methods.²⁷

PU is coated with a spacer to which heparin is covalently bound. Clinical trials in humans showed that a heparin-coated stent was unaffected over a period of 6 to 8 weeks, which is attributed to the electronegativity that repels cellular organisms.²⁸ No detectable biofilm was found, which indicated that it could resist encrustation and blockage by crystal generating P mirabilis, resulting in extended indwelling times.²⁹ Moreover, glycosaminoglycans bind to the urinary components and block the crystal growth sites.^30,31

Clinical trials with rats demonstrated that the effect of glycosaminoglycan heparin was free from encrustation, even at different pH range.³² In vivo studies also revealed that even with encrustation, no significant changes were found on the heparin layer.³³

Silver

Silver has a dynamic potential for use in the prophylaxis of ureteral infections. Silver sulfadiazine/chlorhexidine impregnated stents, however, did not show enhanced performance against bacterial adhesion; their mean time of blockage in vitro condition was very short, about 17.7 hours.²³ A catheter surface with impregnated silver nanoparticles shows less than 10% of bacterial colonization when compared with uncoated. The mean duration of stent placement was greater than uncoated. The duration of antimicrobial activity was about 370 days, with absence of irritation.³⁴

Another approach in coating is the release of bioactive substances to prevent the adhesion of microorganisms. PU dipped in a bacterial suspension and incubated in a media with and without silver nitrate in vitro showed that the bacterial count was less in the former when compared with the control without silver nitrate.³⁵

Polyvinylpyrrolidone (PVP)

PVP is a water-soluble polymer with a water absorbing capacity of 40% of its weight. It is used as a coating material or additive to coating because of its excellent wetting properties. PVP-coated PU presents a smooth, soft, and nonadhesive surface, which minimizes the difficulties during insertion.³⁶ This material is more hydrophilic and lubricious than uncoated PU. Adherence of hydrophobic E faecalis and struvite encrustation in vitro was found to be less on this material than uncoated PU, and adherence of hydrophilic E coli was also less than on silicone.³⁷

Diamondlike carbon (DLC)

The carbon coating is more resistant toward encrustation and bacterial adhesion than the normal PU because of its hydrophilic nature. DLC coating of low thickness and refractive index proved to be a better option. No clinical or in vitro studies have been reported.³⁸

Use of an antibiotic as a coating agent is also seen to prevent biofilm formation, but formation of antibiotic resistant strains is an issue that limits long-term use.

Modification of the substrate

In this strategy, normal PU is modified with certain additives and with various designs to enhance performance and long-term use.

Tecoflex^®

This is an aliphatic PU with high radiopacity, and it is a product of the reaction between methylene bis (cyclohexyl) diisocyanate, poly(tetramethylene ether glycol), and 1, 4 butane diol chain extender. Tecoflex finds its use as a stent because it can soften considerably within minutes of insertion. An example is Quadra-Coil^® (ACMI, Southborough, MA) Multi-Length Ureteral Stent made from high-performance Tecoflex with an advanced hydrophilic coating. Explanted stents from humans revealed severe encrustation of calcium oxalate monohydrate crystals, proteins, and uric acid. There was a significant difference in the extent of encrustation with respect to sex and age, which necessitates a deeper study of this polymer and the lithogenic factors that affect its performance.³⁹

Hydrothane^®

Hydrothane (Cardiotech International, Woburn, MA) is a polytetramethylene glycol, based aliphatic PU in which the glycol units confer increased hydrophilicity with a good water absorption capacity (5%–25% by weight). It has very high tensile strength and elongation. The absence of aromatic groups in the polymer enhances biologic inertness by reducing the generation of van der Waals forces between the polymer moieties and the side-chain functional groups of the proteins.⁴⁰ The hydrophilic moieties reorient toward an aqueous environment, and the proteins are adsorbed on the hydrophobic domains.⁴¹ Hydrothane is not a suitable substrate for cell adhesion and growth, but reorientation of the hydrophilic moieties can lead to the activation of complement system.

