What Is the Artificial Liver?

Artificial liver is abbreviated as artificial liver, and its English name is Artificial extracorporeal liver support. It has a short history as an independent organ. The research on artificial liver began in the 1950s. In 1956, Sorrentino demonstrated that fresh liver tissue homogenate could metabolize ketone bodies, barbitur and ammonia, and first proposed the concept of "artificial liver".

Chinese name: Artificial liver
Foreign name: Artificial extracorporeal liver support

Full name: Artificial liver
Start research: 1950s

Introduction of artificial liver

Artificial liver assists in the treatment of liver insufficiency or related diseases by temporarily or partially replacing liver function with the help of external mechanical, chemical or biological devices. The biggest difference between artificial liver and general medical drug treatment is that the former is mainly treated by "functional replacement" The latter is mainly treated by "function enhancement". Therefore, in the clinical application of this new technology, special attention should be paid to the identification of indications. Each therapy has its own advantages and disadvantages, which should be selected due to human disease. There is currently no unified artificial liver. Classification, traditionally divided into non-biological artificial liver, biological artificial liver and combined biological artificial liver according to the composition and properties of artificial liver. In the 1950s, most researchers believed that the main cause of liver coma was the toxic substance in the body. Anomalous accumulation, and most of these toxins are dialyzable small molecule substances (less than 500 Daltons), so the design of the early artificial liver device was mainly to provide the blood purification function of small molecule poisons.

If you divide the artificial liver again, it can be understood as mechanical or physical and biological. Mechanical is mainly

Artificial liver The mechanism is to use the unique biofilm and chemical substance adsorption through physical means to remove the harmful substances to the human body from the patient and supplement the substances needed in the body, while the biological artificial liver uses the human bioreactor in vitro to utilize the human From the point of view, biological artificial liver is more in line with the name of "artificial liver". However, due to the many problems of biological artificial liver, Far from meeting the clinical needs, the current treatment of artificial liver is still mainly physical.

Artificial liver technology

Artificial liver hemoperfusion

The exact meaning is blood adsorption, that is, substances dissolved in the blood are adsorbed to solid substances with rich surface area to remove poisons from the blood. The hemoperfusion device mainly consists of a blood perfusion machine, accessories (arterial and venous lines, etc.) and a blood perfusion device.

There are two commonly used perfusion devices : one is activated carbon and the other is synthetic resin. Activated carbon is mainly made from coconut husk. Others include petroleum, wood, polyvinyl alcohol, bones, and sugar. Direct contact between activated carbon and blood will cause the destruction of blood constituents such as red blood cells, white blood cells and platelets, and there is a danger of micro-embolization of organ blood vessels caused by the shedding of carbon particles. In 1970, Canadian scholar Zhang Mingrui applied microcapsules made of activated carbon with semi-permeable membrane of albumin collodion to hemoperfusion, which not only improved the blood compatibility of activated carbon, but also effectively prevented the carbon particles from falling off. Activated carbon can effectively adsorb small and medium molecular water-soluble substances with a molecular weight of less than 5000 Daltons, such as thiols, r-aminobutyric acid, and free fatty acids, but it cannot effectively adsorb blood ammonia, and it also has a strong ability to adsorb toxins bound to albumin. difference. Adsorption resins are high molecular polymers with a network structure, including neutral and anion-cation exchange resins. Adsorbent resin is used more clinically, its adsorption capacity is slightly inferior to that of activated carbon,

Artificial liver Water-based substances such as bile acids, bilirubin, free fatty acids, and amides have higher adsorption rates. Adsorbent resin has a good effect of removing endotoxin and cytokines, and its selective endotoxin binding effect can significantly improve the symptoms of poisoning in patients.

At present, hemoperfusion is one of the methods of artificial liver, which is mainly used for severe coma of severe hepatitis, which is accompanied by sepsis, cholestasis and pruritus. The disadvantage of hemoperfusion technology is that it cannot effectively adsorb small molecule poisons. Protein-bound toxins also have poor adsorption capacity. Because of the use of non-specific adsorbents, in addition to the removal of toxic substances, some liver cell growth factors and hormones are also removed. If the adsorbent is poorly biocompatible, it may also activate the complement system and cause systemic inflammatory reactions.

Artificial liver plasma exchange

Plasma exchange is a commonly used artificial liver technique. The classic method is to extract the patient's blood, separate the plasma and cell components, discard the plasma, and return the cell components and the supplemented albumin, plasma, and equilibrium fluid to the body to achieve the purpose of removing pathogenic mediators. Modern technology can not only separate whole plasma, but also isolate a certain type or a certain type of plasma components to selectively or specifically remove pathogenic media, further improving the efficacy and reducing complications. The early commonly used plasma separation method was a closed centrifugal plasma separator. In the late 1970s, a membrane plasma separation device appeared. Whole blood directly filtered out plasma through the membrane, making plasma exchange more technically simple and practical. At present, the membrane separation method is mostly used for treatment. The membrane plasma separator is a hollow fiber type or a flat plate filter made of a high molecular polymer. The hole allows the plasma to be filtered, but can block all the cell components.

Disadvantages of artificial liver plasma exchange

Potential infections (pathogens not detected by current detection methods, HIV, etc.), allergies, citrate poisoning, etc. blood

Plasma exchange After the plasma replacement treatment, the concentration of the pathogenic medium in the blood can be increased again for two reasons. First, because the cause has not been removed, the body will continue to generate the medium, and it may also be due to its low concentration. The stimulation of the body is accelerated; the second is that the pathogenic medium may be redistributed in body fluids. Plasma exchange is currently a more mature liver replacement therapy. Despite the rapid development of various biological and non-biological artificial liver technologies, plasma exchange is still the main and basic artificial liver treatment method for patients with liver failure at present. For most diseases, the therapy does not affect the basic pathological process, still It is not etiological treatment, so while treating, the treatment of the cause must not be ignored.

