Lithontripic-eluting Stent And Regional Lithontripic Infusion For The Treatment Of Difficult Bile Duct Stones

Background and Aims The management of difficult bile duct stone remains a challenge throughout the world.It has been reported that sodium cholate(SC)and disodium ethylene diamine tetraacetic acid(EDTA disodium,EDTA for short)are capable of dissolving bile duct stones.Unfortunately,to date,an ideal way to deliver the drugs to bile duct is still lack.Drug-eluting stents and perfusion via nasobiliary duct seem to be effective ways to deliver lithontripic into bile duct,resulting in dissolution of bile duct stones gradually.In this study,we aim to explore the efficacy of these two methods as alternative management of difficult bile duct stone.Methods(1)Three different types of SC/EDTA-eluting stent were manufactured by dip coating,coaxial electrospinning and dip coating combined with electrospinning respectively.The stents were assigned as stent NO.1,stent NO.2 and stent NO.3 respectively.The drug-eluting pattern and efficacy in stone dissolving of these stents were evaluated to select the best way of manufacturing drug-eluting stent.And the newly-developed drug-eluting stents were further put into the porcine gallbladder to evaluate their biosecurity.(2)Proper proportion of SC and EDTA were selected based on the results of their efficacy in dissolving stones and cytotoxicity test in vitro.An in vitro model imitating common bile duct with biliary stones in it was developed through 3D-printing for the use of bile perfusion and drug perfusion at the same time.Then the efficacy in dissolving stones were studied.The selected proportion of SC and EDTA were perfused into porcine gallbladder to evaluate its biosecurity.Results(1)The study of drug-eluting pattern revealed that stents NO.3were able to release drug gradually as expected,however,drug burst release was observed in stents NO.1 and stents NO.2.Efficacy in ex vivo biliary stone dissolution of all the stents were studied in two conditions.While all the stents together with biliary stones were immersed in still solution,stents NO.3 showed the best dissolution performance,followed by stents NO.2,stents NO.1 and naked stents without drug load.While they were placed together with biliary stones in bile flow,none showed the capacity of stone dissolution.In vivo study revealed that after the placement of stents NO.3 and naked stents without drug load into porcine bladder,there existed no difference in serological indicators,and inflammatory response were observed in both groups without statistical difference(p>0.05).(2)2%EDTA+5%SC,2%EDTA+2%SC,5%SC and2%EDTA were selected as the proper formula.While biliary stones were immersed in these formula,2%EDTA+5%SC showed the best dissolution performance,followed by 2%EDTA+2%SC,5%SC and 2%EDTA.While biliary stones were placed in the flow mixed of bile and litholytic formula,2%EDTA+5%SC still showed the best dissolution performance.In vivo study revealed that 2%EDTA+5%SC resulted in mild elevation of transaminase,and different extent of inflammatory response in gallbladder,CBD and duodenum,but without influence on kidney and liver tissue.Conclusions(1)SC/EDTA-eluting stent manufactured by dip coating combined with electrospinning can achieve controlled drug release and satisfactory biosecurity.Drug loading capacity for effective biliary stone dissolution needs to be further studied.(2)A combination of SC and EDTA was significantly superior to single use in stone dissolution.Formula of 2%EDTA+5%SC was proved to have satisfactory efficacy in stone dissolution and good biosecurity.