DESCRIPTION OF THE STATE-OF-THE-ART
The stents have been used for decades in Urology. Mainly there are 2: ureteral and urethral and 2 conformations: ureteral double-JJ stent and segmentary stents, this latter is mostly metallic. The ideal stent has not been designed yet. Nevertheless, several authors have outlined its characteristics very well. The perfect urinary stent should demonstrate optimal flow characteristics and should be well tolerated by the patient. Biocompatibility, radiopacity, visibility on ultrasound, ease of insertion and removal are also important features. Moreover, resistance to infection, corrosion and encrustation are characteristics that are crucial for long-term ureteral patency. A stent providing long-term urinary tract patency, cause minimal tissue reaction, minimize migration rate and combining the above features represents the ultimate goal of urological stent research in cancer patients, kidney transplant, congenital disorders, radiotherapy, renal or ureteral stones, etc.
Urinary stents represent a minimally invasive alternative to preserve urinary drainage whenever urinary tract patency is deteriorated or is under a significant risk to be occluded. Over the last four decades ureteral stents have become an indispensable tool in urological practice. Ureteral stents are used to support ureteral anastomoses, to provide urinary drainage after physical or surgical damage, to bypass ureteral obstruction. Double-JJ stents also require regular changes.However, stenting is often accompanied by significant complications, including lower urinary tract symptoms, flank pain, and urinary infections. Urinary symptoms and pain associated with stenting interfere with daily activities and reduced quality of life in up to 80% of patients. The results of the Int. Continence Soc. identified storage symptoms, incontinence (60%), bladder pain (80%) as great bothersome problems. As many as 32% of patients had sexual dysfunction, and an inability to work (27%). The stent has a significant impact on patients' general health. Considering that stents are foreign bodies, these provide an artificial surface that facilitates bacterial adhesion and biofilm formation as well as encrustation. Although the exact cause for these is unknown, the adsorption of urinary components to the stent surface has been hypothesized to play an important role.
The discomfort is often related to the stent material and design. Many studies have been performed to identify the ideal stent´s material and shape, without definitive conclusions. Thus, there seems to be no clear advantage of any polymer in terms of these associated side effects. Several new ideas on stent design´s, composition material and stent coating are currently under evaluation, foreseen to eliminate the aforementioned drawbacks of stent employment.
Metal urinary stents are designed to preserve long-term urinary solutions for overcoming urinary obstruction, avoiding the need of frequent exchange. They have been extensively used for both malignant and benign chronic urinary tract obstruction. In principle, stents may be left indefinitely. However their use is associated with a great number of complications, which frequently reduce stent´s patency and limit their long-term efficacy. Many of the complications are migration, that is the major problem (27%-80%). Malfunction and encrustation rates, may occur at the end of the stents. Encrustation of stents has various detrimental effects resulting in morbidity and potentially mortality. Patients with encrustated stents metallic may present clinical signs like: flank pain, infection/sepsis, and deterioration of renal function.
The quality of life is decreased and complications of metallic stents can seriously damage the renal function About the lower urinary tract stents, they are generally made from a metal alloy with adequate rigidity to preserve urethral patency, and designed to relieve bladder outlet obstruction in prostate cancer. In Europe, prostate cancer is the most common solid neoplasm, with an incidence rate of >200 cases per 100,000 men, outnumbering lung and colorectal cancer. Furthermore, prostate cancer is currently the second most common cause of cancer death in men. The use of urethral stents offers an alternative treatment for the relief of symptoms of bladder outlet obstruction in patients whom definitive surgery is contraindicated. However use of urethral stents is not free of complications, because may cause UTI, and may result in encrustation, stent fracture, and migration. Unfortunately, to date no stent embraces all the properties of ideal urethral stent.
The stent industry quite quickly realized that instead of searching for the ideal composition material for the creation of novel stents, current materials and stent designs could be used as the platforms to be covered with other substances with desirable characteristics. Stent coating is the part of stent evolution with the most significant development and the most promising future prospects. The idea behind developing a biodegradable urinary stent is to develop an alternative to the conventional stents. The stent should be easy to remove or ideally in situ biodegradable.
Drug-eluting stents are in their infancy, but they have been tried to relieve stent-related symptoms. One problem of these devices is that physicochemical basis for controlled drug release by drug eluting stents has not established yet. A few groups are working on this potentially useful development and might eventually find solutions to this problem.
The most innovative proposal for urinary stent development is tissue engineering and Nano-technology. Currently, vascular stents lead the market in materials technology and bioactive coatings. Undoubtedly, this knowledge will make its way into the urological field to provide more comfortable and better stents. Stents that elute chemotherapeutic agents could improve the current repetitive and invasive urinary tract instillations used in upper urinary tract malignancy.