ChronoFlex^®

ChronoFlex (Cardiotech International, Woburn, MA), a medical-grade PU is synthesized by the addition of diphenylmethane 4, 4′-diisocyanate to polycarbonate diol, which is followed by the addition of a mixture of chain extenders and a molecular weight regulator. This polymer retains a hydrophobic protein such as α₁ microglobulin, which suggests that it favors the formation of a stable conditioning layer on its surface on incubation with serum and urine. The polymer also supports fibroblast adhesion, growth, and cell cycle. Adhesion of Pseudomonas aeruginosa on the serum- and urine-treated Chronoflex was higher when compared with Hydrothane, which demonstrates different patterns of protein adsorption on these polymers.⁴¹

Percuflex^®

This is a proprietary olefinic block copolymer (Boston Scientific, Natick, MA). It softens and become flexible at room temperature. The stents made from this material have a soft and smooth surface. Adherence of hydrophobic E faecalis on this stent is greater than E coli.¹² Although this polymer has better physical properties than PU, the level of encrustation is similar to polyurethane (PU). Encrustations of calcium and magnesium levels are similar on both the polymers.⁴² Polaris ultra ureteral stents are made of Percuflex with a bladder and renal coil of the same polymeric material. The former coil is used to reduce the bladder irritation and the latter to facilitate ease of removal. These stents are not preferred in cases of malignant extrinsic obstruction because small forces could compress these stents.⁴³

Aquavene^®

Aquavene^® (Menlo Care, Menlo Park, CA) is made of a hydrophilic polymer, such as hydrogel, in combination with a nonhydrophilic component, such as urethane/silicone/polyvinyl chloride. It swells up, increasing in size, and maintains its strength. The ratio of the hydrophilic to the nonhydrophilic component controls the expansion on hydration. In a simulated urine flow study for 24 weeks, Aquavene showed superior resistance to encrustation and intraluminal blockage. The weight loss of about 9% weight by weight (w/w) was observed when compared with base PU. Noncross-linked poly(ethylene oxide) hydrogel is considered to be responsible for the prevention of blockage during encrustation. Aquavene is harder in dry conditions and softens rapidly when hydrated, which facilitates easy insertion and improved patient comfort.⁴⁴

Sof-Flex^®

This is a proprietary polymeric material (Cook Urological, Spencer, IN) that is generally used for temporary internal drainage from the ureteropelvic junction to the bladder. It is a microthin layer of hydrophilic polymer that, when activated, attracts and holds water and other liquids, creating a low-frictional surface. Ureteral stents explanted from patients who were treated with ciprofloxacin showed no biofilm but high levels of encrustation of calcium carbonate and oxalate.^45,46 Antibiotic adsorption was observed on the stent when the patients were undergoing oral antibiotic therapy.⁴⁶

Other polymers

In addition to PU, other polymers are also tested and used as ureteral stents. They have been found to be superior to PU in all aspects, exhibiting less adhesion and enhanced biodegradability.

Silicone

Silicone is a biomaterial that is regarded as the “gold standard” and has been in use for a long time. It has the best biocompatibility but has a lower drainage efficacy.⁴⁷ Because its surface is uniform without irregularities, it is less prone to encrustation by struvite and hydroxyapatite than PU.¹⁰ Adherence of hydrophobic E faecalis is greater than that of E coli. Also, the amount is higher when compared with PU and hydrogel-coated PU.¹² Despite encrustation, the mean time of blockage is 47 hours.²³

Explanted stents made of silicone also show the least encrustation when compared with other polymers. Bacterial colonization could be prevented by continuous administration of ciprofloxacin (500 mg). High levels of encrustations, however, primarily of calcium carbonate and calcium oxalate, are observed.⁴⁵ A coating consisting of lecithin, silver citrate, and liquid silicone is found to decrease bacterial adherence on the silicone surface. Still, this does not support long-term catheterization, however.^48,49

Silicone causes less superficial epithelial destruction in the upper urinary tract, but it is still prone to encrustation.¹⁷ Although silicone is regarded as the gold standard for ureteral application, it is not used as a stent because of its high coefficient of friction. Therefore, modifications of the polymer by coatings or blending with copolymers have been practiced.

