Machine perfusion of the liver and in vivo animal models: A systematic review of the preclinical research landscape.

Machine perfusion (MP) is often referred to as one of the most promising advancements in liver transplantation research of the last few decades, with various techniques and modalities being evaluated in preclinical studies using animal models. However, low scientific rigor and subpar reporting standards lead to limited reproducibility and translational potential, hindering progress. This pre-registered systematic review (PROSPERO: CRD42021234667) aimed to provide a thematic overview of the preclinical research landscape on MP in liver transplantation using in vivo transplantation models and to explore methodological and reporting standards, using the ARRIVE (Animal Research: Reporting of In Vivo Experiments) score. In total 56 articles were included. Studies were evenly distributed across Asia, Europe, and the Americas. Porcine models were used in 57.1% of the studies, followed by rats (39.3%) and dogs (3.6%). In terms of graft type, 55.4% of the studies used donation after cardiac death grafts, while donation after brain death grafts accounted for 37.5%. Regarding MP modalities, the distribution was as follows: 41.5% of articles utilized hypothermic MP, 21.5% normothermic MP, 13.8% subnormothermic MP, and 16.9% utilized hypothermic oxygenated MP. The stringent documentation of ARRIVE elements concerning precise experimental execution, group size and selection, the choice of statistical methods, as well as adherence to the principles of the 3Rs, was notably lacking in the majority of publications, with less than 30% providing comprehensive details. Postoperative analgesia and antibiotics treatment were not documented in 82.1% of all included studies. None of the analyzed studies fully adhered to the ARRIVE Guidelines. In conclusion, the present study emphasizes the importance of adhering to reporting standards to promote reproducibility and adequate animal welfare in preclinical studies in machine perfusion. At the same time, it highlights a clear deficiency in this field, underscoring the need for further investigations into animal welfare-related topics.

Systematic Review on Characteristics and Reporting Quality of Animal Studies in Liver Regeneration Triggered by Portal Vein Occlusion and Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy: Adherence to the ARRIVE Guidelines.

BACKGROUND: Portal vein occlusion and associating liver partition and portal vein ligation for staged hepatectomy techniques are in the spotlight of oncological liver surgery. Research involving animal models is indispensable to study the mechanisms of liver regeneration. Inaccurate reporting acts as a significant barrier during the correct interpretation of preclinical findings. Hence, we performed a systematic review to evaluate the status quo of the reporting standards and to assess the potential factors influencing reporting in animal studies, which are focusing on portal vein occlusion and/or associating liver partition and portal vein ligation for staged hepatectomy techniques. MATERIALS AND METHODS: A systematic review was performed in the PubMed and Ovid MEDLINE databases. Baseline study characteristics were recorded, and quality assessment was performed using the Animals in Research: Reporting in vivo Experiments (ARRIVE) checklist. RESULTS: A total of 107 research articles were included for the comprehensive assessment. In the subgroup analysis, newer reports and studies from the post-ARRIVE era, and reports from Europe were all associated with significantly higher ARRIVE scores (P < 0.05). Univariable regression analysis confirmed these factors as predictors of higher reporting quality. However, in the multivariable analysis, only publishing in the post-ARRIVE era has been found as single independent predictor of higher reporting standards (P = 0.028 post-ARRIVE total score 75th percentile; P = 0.000 post-ARRIVE total score median). CONCLUSIONS: Although an improving trend has been observed in reporting quality over the past years, this effect was clearly insufficient. Our results emphasize the need for further measures to improve the methodical quality at all levels of planning, execution, and reporting of preclinical studies in liver regeneration research.

Liver regeneration after different degrees of portal vein ligation.

BACKGROUND: Selective portal vein ligation (PVL) is followed by ipsilateral atrophy and contralateral hypertrophy of the liver lobes. Although the atrophy-hypertrophy complex induced by PVL is a well-documented phenomenon, the effect of different degrees of extended portal vein occlusion on liver regeneration is not known. The aim of this study was to assess the effects of different degrees of portal occlusion on portal pressure and liver regeneration. MATERIALS AND METHODS: Male Wistar rats (n = 96; 220-250 g) were randomized into three groups and underwent 70%, 80%, or 90% portal vein ligation, respectively. The portal pressure was measured immediately and 24, 48, 72, 120, and 168 h after PVL (n = 6/group/time point). The hepatic lobes and the spleen were weighed, and liver regeneration ratio was calculated. Changes in liver histology and the mitotic activity were assessed on hematoxylin-eosin stained slides. RESULTS: Higher degree of portal occlusion triggered a stronger regenerative response (regeneration ratio of PVL 70%168h = 2.23 ± 0.13, PVL 80%168h = 3.11 ± 0.37, PVL 90%168h = 4.68 ± 0.48) PVL led to an immediate increase in portal pressure, the value of which changed proportionally to the mass of liver tissue deprived of portal perfusion (PVL 70%acute = 17 ± 2 mm Hg, PVL 80%acute = 19 ± 1 mm Hg, PVL 90%acute = 26 ± 4 mm Hg). Findings in histology showed necro-apoptotic lesions in the atrophic liver lobes and increased mitotic cell count in the hypertrophic lobes. The mitotic cell count of PVL 90% peaked earlier and at a significantly higher value than of PVL 70% and PVL 80% (PVL 9024h%: 96.0 ± 3.5 PVL 70%48h: 64.0 ± 2.1, PVL 80%48h: 56.3 ± 4.0). The mitotic index after 24 h showed a strong correlation with the acute portal hypertension. CONCLUSIONS: A higher degree of portal vein occlusion leads to a greater regenerative response, presumably triggered by the proportional increase in portal pressure, which supports the role of the so-called "blood-flow" theory of PVL-triggered liver regeneration.