Regenerative Medicine of Liver: Promises, Advances and Challenges

Liver tissue engineering is a rapidly developing field which combines the novel use of liver cells, appropriate biochemical factors, and engineering principles, in order to replace or regenerate damaged liver tissue or the organ. The aim of this review paper is to critically investigate different possible methods to tackle issues related with liver diseases/disorders mainly using regenerative medicine. In this work the various regenerative treatment options are discussed, for improving the prognosis of chronic liver disorders. By reviewing existing literature, it is apparent that the current popular treatment option is liver transplantation, although the breakthroughs of stem cell-based therapy and bioartificial liver technology make them a promising alternative.

Establishment of Acute Liver Failure Model in Tibet Miniature Pig and Verified by a Non-bioartificial Liver

Background and aims Acute liver failure (ALF) is a severe liver disease with high morbidity and mortality. Animal model is very important to research ALF. This study aimed to establish a reproducible, D-galactosamine-induced, Tibet miniature pig model of ALF and verified by a non-bioartificial liver (NBAL).Methods Thirteen Tibet miniature pigs were randomly divided into four groups (A, B, C, D) after central venous catheterization, then D-galactosamine (D-gal) at 0.45, 0.40 and 0.35g/kg body weight were injected through the central venous catheter in group A, B, C. While in group D, D-gal at 0.35g/kg body weight was injected and treated by a NBAL at 48 h after D-gal administration. Vital signs, blood index values were recorded at every 12 h after D-gal administration and every 2 h during NBAL treatemnt. Meanwhile, clinical manifestations, survival times and results of H&E staining, Tunel, Ki67, Masson assays and Picrosirius red staining were performed.Results Tibet miniature pigs developed different degrees of debilitation, loss of appetite and jaundice after D-gal administration. Survival times of groups A, B, C and D were 39.7±5.9 h, 53.0±12.5 h, 61.3±8.1 h and 61±7 h, respectively. Blood levels of ALT, AST, TBIL, Cr, BUN, Amm, PT and inflammation factors (such as TNF-α, IL-1β, IL-6) levels significantly increased compared with baseline in different groups (Ps < 0.05). Pathological results showed obvious liver cell necrosis positively correlated to the dose of D-gal. However, the NBAL did not increase the survival times of ALF, neither Amm and liver cell necrosis, it just decreased some biochemistry indexes (such as TBIL, ALT, AST).Conclusions: We successfully established a reproducible, D-galactosamine-induced, Tibet miniature pig model of ALF, the NBAL did not improve the survival times of ALF and we think the dosage of 0.35 g/kg is optimal.

Hollow Fiber and Nanofiber Membranes in Bioartificial Liver and Neuronal Tissue Engineering

To date, the creation of biomimetic devices for the regeneration and repair of injured or diseased tissues and organs remains a crucial challenge in tissue engineering. Membrane technology offers advanced approaches to realize multifunctional tools with permissive environments well-controlled at molecular level for the development of functional tissues and organs. Membranes in fiber configuration with precisely controlled, tunable topography, and physical, biochemical, and mechanical cues, can direct and control the function of different kinds of cells toward the recovery from disorders and injuries. At the same time, fiber tools also provide the potential to model diseases in vitro for investigating specific biological phenomena as well as for drug testing. The purpose of this review is to present an overview of the literature concerning the development of hollow fibers and electrospun fiber membranes used in bioartificial organs, tissue engineered constructs, and in vitro bioreactors. With the aim to highlight the main biomedical applications of fiber-based systems, the first part reviews the fibers for bioartificial liver and liver tissue engineering with special attention to their multifunctional role in the long-term maintenance of specific liver functions and in driving hepatocyte differentiation. The second part reports the fiber-based systems used for neuronal tissue applications including advanced approaches for the creation of novel nerve conduits and in vitro models of brain tissue. Besides presenting recent advances and achievements, this work also delineates existing limitations and highlights emerging possibilities and future prospects in this field.

Uncertainty in the impact of liver support systems in acute-on-chronic liver failure: a systematic review and network meta-analysis

Background The role of artificial and bioartificial liver support systems in acute-on-chronic liver failure (ACLF) is still controversial. We aimed to perform the first network meta-analysis comparing and ranking different liver support systems and standard medical therapy (SMT) in patients with ACLF. Methods The study protocol was registered with PROSPERO (CRD42020155850). A systematic search was conducted in five databases. We conducted a Bayesian network meta-analysis of randomized controlled trials assessing the effect of artificial or bioartificial liver support systems on survival in patients with ACLF. Ranking was performed by calculating the surface under cumulative ranking (SUCRA) curve values. The RoB2 tool and a modified GRADE approach were used for the assessment of the risk of bias and quality of evidence (QE). Results In the quantitative synthesis 16 trials were included, using MARS®, Prometheus®, ELAD®, plasma exchange (PE) and BioLogic-DT®. Overall (OS) and transplant-free (TFS) survival were assessed at 1 and 3 months. PE significantly improved 3-month OS compared to SMT (RR 0.74, CrI: 0.6–0.94) and ranked first on the cumulative ranking curves for both OS outcomes (SUCRA: 86% at 3 months; 77% at 1 month) and 3-month TFS (SUCRA: 87%) and second after ELAD for 1-month TFS (SUCRA: 76%). Other comparisons did not reach statistical significance. QE was moderate for PE concerning 1-month OS and both TFS outcomes. Other results were of very low certainty. Conclusion PE seems to be the best currently available liver support therapy in ACLF regarding 3-month OS. Based on the low QE, randomized trials are needed to confirm our findings for already existing options and to introduce new devices.