C-Flex^®

C-Flex is a thermoplastic elastomer (Cook Urological, Spencer, IN) that is made up of styrene/ethylene-butylene/styrene block copolymers. Hydrogel coated C-Flex ureteral stents, when exposed to supersaturated artificial urine, showed that the organic layer on the nonencrusted stents enhanced crystallization. The organic layer included Tamm-Horsfall protein, human serum albumin, and α₁ microglobulin.⁵⁰ Calcium and magnesium encrustation in the presence of urease is observed on hydrogel-coated C-Flex stents when compared with the uncoated polymers of the same substrate.⁵¹ C-Flex is more resistant to external compressive forces.⁵² It is suggested that C-Flex stents could be used efficiently in a protein-free environment, but this necessitates further modification to facilitate their use efficiently in urine, which contains proteins.

Poly(ɛ-caprolactone) and poly(ɛ-caprolactone)-PVP iodine (I) blends

This is prepared by mixing PCL (polycaprolactone) and PCL/PVP-I in dichloromethane maintaining the solid content to 10% weight by weight (w/w). Mechanical and the rheologic properties of PCL are not altered because of the incorporation of PVP-I. In spite of its degradability and least encrustation, the mechanical properties of the blend are inappropriate for clinical application, due to the reduction in ultimate tensile strength and percentage elongation.⁵³ Modification with other copolymer blends to enhance mechanical stability has been attempted.

Silitek

Silitek (ACMI, Southborough, MA) is a polyester copolymer that is firm and resists extrinsic compression. In vitro adherence of both hydrophobic E faecalis and E coli are higher on this material when compared with other polymers.¹²

PMMA

PMMA is a vinyl polymer made by free radical polymerization of methylmethacrylate, monomer. PHEMA is a polymer that forms a hydrogel in water. Copolymers formed from different ratios of PMMA and PHEMA demonstrated that with increasing content of the latter polymer, there was a decrease in the hydrophobicity and adhesion of coagulase-negative staphylococci.⁵⁴ PMMA polymers were more resistant to encrustation than the hydrophilic polymers. The adherence of hydrophilic E coli to the copolymers increased with decreasing the hydrophobicity in vitro.⁵⁵

Biodegradable polymers

Polylactic acid (PLA)

PLA is a biodegradable aliphatic polyester. Like most thermoplastics, it can be processed into fibers or films. PLA does not have any bactericidal effect. P aeruginosa adhered in greater numbers than other bacteria without fimbriae. Bacterial adherence is correlated with the bacterial type but not with the type of material.⁵⁶ Self-reinforced poly DL lactide increased expansion capacity. This reduced the risk of pressure-induced kidney damage and upper urinary tract infection. Because of its biodegradation, it becomes necessary to remove the material.⁵⁷ Because of its antireflux properties, it can have prolonged indwelling time. On the contrary, the long-term use of normal nonlactic Double J stents is restricted because of vesicoureteral reflux.⁵⁸

Polyglycolide

Polyglycolic acid (PGA) is a linear aliphatic thermoplastic polymer prepared by the condensation of glycolic acid. Neither encrustation nor biofilm adherence was found on the PGA stent. Degradation rate was slow and the stent breaks into cubic fragments of various sizes upon degradation. The indwelling time is short, which is attributed to the formation of low acidic metabolites that leads to low pH.⁵⁶ Poor mechanical properties reduce the propensity as ureteral stents.

Temporary ureteral drainage stents (TUDS)

TUDS (Boston Scientific/Microvasive, Natick, MA) are made up of a proprietary polymeric material that is biodegradable and is used to maintain the drainage and prevent postoperative complications for 2 days. Phase I trials illustrated that the safety profile of TUDS was favorable with no complications that could be attributed to the device.⁵⁹ Moreover, Phase II clinical trials proved very clearly that these were effective in adequate urine drainage and patient satisfaction, thereby eliminating the need for stent removal.⁶⁰

Metal stents

There are four types of metallic stents. The self-expandable polytetrafluoroethylene-covered nitinol stent is generally used for the management of strictures. This stent is safe, and the nitinol covering inhibits ureteral hyperplasia. About 15% migration of stents is reported.⁶¹ A thermoexpandable stent is mainly composed of nickel-titanium alloy, which is also used for long-term management of malignant strictures.⁶² The covered metal stents are introduced to address the problem of hyperplasia growth, but these stents have a high migration rate (82%) because of the nonanchorage of the coating material.⁶³ The fourth type is a balloon expandable stent. One patient died after 2 months of implantation. The autopsy revealed a fibrotic reaction in the lumen of the stent because of the overextension of the ureteral wall, leading to urothelial trauma.⁶³ Use of metal stents in the urinary tract under clinical settings has always resulted in unfavorable results, although no acute and systemic infection has been reported. High and fast migration of the stents into the bladder poses a serious threat to patients.

