Parameters of biliary hydrodynamic injection during endoscopic retrograde cholangio-pancreatography in pigs for applications in gene delivery (original) (raw)
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American Journal of Physiology-Gastrointestinal and Liver Physiology
Cholangiopathies are progressive disorders with largely unknown pathoetiology and limited treatment options. We aimed to develop a novel surgical technique with direct access to the bile ducts that would complement existing mouse models of cholestasis, biliary inflammation, and fibrosis and present a new route of administration for testing of potential treatment strategies. We developed a surgical technique to access the murine biliary tree by injection of different solvents through catheterization of the gall bladder with simultaneous clamping of the common bile duct. To demonstrate the applicability of the technique, we injected either phosphate-buffered saline or dimethyl sulfoxide in concentrations of 50 or 65% and compared these groups with sham-operated mice. The surgery was optimized to achieve a mortality rate close to 0. There were no significant changes in pain, activity level, or mortality from the day of the surgery until euthanization for any groups. Injection of phosph...
Gene Therapy, 2010
Hydrodynamic gene delivery to the liver is an attractive approach for clinical liver gene therapy, but critical aspects of technique remain uncertain. There has not been to date any report of high levels of hydrodynamic gene delivery to the liver, except in rodents. Regional hydrodynamic delivery to individual lobes/segments of the liver is being pursued in preclinical pig models, where reporter gene expression has been o1% of rodent levels, and in one clinical study, where there was no substantive evidence of gene expression. In none of these studies did surgical technique include outflow obstruction of the DNA solution. Here we report a novel technique for regional hydrodynamic gene delivery to the left lateral lobe of the rat liver. The technique gives high levels of gene delivery specific to the left lateral lobe with low volumes (B1.5 ml) of DNA solution, and permits an evaluation of hydrodynamic delivery in the presence and in the absence of outflow obstruction. We report that outflow obstruction is an absolute requirement for effective hydrodynamic gene delivery to individual lobes/segments of the liver, and therefore that minimally invasive techniques will not be possible in the clinic.
World journal of gastroenterology : WJG, 2014
To evaluate the technical feasibility of a modified tapered metal tip and low profile introducer for one-step endoscopic ultrasound (EUS)-guided biliary drainage (EUS-BD) in a new experimental biliary dilatation porcine model. A novel dedicated device for one-step EUS-guided biliary drainage system (DEUS) introducer has size 3F tapered catheter with size 4F metal tip for simple puncture of the intestinal wall and liver parenchyma without graded dilation. A self-expandable metal stent, consisting of both uncovered and nitinol-covered portions, was preloaded into DEUS introducer. After establishment of a biliary dilatation model using endoscopic hemoclips or band ligation with argon plasma coagulation in 9 mini-pigs, EUS-BD using a DEUS was performed following 19-G needle puncture without the use of fistula dilation devices. One-step EUS-BD was technically successful in seven pigs [7/9 (77.8%) as intention to treat] without the aid of devices for fistula dilation from the high body of...
Hydrodynamic gene delivery to the pig liver via an isolated segment of the inferior vena cava
Gene Therapy, 2008
Hydrodynamic gene delivery is an attractive option for non-viral liver gene therapy, but requires evaluation of efficacy, safety and clinically applicable techniques in large animal models. We have evaluated retrograde delivery of DNA to the whole liver via the isolated segment of inferior vena cava (IVC) draining the hepatic veins. Pigs (18-20 kg weight) were given the pGL3 plasmid via two programmable syringe pumps in parallel. Volumes corresponding to 2% of body weight (360-400 ml) were delivered at 100 ml s À1 via a Y connector. The IVC segment pressure, portal venous pressure, arterial pressure, electrocardiogram (ECG) and pulse were monitored. Concurrent studies were performed in rats for interspecies comparisons. The hydrodynamic procedure generated intrahepatic vascular pressures of 101-126 mm Hg, which is B4 times higher than in rodents, but levels of gene delivery were B200-fold lower. Suprahepatic IVC clamping caused a fall in arterial pressure, with the development of ECG signs of myocardial ischaemia, but these abnormalities resolved rapidly. The IVC segment approach is a clinically acceptable approach to liver gene therapy. However, it is less effective in pigs than in rodents, possibly because of larger liver size or a less compliant connective tissue framework.
