@article {17341, title = {Tailor-made biodegradable urological stents}, booktitle = {4th IMED conference}, year = {2012}, month = {2012-11-17 00:00:00}, address = {Lisbon, Portugal}, abstract = {

An urological stent is defined as a thin tube, which is inserted in the ureter or urethra to prevent or treat the obstruction of urine flow from the kidney or bladder. Metals, silicone, latex, polyvinylchloride and polyurethanes are the most widely used materials for the preparation of stents, although, they usually present different drawbacks: severe clinical complications may result from the use of these materials, namely, fractures, encrustations and infections. Particularly serious are bacterial infections, which represent the cause of several morbidity and mortality cases. Different medical conditions require the placement of a stent, for example: patients with kidney stones; patients with benign prostatic hyperplasia (BPH); patients who had an ureteroscopy; patients with urinary tract infections and diabetes; or other causes, e.g. prostate cancer or tumors. The indwelling time for these stents depends on the patient medical condition. In some of the cases, the stents are temporary and it is often required a second surgery to remove the stent.

Biodegradable natural-origin polymers present inherent characteristics, which confer to them several advantages in the biomedical field. Some natural-based hydrophilic materials present advantageous properties, such as, biocompatibility, lubricity, as well as excellent resistance to biofilm formation and encrustation. It has been reported in the literature that the coating of polymeric stents with hydrogels is able to improve the properties of the stent; however simple hydrogel stents have never been reported. Hydrogels are biocompatible polymeric networks which may present relevant mechanical properties, appropriate degradation rates, have shown reduced biofilm formation and present, as detailed here, an interesting alternative to conventional urological stents.

The main objective of the present research work is the preparation of aerogel hollow tubes from natural origin polysaccharides, as for example: alginate, gellan gum and their blends with gelatin. Hollow tubes will be prepared following conventional aerogel processing steps and will be characterized by different techniques. The aerogel is formed from an initial aqueous solution of biopolymer from which gelation is induced by a crosslinking agent (e.g. calcium chloride for alginate and gellan gum). Afterwards, the materials are subjected to a solvent exchange procedure where an alcohol replaces water and the material is dried using supercritical carbon dioxide. This drying step presents great advantages over the conventional drying methods, such as freeze-drying or vacuum drying. This is due to the thermodynamics of the process, which, in the case of supercritical fluid drying, avoids a phase transition that are usually responsible for the shrinkage and deformation of the materials.

This procedure generates an aerogel-based stent with a diameter between 1.5 and 6 mm, which is dependent on the type of biopolymer. In the presence of water the aerogel is transformed into an hydrogel. These hydrogels have high water uptake ability (approximately 1000\%), although, they do not present an extensive swelling behavior. These tubes are able to maintain their shape and integrity upon immersion in simulated body fluids, as already verified for periods up to 30 days of immersion.

A major concern in urological stents is the possibility of developing encrustation. This phenomenon is related with the deposition of salts present in the urine on the stent internal surface. When encrustation occurs it promotes the blockage of urine flow, which may cause distress and pain to the patients. Particularly relevant are magnesium salts in the form of struvite. Initial tests on the capacity of these stents to inhibit encrustation were already performed through their immersion in artificial urine solution for a timeframe up to 30 days. Scanning electron microscopy and energy dispersive X-ray spectroscopy have proven that encrustation was not promoted for all the biopolymers herein proposed.

Another concern is the need for a second surgery to remove the stent. This can be avoided using biodegradable materials. Polymer degradation in solution is usually promoted by the hydrolysis of the polymeric chains. Cross-linked polymers are able to improve the material structural stability extending their degradation timeframe. In vitro performance demonstrates that the degradation of the proposed materials in solution can be tuned from 14 to 60 days. In this perspective, it is possible to design polymeric stents with the degradation timeframe that best suit the treatment strategy. Therefore, this approach is able to prevent the need for a second surgery for stent removal.

An important property to be tuned is the permeability of the stents. Most of the applications targeted by this research work, do not require an impermeable barrier, although, permeability might induce local accumulations of toxic metabolites present in the urine. In this regard, permeability studies will be conducted. For these tests two different approaches will be evaluated: 1) stents with an internal flux of fluorescently-marked biomolecules of different molecular weights will be immersed in a solution that mimics the physiological medium, and the diffusion of the marked biomolecules will be evaluated by spectrophotometry executed on the immersion solution; or 2) the biopolymers will be processed to generate a membrane, with the same thickness as the stents, and permeability will be evaluated following standardized diffusion tests in Franz diffusion cells.

In vitro studies are required in order to evaluate cytotoxicity and biological performance of the materials. The raw materials used in the preparation of the stents are known to be cytocompatible, although, it is necessary to evaluate the impact of the processing methodologies in the biocompatibility of these stents. In this perspective, it is projected the evaluation of their cytotoxicity.

The proposed work will be carried out in the 3Bs Research Group from the University of Minho. The group extensive knowledge in biodegradable polymers targeting biomedical applications, namely in the polysaccharides herein described, will support this research, being considered as the ideal host for the candidate to execute the proposed work (see www.3bs.uminho.pt for a detailed information on all the 3Bs research topics, expertise and experience). Moreover, the 3Bs industrial connections in the biomedical field allow a faster commercialization of the developments achieved within the 3Bs group.

Finally, this research project intends to prepare urological stents based on biodegradable natural polymers with inherent anti-bacterial properties; adequate morphology and mechanical performance; able to avoid encrustation; and reducing the need for a second surgery. These properties are foreseen as major breakthroughs in the development a new generation of urological stents.

}, keywords = {polyssaccharides, Stents}, author = {Barros, A. A. and Duarte, A. R. C. and Pires, R. A. and Mano, J. F. and Reis, R. L.} }