Future Directions

Encrustation depends on urine concentration, its pH, and urolithiasis, whereas biofilm formation depends on the ability of a small number of bacterial cells to adhere to the surface, which in turn depends on the fimbriae and exopolysaccharide to cement them to the surface to reach the irreversible adhesion state. Bacteria in the biofilm can usually survive the use of sterilants and/or antibiotics at concentrations 1000 to 1500 times higher than the concentrations that kill floating (planktonic) cells of the same species.⁶⁴

Although polyethylene- and polystyrene-based stents satisfy the requisite, they have a greater propensity to lose their flexibility. Silicone has a high frictional coefficient, and the size of the internal diameter is limited, leading to poor drainage and stent migration.

Coating reduces biofilm formation and enhances surface regularities, but it leads to the increased risk of encrustation, because the coating compounds may influence certain factors, such as pH and oxalate concentration. All these issues suggest that a new polymer that is lubricious to prevent adhesion of even a single bacteria strain and free of encrustation is needed. Of course, encrustation makes the surface rough, which in turn aids bacterial adhesion.

This review reveals that recent research is focused more toward modification of the polymer for developing a stent that is more inert instead of it being used for short-term treatment (Fig. 2). The future of stents would be a drug-eluting and drug-coated stent, prepared from a biodegradable polymer, including PLA and PGA. Although suitability of such stents has been tested in the laboratory, no clinical trials have been performed. Biodegradable stents lead to stent breakage, necessitating removal.

FIG. 2.

Approaches toward solving issues. PEO/PTMO = poly(ethylene oxide)/poly(tetramethylene oxide); SPU = segmented polyurethane; PC-PC/PVP I = poly(e-caprolactone) and poly(e-caprolactone)/polyvinyl pyrrolidone iodine; PMMA = polymethylmethacrylate; PHEMA = poly (2-hydroxyethyl methacrylate); PU = polyurethane; PLA = polylactic acid; PGA = polyglycolic acid; TUDS = temporary ureteral drainage stents; sIPN = sequential interpenetrating polymer network; PVP = polyvinyl pyrrolidone.

Improving coating technology could prolong indwelling times. Use of various proteins to reduce bacterial adhesion could be pursued. A recombinant p29 collagen binding protein isolated from Lactobacillus fermentum greatly reduced the adhesion of two bacterial strains, namely E coli and E faecalis under in vitro conditions.⁶⁵ Various probiotic organisms and their byproducts inhibit the growth/virulence of pathogens. Such a coating could decrease the dependence on antimicrobial agents.⁶⁶

A single polymer as such is not suitable as a stent, but a blend of various copolymers could be made with desired properties by selecting copolymers with reduced encrustation and antibacterial properties.

This review also reveals the complexity of translating in vitro data to clinical trial, which necessitates the need for more research with clinical trials. Further development should also be aimed at using various combinations of potent proteins and antimicrobial agents as a coating that could penetrate even the mature and well-formed biofilm.

Footnotes

Acknowledgment

The authors thank Departmental Computational Facility, IIT Madras.

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

, Sosa

. Ureteroscopy and retrograde ureteral access. Walsh

, Retick

, Vaughan

, Wein

. Campbell's Urology, 8th. Philadelphia: Elsevier Science, 2002; 97.

Saint

, Chenoweth

. Biofilms and catheter-associated urinary tract infections. Infect Dis Clin North Am, 2003; 17:411–432.

, Chen

, Chung

et al. Determining the appropriate length of a double-pigtail ureteral stent by both stent configurations and related symptoms. J Endourol, 2008; 22:1427–1431.

Sabbuba

, Hughes

, Stickler

. The migration of Proteus mirabilis and other urinary tract pathogens over Foley catheters. BJU Int, 2002; 89:55–60.

, Ku

, Byun

et al. Systemic chemotherapy in patients with indwelling ureteral stenting. Int J Urol, 2005; 12:548–551.

Winson

. Catheterization: A need for improved patient management. Br J Nurs, 1997; 6:1229–1252.