Molecular Therapy - Methods & Clinical Development, 2022
Hepatic gene therapy by delivering non-integrating therapeutic vectors in newborns remains challenging due to the risk of dilution and loss of efficacy in the growing liver. Previously we reported on hepatocyte transfection in piglets by intraportal injection of naked DNA vectors. Here, we established delivery of naked DNA vectors to target periportal hepatocytes in weaned pigs by hydrodynamic retrograde intrabiliary injection (HRII). The surgical procedure involved laparotomy and transient isolation of the liver. For vector delivery, a catheter was placed within the common bile duct by enterotomy. Under optimal conditions, no histological abnormalities were observed in liver tissue upon pressurized injections. The transfection of hepatocytes in all tested liver samples was observed with vectors expressing luciferase from a liver-specific promoter. However, vector copy number and luciferase expression were low compared to hydrodynamic intraportal injection. A 10-fold higher number of vector genomes and luciferase expression was observed in pigs using a non-integrating naked DNA vector with the potential for replication. In summary, the HRII application was less efficient (i.e., lower luciferase activity and vector copy numbers) than the intraportal delivery method but was significantly less distressful for the piglets and has the potential for injection (or re-injection) of vector DNA by endoscopic retrograde cholangiopancreatography.
Manometric changes during retrograde biliary infusion in mice
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2000
The manometric, ultrastructural, radiographic, and physiological consequences of retrograde biliary infusion were determined in normostatic and cholestatic mice. Intraluminal biliary pressure changed as a function of infusion volume, rate, and viscosity. Higher rates of constant infusion resulted in higher peak intraluminal biliary pressures. The pattern of pressure changes observed was consistent with biliary ductular and/or canalicular filling followed by leakage at a threshold pressure. Retrograde infusion with significant elevations in pressure led to paracellular leakage of lanthanum chloride, radiopaque dye, and [14C]sucrose with rapid systemic redistribution via sinusoidal and subsequent hepatic venous drainage. Chronic extrahepatic bile duct obstruction resulted in significantly smaller peak intrabiliary pressures and lower levels of paracellular leakage. These findings indicate that under both normostatic and cholestatic conditions elevated intrabiliary volumes/pressures re...
GE Portuguese journal of gastroenterology, 2018
Biliary tract complications following liver transplant remain an important source of morbidity and mortality. Endoscopic retrograde cholangiopancreatography (ERCP) has become a common therapeutic option before other invasive procedures. The aim of this study was to evaluate ERCP efficacy in managing this type of complications. Retrospective study of all patients who underwent therapeutic ERCP due to post-liver transplant biliary complications between September 2005 and September 2015, at a deceased donor liver transplantation centre. Therapeutic ERCP was performed in 120 patients (64% men; mean age 46 ± 14 years). Biliary complications were anastomotic strictures (AS) in 70%, non-anastomotic strictures (NAS) in 14%, bile leaks (BL) in 5.8%, and bile duct stones (BDS) in 32%. The mean time between liver transplant and first ERCP was: 19 ± 30 months in AS, 17 ± 30 months in NAS, 61 ± 28 months in BDS, and 0.7 ± 0.6 months in BL (< 0.001). The number of ERCP performed per patient wa...
Electronic Poster-Biliary (EP223-EP258)
2021
P. J. Gil Vázquez, D. Ferreras Martinez, B. Gómez Pérez and F. Sánchez Bueno Hospital Clínico Universitario Virgen de la Arrixaca, Spain Introduction: The standard treatment of choledocholithiasis is endoscopic retrograde cholangiopancreatography (ERCP). In this way, it needs two interventions: ERCP and laparoscopic cholecystectomy (LC), so it is necessary two anesthetic processes, more possibilities of failure, complications, hospital stay and more expenses. Thanks to laparoscopic common bile duct exploration (LCBE) complete treatment is possible with a single intervention. Method: We designed this prospective, non-randomized study to analyze LCBE approach in terms of hospital stay and cost-effectiveness. Results: There are 118 patients in the study (67 women; mean age of 69.8 17.3 years old). Sixty-six patients received ERCP+LC management. Fifteen of them failed to clean the bile duct. LCBE was carried out in 59 patients (49 plus 11 ERCP failure). Seven of them required conversion...