Design, Safety and Efficacy Evaluation of Gemcitabine-eluting Nanoyarn-integrated Heparinized Self Expanding Metallic Stents for Long-Term Management of Malignant Biliary Obstruction

Malignant biliary obstruction presents a significant therapeutic challenge and has serious consequences including cholangitis and death. Clinically, biliary stenting using self-expanding metallic- stent(SEMS) relieves this obstruction. However, stent occlusion occurs with time due to tumor/epithelial in-growth and bacterial colonization. To achieve sustained palliative benefit of stent-based approaches, both biliary sludge formation and in-growth need to be obviated. In this study, an innovative approach was adopted to inhibit sludge deposition and tissue in-growth by developing a heparinized drug-eluting SEMS. For this, heparinisation was performed on dopamine-functionalised-stents, which averted bile protein adsorption in vitro. Further, Gemcitabine loaded polycaprolactone electrospun-nanoyarns were integrated with heparinized-SEMS to achieve sustained drug release for nearly six months in vitro. Nanoyarn integration with heparinized-SEMS did not hamper its crimping, ease of deployment or functional behaviour. In vivo safety and efficacy were evaluated for five months after implantation in porcine bile duct through Endoscopic Retrograde Cholangiopancreatography. Minimal sludge deposition with no obstruction in bile flow, good stent patency and localized-sustained drug elution were observed for nanoyarn-integrated heparinized-SEMS. No alterations in the biochemical parameters, nor any inflammatory reactions were observed in vivo, all in comparison to control-SEMS. Overall, our research established an efficient multipronged strategy to tackle malignant biliary obstruction. STATEMENT OF SIGNIFICANCE: Bile duct occlusion due to cancer has several life-threatening consequences. This is clinically treated using metallic stents, with simultaneous intravenous use of anti-cancer drugs at high-doses. Nevertheless, tumor-growth along with bile-sludge accumulation happens after stenting, causing re-occlusion. Existing research uses stent modifications that fail to tackle both simultaneously, yielding short-term efficacy. To address this, heparinized-metallic stents were modified using chemo-drug eluting polymeric-nanoyarn integration. The key features of this device are: (i)nanoyarn-integrated, uncovered stent design facilitating easy endoscopic implantation in bile duct, (ii)reduced bile-sludge deposition, (iii)prolonged, low-dose, localised drug release that can mitigate tumor-growth and (iv)provide long-term stent patency without stent migration. This device proved to be safe, functional and efficacious for a period of five months in pig bile duct.