, Belay

, Mitchell

. Protection of catheter surfaces from adhesion of Pseudomonas aeruginosa by a combination of silver ions and lectins. World J Microbiol Biotechnol, 2001; 17:173–179.

Axelsson

, Schönebeck

, Winblad

. Surface structure of unused and used catheters. A scanning electron microscopic study. Scand J Urol Nephrol, 1977; 11:283–287.

Lam

, Gupta

. Update on ureteral stents. Urology, 2004; 64:9–15.

10.

Tunney

, Keane

, Gorman

. Assessment of urinary tract biomaterial encrustation using a modified Robbins device continuous flow model. J Biomed Mater Res, 1997; 38:87–93.

11.

Tunney

, Keane

, Gorman

. Encrustation assessment using the Modified Robbins device. Eur J Pharmaceut Sci, 1996; 4:177–177.

12.

Tunney

, Keane

, Gorman

. Bacterial adherence to ureteral stent biomaterials. Eur J Pharmaceut Sci, 1996; 4:177–177.

13.

Keane

, Bonner

, Johnston

et al. Characterization of biofilm and encrustation on ureteric stents in vivo. Br J Urol, 1994; 73:687–691.

14.

Robert

, Boularan

, Sandid

, Grasset

. Double-J ureteric stent encrustations: Clinical study on crystal formation on polyurethane stents. Urol Int, 1997; 58:100–104.

15.

Gorman

, Jones

, Bonner

et al. Mechanical performance of polyurethane ureteral stents in vitro and ex vivo. Biomateria1s, 1997; 18:1379–1383.

16.

El-Faqih

, Shamsuddin

, Chakrabarti

et al. Polyurethane internal ureteral stents in treatment of stone patients: Morbidity related to indwelling times. J Urol, 1991; 146:1487–1491.

17.

Cormio

. Ureteric injuries: Clinical and experimental studies. Scan J Urol Nephrol, 1995; 171,suppl:1–66.

18.

Damiano

, Oliva

, Esposito

et al. Early and late complications of double pigtail ureteral stent. Urol Int, 2002; 69:136–140.

19.

Kitamura

, Zerwekh

, Pak

. Partial biochemical and physicochemical characterization of organic macromolecules in urine from patients with renal stones and control subjects. Kidney Int, 1982; 21:379–386.

20.

Robertson

, Peacock

, Nordin

. Inhibitors of the growth and aggregation of calcium oxalate crystals in vitro. Clin Chim Acta, 1973; 43:31–37.

21.

Choong

, Wood

, Whitfield

. A model to quantify encrustation on ureteric stents, urethral catheters and polymers intended for urological use. BJU Int, 2000; 86:414–421.

22.

John

, Rajpurkar

, Smith

et al. Antibiotic pretreatment of hydrogel ureteral stent. J Endourol, 2007; 21:1211–1216.

23.

Morris

, Stickler

. Encrustation of indwelling urethral catheters by Proteus mirabilis biofilms growing in human urine. J Hosp Infect, 1998; 39:227–234.

24.

Rojas

, Slunt

, Grainger

. Polyurethane coatings release bioactive antibodies to reduce bacterial adhesion. J Control Release, 2000; 63:175–189.

25.

Candela

, Bellman

. Ureteral stents: Impact of diameter and composition on patient symptoms. J Endourol, 1997; 11:45–47.

26.

Jones

, Bonner

, Gorman

et al. Sequential polyurethane–poly (methylmethacrylate) interpenetrating polymer networks as ureteral biomaterials: Mechanical properties and comparative resistance to urinary encrustation. J Mater Sci Mater Med, 1997; 8:713–717.

27.

Schierholz

, Seyfert

, Rump

et al. Strategies for the prevention of catheter material-associated thrombosis and bloodstream infection. Infusionsther Transfusionsmed, 1999; 26:278–287.

28.

Riedl

, Witkowski

, Plas

, Pflueger

. Heparin coating reduces encrustation of ureteral stents: A preliminary report. Int J Antimicrob Agents, 2002; 19:507–510.

29.

Tenke

, Riedl

, Jones

et al. Bacterial biofilm formation on urologic devices and heparin coating as preventive strategy. Int J Antimicrob Agents, 2004; 23,suppl 1:S67–S74.

30.