PROGRESS BEYOND THE STATE-OF-THE-ART
The improvement in the field of urinary stents depends on a number of factors that involve the creation of a European Multidisciplinary Network, bringing together experts from fields nowadays distant from each other, such as bioengineering and clinicians or translational researchers. Another important improvement is to bring all the small European groups into a knowledge network, where experiences and different perspectives regarding this topic can be shared.The progress in the field of urinary stents must lean on the following pillars:
- Computational Simulation and stent design improvement. One of the main facts that provoke complications and most of the side effects of stents its poor design, unsuitable for the specific environment of the urinary tract. This happens with both double-JJ and metallic stents at ureteral, and urethral level. Thus, the creation of a multidisciplinary group will allow reaching an agreement upon the current defects to focus on the design of new stents with less morbidity. The development of computer simulation and modelling, along with fluid dynamics, enables nowadays the performance of simulations in a computational setting. It is therefore essential to create a computational platform where to evaluate new designs. In this way we have a controlled environment whose parameters can be modified in order to assess all kinds of urinary prosthesis, with no need for manufacturing or animal testing during the initial steps of development.
Within this COST Action, the conditions to create the simulation environment of the urinary tract will be established. These conditions are going to be agreed considering the characteristics of the urinary tract regarding anatomy, pressures; as well as biomechanics, the presence of lithiasis, extrinsic and intrinsic compressions, etc.
- Biomaterial’s and stent coating improvement. Another cause of stent complications and failure is the inappropriate choice of biomaterials and coatings. Currently, the materials used to make stents do not avoid encrustation, biofilm formation and bacterial colonization. More than 70% of the urinary prosthesis are colonised by bacteria. This involves health problems, a high stent replacement rate and an increase of pharmaceutical expenses for antibiotics and analgesics.
Through this Action, with the collaboration of experts in biomaterials and coatings, a Database of the suitable biomaterials for their use in the urinary tract (polymeric, non-polymeric, biodegradable, etc.) will be created. Such materials that have already been described for other uses, mostly in the cardiovascular field, which is the most developed field concerning stent biomaterials and coatings.
- Drug-eluting stents, Biocovered and Bioactive stents. There is an absent use of drug-eluting, biocovered or bioactive stents in urological practice. Nevertheless, these types of stents have shown high efficacy in the cardiovascular field, minimizing the occurrence of restenosis, the major drawback of coronary interventions. These features have already been considered to cover drug-eluting stents for intracoronary use to avoid restenosis, so they could be used in urology. Biocovered stents, which are stents covered with autologous membranous tissues, were developed by applying a novel concept based on in vivo tissue engineering. Bioactive stents are stents with alteration in the surface chemistry of the compound in order to acquire bioactive functions. These can promote specific biological responses from host tissues.
The use of stents with properties beyond the standard characteristic of acting as a scaffold within the urinary tract can reduce the side effects related to the inflammatory reaction to a foreign body, which is what happens with the standard stents. The potential designs that might be developed after this Action could be the future of urinary stents, as these new designs would allow urine drainage, being at the same time more biocompatible and decreasing the adverse effects. Hence, it is necessary to create a working group focused on identifying which drugs, biological coatings and bioactive stents could be applied in the field of urology. To this end it would be essential to develop guidelines about this stents and their interaction in the urinary tract and with the urine
INNOVATION IN TACKLING THE CHALLENGE
Here the innovation potential of this Action is described with reference to each of the five Objectives outlined in Research Coordination objectives.
One of the main facts responsible for the weak development of urinary stents, despite their wide use, is that the current research groups are of limited size. It is necessary to share different disciplines to face the challenges of stent design improvement, new biomaterials, as well as the application of new drugs that can be attached to stents for their release within the urinary tract. It is therefore essential to create a European Network of experts panel in different knowledge fields in order improvement of stents, which will result in less health costs expenditure, less morbidity in stented patients and in the future creation of European Patents in this field. To this end, this Action intends to create a link between experts to share different points of view regarding urinary stents, by means of meetings, training schools, STSM, scientific papers and guidelines.
Secondly, a Systematic Review and Meta-analysis will be made from both Urological, Medical Engineering, Industry partners, Patient-Scientific associations and policy officers to determine the causes of stent failure. The aim is to describe the most important factors that are responsible for the high side effects rate and the almost non-existing use of metallic stents in the urinary tract.
The innovative nature of this Action will come from the capability of this whole group to create some Guidelines that will describe from the beginning how to evaluate a new stent design. They will be the first Guidelines to describe the different necessary step to assess a new urinary stent, from a computational simulation level, to a pre-clinical trial level, including exvivo and animal model testing. This will allow the scientific community to have at its disposal a document that specifies the different steps to introduce new urinary stent designs in the clinical setting.
One great value of ENIUS is that it will allow, through the networks, training schools and workshops, to inform about the stent advances, which are already showing important efficacy in the vascular system. To this end, a systematic review will be performed and a WG will be formed to transfer these findings into the field of urinary tract.
The last innovation this Action proposes is to develop a realistic computational environment to evaluate new urinary stent designs by means of computational simulation, and the study of computational fluid dynamics. There is no computational platform to simulate the urinary tract environment so far. The joint work of urologists and engineers specialized in silico modelling and fluids dynamics will allow the creation of a simulation model that will assess all different kinds of designs of urological medical devices. This may be used in the future by any group interested in determining the physical and urodynamic effects and interactions of their new stents designs.