The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term immunosuppression. Organoid-derived adult liver stem cells can be cultured indefinitely to create sufficient cell numbers for transplantation, and they are amenable to gene correction. This study provides preclinical proof of concept of the potential of cell transplantation in a large animal model of inherited copper toxicosis, such as Wilson’s disease, a Mendelian disorder that causes toxic copper accumulation in the liver. Hepatic progenitors from five COMMD1-deficient dogs were isolated and cultured using the 3D organoid culture system. After genetic restoration of COMMD1 expression, the organoid-derived hepatocyte-like cells were safely delivered as repeated autologous transplantations via the portal vein. Although engraftment and repopulation percentages were low, the cells survived in the liver for up to two years post-transplantation. The low engraftment was in line with a lack of functional recovery regarding copper excretion. This preclinical study confirms the survival of genetically corrected autologous organoid-derived hepatocyte-like cells in vivo and warrants further optimization of organoid engraftment and functional recovery in a large animal model of human liver disease.

Background Vascular access port (VAP) systems are widely used in human medicine to provide long-term venous access. However, in veterinary medicine the use of VAP systems is not common practice and publications on their potential applications have been limited. A VAP system was used as part of an experimental study on liver regeneration and implanted in the canine portal vein to create direct access to the portal venous circulation of the liver. The aim of the present study is to describe the surgical technique, its use, and the complications of a VAP system in three research dogs. Results The VAP system was successfully used for the intraoperative measurement of portal blood pressure, the administration of cell suspensions, and the collection of portal venous blood samples. Long-term complications consisted of dislocation of the VAP system in one dog (2 months after implantation) and thrombus formation at the catheter tip in two dogs (3 months after implantation). Both complications prevented further use of the VAP but had no adverse clinical implications. Conclusions This pilot study suggests that the VAP system is an effective and safe technique to obtain long term access to the portal venous system in dogs. However, complications with port detachment and thrombosis may limit long term use of VAPs in the portal system of dogs.

Tramadol is a veterinary analgesic for dogs. In this study, the steady-state pharmacokinetics of a sustained-release (SR) tablet (Tramagetic OD®) and immediate-release capsules (IR) were compared. In a crossover design, six dogs received five doses of IR 50 mg four times a day (qid), or two doses of SR 200 mg once a day (sid). Eight blood samples were collected per dog, per formulation, up to 6 and 24 h after the last dose, respectively. Serum concentrations of tramadol and its metabolites were measured with LC-MS/MS. Metabolite M1 levels were below the lower limit of quantification (LLOQ) in all samples. The non-compartmental analysis of the time–concentration data showed a later Tmax with the SR formulation (median 6.00 h (3.00–9.00)) and a lower Cmax/D (median 7.74 µg/L/mg/kg (0.09–25.3)) compared to the IR formulation (median Tmax 1.75 h (0.75–2.00) and median Cmax/D 11.1 µg/L/mg/kg (4.8–70.4)). AUCtau/D after SR administration was 55.5 h × kg × µg/L/mg (0–174.1) compared to 29.8 h × kg × µg/L/mg (12.2–140.8) after IR administration. The terminal elimination half-lives were 2.38 h (1.77–6.22) and 1.70 h (0.95–2.11) for the SR and IR formulations, respectively. Strong conclusions cannot be drawn from this study because of the high percentage of samples that were below LLOQ and the great interindividual variability, but these results suggest that Tramagetic OD can be administered less frequently in dogs.