Fellstrom

, Danielson

, Karlsson

, Ljunghall

. Crystal inhibition: Binding of heparin and chondroitin sulphate to calcium oxalate, sodium urate and uric acid crystals. Urolithiasis and Related Clinical Research. New York: Plenum Press, 1985; 831–834.

31.

Yoshimura

, Yoshioka

, Miyake

et al. Glycosaminoglycans in crystal-surface binding substances and their role in calcium oxalate crystal growth. Br J Urol, 1997; 80:64–68.

32.

Hildebrandt

, Sayyad

, Rzany

et al. Prevention of surface encrustation of urological implants by coating with inhibitors. Biomaterials, 2001; 22:503–507.

33.

Cauda

, Cauda

, Fiori

et al. Heparin coating on ureteral Double J stents prevents encrustations: An in vivo case study. J Endourol, 2008; 22:465–472.

34.

Peter

. Silver as antimicrobial substance in biomaterials. Int J Antimicrob Agents, 2005; 26,suppl:S1–S19.

35.

Schierholz

, Yücel

, Rump

et al. Antiinfective and encrustation-inhibiting materials—myth and facts. Int J Antimicrob Agents, 2002; 19:511–516.

36.

Nurdin

, Weilandt

, Textor

et al. Reduced frictional resistance of polyurethane catheter by means of a surface coating procedure. J Appl Polym Sci, 1996; 61:1939–1948.

37.

Tunney

, Gorman

. Evaluation of a poly(vinyl pyrollidone)-coated biomaterial for urological use. Biomaterials, 2002; 23:4601–4608.

38.

Jones

, Garvin

, Dowling

et al. Examination of surface properties and in vitro biological performance of amorphous diamond-like carbon-coated polyurethane. J Biomed Mater Res B Appl Biomater Applied Biomaterials, 2006; 78:230–236.

39.

Bouzidi

, Traxer

, Doré

et al.

[Characteristics of encrustation of ureteric stents in patients with urinary stones.]

(Fre) Prog Urol, 2008; 18:230–237.

40.

Rabinow

, Ding

, Qin

et al. Biomaterials with permanent hydrophilic surfaces and low protein adsorption properties. J Biomater Sci Polym Ed, 1994; 6:91–109.

41.

Santin

, Wassall

, Ambrosio

et al.

Hydrothane^® interactions with biological components: A comparison with Chronoflex.^®

J Appl Biomater Biomech, 2003; 1:67–75.

42.

Gorman

, Garvin

, Quigley

, Jones

. Design and validation of a dynamic flow model simulating encrustation of biomaterials in the urinary tract. J Pharm Pharmacol, 2003; 55:461–468.

43.

Christman

, L'esperance

, Choe

et al. Analysis of ureteral stent compression force and its role in malignant obstruction. J Urol, 2009; 181:392–396.

44.

Gorman

, Tunney

, Keane

et al. Characterization and assessment of a novel poly(ethylene oxide)/polyurethane composite hydrogel (Aquavene) as a ureteral stent biomaterial. J Biomed Mater Res, 1998; 39:642–649.

45.

Reid

, Tieszer

, Denstedt

, Kingston

. Examination of bacterial and encrustation deposition on ureteral stents of differing surface properties, after indwelling in humans. Colloids and Surfaces B: Biointerfaces, 1995; 5:171–179.

46.

Wollin

, Tieszer

, Riddell

et al. Bacterial biofilm formation, encrustation, and antibiotic adsorption to ureteral stents indwelling in humans. J Endourol, 1998; 12:101–111.

47.

Hofmann

, Hartung

. Ureteral stents—materials and new forms. World J Urol, 1989; 7:154–157.

48.

Reid

, Millsap

, Denstedt

. Biomaterials in Urology II: Future usage and management. J Endourol, 1999; 13:1–7.

49.

Kumon

, Hashimoto

, Nishimura

et al. Catheter-associated urinary tract infections: Impact of catheter materials on their management. Int J Antimicrob Agents, 2001; 17:311–316.

50.

Santin

, Motta

, Denyer

, Cannas

. Effect of the urine conditioning film on ureteral stent encrustation and characterization of its protein composition. Biomaterials, 1999; 20:1245–1251.

51.

Desgrandchamps

, Moulinier

, Daudon

et al. An in vitro comparison of urease-induced encrustation of JJ stents in human urine. Br J Urol, 2003; 79:24–27.

