3D Bioprinted Liver Tissue for Hepatocellular Carcinoma (HCC) - Medical Science Assignment Help

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Abstract Hepatocellular carcinoma (HCC) is a sustained, inflammatory type of primary liver cancer responsible for 781,631 global deaths in 2018. The most effective treatment for HCC to date is transplantation compounded with immunosuppressant therapy. 3D bioprinting is an emerging application that owes much of its current success to earlier findings in regenerative medicine and materials science. While there have been mixed degrees of success between organ types, the organs in highest demand for transplantation – the liver and kidney, continue to elude mastery. 3D bioprinted livers are of particular interest due to its incredibly complex vasculature and the limitless pharmaceutical testing potentials it may yield. All bioprinting methods in addition to three major milestones within artificial livers are detailed in the following review. Organovo’s ExVive™ remains the most promising prototype among these studies with human clinical trials to commence within the decade. Artificial organ mastery is likely to force obsolescence upon immunosuppressants and human trials, markedly reducing the biochemical burden on liver cancer patients, the general population and transplant seekers on waiting lists. Despite the limitless possibilities by these advancements, 3D bioprinting has not been received without controversies that centre on monopolisation and accessibility. Keywords: hepatocytes, regenerative medicine, transplantation, disease Introduction Liver cancer is the fifth most common type of cancer and is second highest among cancer-related deaths worldwide1 . The distribution of liver cancer types is dominated by the primary variety, wherein malignant cells originate and spread from the liver itself. The most common type of primary liver cancer, attributing 75-85% of cases – is Hepatocellular carcinoma (HCC) or ‘malignant hepatoma’. The two highest risk factors for HCC are chronic viral hepatitis (types B and C) and excessive alcohol consumption. The final stages of liver fibrosis often manifest into HCC. The highest prevalence of HCC (>80%) occurs in developing regions (East Asia and Sub-Saharan Africa) and from birth where risk factors such as Hepatitis B – are endemic and completely untreated 2 . Between 1990 and 2013, higher incidences of Hepatitis B and C lead to an increase of 63% in global HCC deaths3 . Unlike other chronic conditions in developed nations, the incidence of HCC appears to be increasing in Australia United States of America. However this may be suggestive of a positive trend since HCC is known to have an unusually due to its high latency for diagnosis. The increase in reported diagnoses may indicate that HCC is being diagnosed more frequently and thereby earlier in its progression. A higher latency in diagnosis is predictive of any disease progressing to an irreversible and fatal stage, the effects of which are observed in the >85% mortality rate over 5 years4 for HCC. Only up to a mere 15% of recently diagnosed HCC cases are potentially curable via transplantation and 20-30% of these patients will experience further progression to the extent where they become ultimately untreatable5 . A probable reason for delayed diagnosis may be accounted for by the non-pathognomonic nature of HCC symptoms. Aside from transplantation 2 compounded with immunosuppressant therapy, there is no definitive cure for HCC. Aside from transplantation, the current methods of treatment – chemotherapy, hepatectomy (partial or complete excision of the liver) and radiofrequency ablation have yielded ineffectual outcomes for late-stage HCC. However, radiofrequency ablation is a good non-invasive method with a low rate of recurrence for early stages of HCC (tumours <3cm) 6 . The liver performs over 500 essential functions for the human body- most notably lipid metabolism, cholesterol maintenance, glycogen storage, bile secretion and synthesis of plasma proteins such as albumin which dictates blood volume. Liver failure presents seemingly limitless complications which become compounded including the inability to produce blood clots (continual bleeding due to a deficiency in Vitamin K, which precedes coagulation factors), malabsorption, cirrhosis (scarring) and jaundice7 . Hepatocytes are the main functional cells of the liver that comprise around 80% of its mass. The arrangement of hepatocytes is specific to the liver in that the cells are organised in a singular layer with branching tubular connections (anastomose) which form capillary sinusoids that remove defective red blood cells, antigens and microorganisms8 . The distinct pathogenesis of HCC remains unclear and several unconfirmed biomarkers continue to be researched. The most notable biomarkers are the enzymatic epigenetic modifiers RASSF1A, P16 and DLC1 RhoA GTPase activating protein 9 which induce DNA methylation and histone modifications. Hypermethylation of the cadherin1 (CDH1) gene held some association to HCC. Many studies focus on closely related conditions that often precede HCC development such as diabetes mellitus, type B and C hepatitis. A broader theory states that any DNA damage via Reactive Oxidation Species from hepatic fatty infiltration plays an instrumental role in mutating the tumour suppressor gene p5310 .

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