Artificial liver continuous blood purification technology

Artificial liver With the continuous research on the pathophysiology and pathogenesis of acute renal failure and the gradual innovation of blood purification technology, researchers have found that the traditional intermittent hemodialysis technology has its unavoidable defects. It can cause hemodynamic instability during the rapid removal of solute moisture and may increase kidney damage. Prolong the recovery time of acute renal failure. In 1977 Kramer and others first proposed the concept of continuous arteriovenous hemofiltration, which largely overcomes the shortcomings of intermittent hemodialysis, thereby marking the birth of a new blood purification technology-continuous renal replacement therapy.

Research Status of Artificial Liver

In recent years, this technology has developed vigorously at home and abroad, and the scope of clinical applications has been expanding. It has expanded from the initial improvement of the efficacy of critical acute renal failure to the emergency treatment of various clinically common critical cases, such as acute liver failure. Hepatorenal syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, etc. have been successfully applied. It is usually the first choice for clinical treatment of severe patients, especially patients with hemodynamic instability and severe hypercatabolism. It can control water, electrolyte and acid-base balance, maintain homeostasis, and ensure the need for a large amount of liquid input to intake sufficient protein and heat energy.

However, with the expansion of the application of this technology, some people have questioned its "blood purification" ability: First of all, further research on the effect of TNF clearance is needed, because active TNF mostly exists in the form of trimers, and monomers Most of them bind to soluble receptors with a molecular weight of 27-33KD, which is greater than the membrane retention, which limits the clearance of TNF. Secondly, due to the interaction between cytokines, the charge, the hydrophilic and hydrophobic sites of the membrane, and the characteristics of binding to proteins and the role of cell receptors, especially the convection and adsorption transport of cytokines through the filter membrane are ever-changing. It affects the ability of the high-permeability filter to remove cytokines, and it is difficult to achieve a satisfactory clinical effect.

Artificial liver molecular adsorption recycling system

Recently, the molecular adsorption recycling system (MARS) for clinical use is composed of albumin recycling system, activated carbon, resin, and dialysis. It can remove fat-soluble, water-soluble, and large-, medium-, and small-molecular-weight compounds bound to albumin. Toxins also have a good regulation effect on water electrolyte and acid-base imbalance. The molecular adsorption recycling system includes three cycles: blood circulation, albumin circulation, and dialysis circulation.

The advantage of MARS is that the intermediate protein and plasma do not come into contact with activated carbon and anionic resin. There will be no adsorption and destruction of coagulation factors and proteins, and no loss of liver cell health.

Artificial liver Growth factors and other nutrients have the advantages of stable hemodynamics, continuous removal of small and medium molecule toxins, and correction of electrolyte disorders. MARS artificial liver is mainly used to improve the brain function of hepatic encephalopathy in severe hepatitis, improve hemodynamics and liver synthesis, and has a good therapeutic effect on hepatorenal syndrome.

Artificial liver biotype or combination biotype artificial liver

This is an artificial liver support system that combines the organs, tissues and cells of the same or different animal with special materials and devices.

Bio-type artificial liver includes conventional isolated liver perfusion, human-mammalian cross perfusion, and initial in vitro bioreactor (containing liver tissue homogenate, fresh liver sections, liver enzymes or artificially cultured liver cells, etc.).

Artificial liver research history

Early biological artificial liver devices were gradually abandoned due to uncertain effects, large side effects and complicated operation.

In the late 1980s, biological artificial liver generally refers to an in vitro biological response system based on artificially cultured liver cells. It not only has liver-specific detoxification functions, but also has higher efficacy, such as participating in energy metabolism, having biosynthetic transformation functions, and secreting active substances that promote liver cell growth. Because the toxic substances in the plasma of patients with liver failure have damage to the hepatocytes in vitro, the current bioartificial liver generally uses activated carbon adsorption or plasma replacement to remove some of the toxic substances in the patient's plasma, and then exchanges substances with the liver cells in the reactor. . This type of device that combines non-biological and bio-type artificial livers is the so-called combined bio-artificial liver. Animal and preliminary clinical studies suggest that this type of artificial liver device has a certain effect on fulminant liver failure.

Domestic status of artificial liver

Artificial liver mockup At present, biological artificial liver support instruments have been approved by the State Drug Administration in China and can be used for clinical treatment. The instrument is composed of a biological culture device and a mixed plasma pool, and forms a hybrid artificial liver support system with functions such as plasma separation, plasma adsorption, and plasma exchange. It has the characteristics of high degree of automation, simple operation, safety and reliability. The clinical results of the treatment of severe hepatitis showed that the effective rate was 36.7%, the effective rate was 46.7%, and the total effective rate was 83.3%. Except for individual bio-artificial liver therapy instruments, which are composed of human C3A cells (human liver fibroblast carcinoma, etc.), the rest mostly use pig liver cells as the biological part. These bioartificial livers are currently undergoing phase II / III clinical trials and have not yet received FDA approval.

Disadvantages of artificial liver bioartificial liver

The first is the use of in vitro cultured heterologous / heterologous hepatocytes and tumor cells that may cause allogeneic rejection, and may have potential zoonotic diseases and carcinogenic risks. Second, the ability of in vitro cultured cells to replace natural livers is limited, and is limited by the hepatocyte culture technology, large-scale production, preservation, and transportation of biological materials, which limits the clinical promotion of biological artificial livers.