A bilayer swellable drug-eluting stent for the treatment of fibrosis-induced ureteral stricture recurrence

• Main Author: Lim, Wei Shan
• Other Authors: Subbu S. Venkatraman
• Format: Theses and Dissertations
• Language: English
• Published: 2018
• Subjects: DRNTU::Engineering::Materials::Biomaterials
• Online Access: http://hdl.handle.net/10356/73390
• Institution: Nanyang Technological University

Ureteric stricture is a long-term condition that can lead to the obstruction in the urinary tract, leading to hydronephrosis and kidney failure. Current therapies are invasive and ineffective in managing stricture recurrence following stenting. It is hypothesized that a bilayer swellable drug-eluting stent (BSDES) that can co-apt with the urothelium for the localized and sustained delivery of drugs into the diseased section can reduce or eliminate stricture recurrence. The BSDES comprises of two layers of coatings. The first layer consists of mitomycin C(MMC) and 70/30 poly-L-lactide-co-caprolactone (PLC). The second layer consists of polyethylene glycol diacrylate (PEGDA) hydrogel. The first layer is needed for sustained release of drug while the second layer is required for close contact with urothelial wall. This thesis examines the development, fabrication, characterization and evaluation of a BSDES, the results achieved as below: Firstly, mass loss and rheological measurements identified 10% w/v PEGDA hydrogel as the candidate hydrogel concentration since there was no significant degradation and it could retain the largest mechanical strength over the 4 weeks. Secondly, plasma treatment (100W, 5 min) was found to be effective in improving the interfacial adhesion between the hydrogel and polymer, allowing the hydrogel to adhere on the stent over the 4 weeks. Moreover, drug release studies were conducted in the static conditions over 1 month. Tunable drug release was demonstrated in the static condition by varying the polymer thickness and drug concentration. In addition, the drug released in the static condition was well above the minimum effective concentration to inhibit HBdSF (0.01 ug/mL). An in-vitro transwell cell study showed that the drug eluted from the coated stent was able to inhibit human bladder stroma fibroblasts (HBdSF) in-vitro.To better understand the effect of hydrogel on drug release and transfer of BSDES, the release study of BSDES was conducted in both in-vitro dynamic fluid flow and porcine ureteric tissue ex-vivo dynamic fluid flow condition. The PEGDA hydrogel gave rise to greater drug release in the dynamic fluid flow condition over the 1-week period but this difference was not observed in the static condition. Moreover, PEGDA hydrogel was found to augment the amount of drug transport into the explanted porcine ureteric tissues ex-vivo. These observations were likely due to the high equilibrium water content hence promoting the drug release. Furthermore, the pilot in-vivo study successfully demonstrated the feasibility of the device in the porcine model. The device was successfully inserted by using the same current clinical stenting methods. The hydrogel swelled and co-apted with the urothelium which MMC was locally delivered to the targeted ureteric section. No hydronephrosis or systemic toxicity was detected. Hydrogel remained intact on the stent. In conclusion, a BSDES prototype was successfully fabricated and tested in this project, and has the potential to treat and manage ureteric stricture recurrence.