52.

Hendlin

, Vedula

, Horn

, Monga

. In vitro evaluation of ureteral stent compression. Urology, 2006; 67:679–682.

53.

Jones

, Djokic

, McCoy

, Gorman

. Poly(ɛ-caprolactone) and poly(ɛ-caprolactone)-polyvinylpyrrolidone-iodine blends as ureteral biomaterials: Characterisation of mechanical and surface properties, degradation and resistance to encrustation in vitro. Biomaterials, 2002; 23:4449–4458.

54.

Hogt

, Dankert

, Feijen

. Adhesion of coagulase-negative staphylococci to methacrylate polymers and copolymers. J Biomed Mater Res, 1986; 20:533–545.

55.

Tunney

, Jones

, Gorman

. Methacrylate polymers and copolymers as urinary tract biomaterials: Resistance to encrustation and microbial adhesion. Int J Pharmaceut, 1997; 151:121–126.

56.

Pétas

, Vuopio-Varkila

, Siitonen

et al. Bacterial adherence to self-reinforced polyglycolic acid and self-reinforced polylactic acid 96 urological spiral stents in vitro. Biomaterials, 1998; 19:677–681.

57.

Lumiaho

, Heino

, Tunninen

et al. New bioabsorbable polylactide ureteral stent in the treatment of ureteral lesions: An experimental study. J Endourol, 1999; 13:107–112.

58.

Lumiaho

, Heino

, Kauppinen

et al. Drainage and antireflux characteristics of a biodegradable self-reinforced, self-expanding X-ray-positive poly-L,D-lactide spiral partial ureteral stent: An experimental study. J Endourol, 2007; 21:1559–1564.

59.

Lingeman

, Schulsinger

, Kuo

. Phase I trial of a temporary ureteral drainage stent. J Endourol, 2003; 17:169–171.

60.

Lingeman

, Preminger

, Berger

et al. Use of a temporary ureteral drainage stent after uncomplicated ureteroscopy: Results from a phase II clinical trial. J Urol, 2003; 169:1682–1688.

61.

Trueba Arguinarena

, Fernández del Busto

. Self-expanding polytetrafluoroethylene covered nitinol stents for the treatment of ureteral stenosis: Preliminary report. J Urol, 2004; 172:620–623.

62.

Kulkarni

, Bellamy

. A new thermo-expandable shape-memory nickel- titanium alloy stent for the management of ureteric strictures. BJU Int, 1999; 83:755–759.

63.

Barbalias

, Liatsikos

, Kalogeropoulou

et al. Externally coated ureteral metallic stents: An unfavorable clinical experience. Eur Urol, 2002; 42:276–280.

64.

Costerton

. Introduction to biofilm. Int J Antimicrob Agents, 1999; 11:217–221.

65.

Cadieux

, Watterson

, Denstedt

et al. Potential application of polyisobutylene-polystyrene and a lactobacillus protein to reduce the risk of device-associated urinary tract infections. Colloids and Surfaces B: Biointerfaces, 2003; 28:95–105.

66.

Reid

, Howard

, Gan

. Can bacterial interference prevent infection? Trends Microbiol, 2001; 9:424–428.

Polymers as Ureteral Stents

Abstract

Introduction

Stents and their characteristics

Polymers as Ureteral Stents

PU and Modified PU

PU

Improving PU

Coatings

Hyaluronic acid

Hydrogel

Sequential interpenetrating polymer networks (sIPNs).

Heparin

Silver

Polyvinylpyrrolidone (PVP)

Diamondlike carbon (DLC)

Modification of the substrate

Tecoflex®

Hydrothane®

ChronoFlex®

Percuflex®

Aquavene®

Sof-Flex®

Other polymers

Silicone

C-Flex®

Poly(ɛ-caprolactone) and poly(ɛ-caprolactone)-PVP iodine (I) blends

Silitek

PMMA

Biodegradable polymers

Polylactic acid (PLA)

Polyglycolide

Temporary ureteral drainage stents (TUDS)

Metal stents

Future Directions

Footnotes

Acknowledgment

Disclosure Statement

Abbreviations Used

References

Tecoflex^®

Hydrothane^®

ChronoFlex^®

Percuflex^®

Aquavene^®

Sof-Flex^®

C-Flex^®