Frost & Sullivan releases the 'Blue Book on the Current Situation and Development Trends of China's Artificial Liver Industry' (with full text available for download)

Liver failure is a common and severe liver disease syndrome in clinical practice. It is characterized by numerous causes, complex pathogenesis, and rapid progression of the condition.

Liver failure is a common and severe liver disease syndrome in clinical practice. According to the 'Guidelines for the Diagnosis and Treatment of Liver Failure (2018 Edition)', liver failure is a serious liver injury caused by multiple factors, leading to severe impairment or decompensation of synthetic, detoxification, metabolic, and biotransformation functions, resulting in jaundice, coagulation dysfunction, hepatorenal syndrome,hepatic encephalopathyA group of clinical syndromes mainly characterized by ascites, etc. Based on medical history, onset characteristics, and the rate of disease progression, liver failure can be divided into four categories: acute liver failure,subacute liver failureChronic and subacute liver failure, as well as acute-on-chronic liver failure.

Source: Analysis by Frost & Sullivan

Multiple factors such as hepatitis viruses, drugs, alcohol, autoimmune diseases, etc., can lead to liver failure. In China, the main cause of liver failure is hepatitis viruses, followed by drugs and hepatotoxic substances (such as alcohol, chemical agents, etc.). In children, liver failure can also be seen in cases of genetic metabolic diseases.

Source: Analysis by Frost & Sullivan

Our country has a large number of patients with liver failure, and the burden of liver failure is heavy, with huge clinical diagnosis and treatment needs.

The causes of liver failure are diverse, among which hepatitis viruses are the main cause. The global number of chronic HBV carriers is about 240 million, and there are 110 million anti-HCV positive patients. China is a country with a large number of liver diseases. With the gradual improvement of immunization programs, the prevention and control effects of viral hepatitis have gradually become apparent, but the patient population remains substantial. The 'Expert Consensus on the Health Management of Viral Hepatitis (2021)' shows that there are about 70 million chronic HBV carriers and 10 million HCV carriers in China.

In addition, there are a large number of new patients each year. According to2022 China Health Statistics YearbookIt shows that the number of newly added hepatitis patients has reached as high as 1.236 million, ranking first among infectious diseases. The mortality rate of viral hepatitis is also as high as 0.04 per 100,000 people. At the same time, due to factors such as economic development and lifestyle changes, the incidence of non-infectious liver diseases such as fatty liver disease, alcoholic liver disease, and drug-induced liver disease is gradually increasing in China, further exacerbating the disease burden of liver failure in our country.

Source: Analysis by Frost & Sullivan

Limited by the uneven diagnostic levels at the grassroots level in our country, it is difficult to unify diagnostic criteria. In addition, the occurrence of liver failure is sporadic throughout the entire liver disease system, and there are currently no official guidelines for accurately counting the prevalence and number of patients with liver failure. Liver failure is characterized by a high short-term mortality rate and a heavy disease burden. It is estimated that approximately 500,000 to 1 million new cases of liver failure occur annually in our country. The mortality rate under general internal medicine treatment can be as high as 50% to 80%, with the mortality rate for patients with stage IV hepatic encephalopathy reaching 90% to 95%.

1) Comprehensive Medical Treatment for Liver Failure - The comprehensive medical treatment for liver failure includes general supportive care, etiological treatment and specific therapies, as well as the prevention of complications. However, there is still a lack of specific drugs and methods.

General supportive treatments include bed rest, enhanced condition monitoring, enteral nutrition, and active correction of hypoproteinemia; etiological and specific treatments are divided into the treatment of HBV DNA-positive patients, drug-induced liver injury, acute fatty liver of pregnancy, orHELLP syndromeTreatment, etc.; the prevention and control of complications mainly target hepatic encephalopathy, cerebral edema, etc.

2) Liver transplantation - Liver transplantation is an effective treatment for liver failure, but it faces clinical challenges such as donor shortages, high costs, and significant surgical difficulty.

Currently, liver transplantation has become a routine procedure for treating end-stage liver disease, and its effectiveness has been widely recognized. According to data from the 'China Organ Transplantation Development Report (2020)', the cumulative survival rates of recipients of organ donation liver transplantation one year and three years after surgery were 83.6% and 74.9%, respectively, for Chinese citizens who died in 2015-2020. The cumulative survival rates of recipients of living donor liver transplantation one year and three years after surgery were 91.8% and 88.7%, respectively, among relatives.

Source: Analysis by Frost & Sullivan

However, from the perspective of current application status, there are still many important factors that severely constrain the development of liver transplantation treatment:

Lack of liver donors:The shortage of liver donors is currently a challenge affecting patients undergoing liver transplantation, as the number of available organs cannot meet the huge demand. According to data from the China Liver Transplant Registry Center, from 2018 to 2020, the annual average number of liver transplant surgeries in China was about 6,000 cases, far lower than the annual increase in the number of newly diagnosed liver failure patients, which is between 500,000 and 1 million.

Expensive:Organ transplantation surgery is expensive and a financially burdensome treatment method. The cost of liver transplantation surgery is about 600,000 to 1 million yuan (excluding donor-related processing costs), with individuals typically bearing 80% of the expenses.

The surgical difficulty is high:Due to the high proportion of critically ill patients in our country, surgery presents significant challenges, and there is still a certain gap between our survival rate and international advanced levels.

3) Artificial Liver Support Therapy - Currently, the applied artificial liver support therapy is based on blood purification and is one of the important treatment options for patients with liver failure.

Artificial liver is currently one of the effective methods for treating liver failure. It can remove inflammatory mediators and toxic substances from the patient's body, possess some of the liver's synthetic and detoxification capabilities, and has been widely used in clinical practice. There are various artificial liver treatment modalities, and the actual cost varies greatly depending on the chosen mode. Although some regions have included artificial liver treatment within the scope of medical insurance reimbursement, the reimbursement ratio is low, and most consumables need to be paid out of pocket, imposing a certain economic burden on patients.

The Report summarizes the main types of artificial liver, their usage frequency in clinical practice, and cost information. For more detailed content, please refer to the full report.

As an alternative to liver function therapy, the artificial liver system relies on the powerful regenerative ability of liver cells to restore liver function or create conditions for liver transplantation.

Artificial liver technologyAn external mechanical, physical, chemical, and biological device is used to remove various harmful substances, replenish essential nutrients, improve the internal environment, and temporarily replace some of the functions of a failing liver.

Currently, artificial liver support systems can be mainly divided into non-biological, biological, and hybrid types.The Report summarizes and categorizes the functions, technologies involved, and systems of these three types of artificial liver systems. In addition, this section elaborates in detail on the application purposes of artificial livers.Promoting the effective regeneration of liver cells is considered one of the treatment goals to improve the survival rate of liver failure. For patients with reversible liver injury, it can create conditions and time for the regeneration of their liver cells, thereby avoiding liver transplantation; patients with liver failure can improve their internal environment through ALSS treatment, creating conditions for liver transplantation or assisting in the initial non-functional state after liver transplantation. In addition, ALSS can be used as an adjuvant measure for extreme liver resection or as a supplementary treatment method under special or stress conditions of the liver.

Source: Analysis by Frost & Sullivan

The technology of non-biological artificial liver is maturing, while biological artificial liver is gradually showing good clinical application prospects.

The Report reviews the historic leaps made by artificial liver technology from basic research to clinical application since the 1950s.

With the development of membrane technology, traditional blood purification techniques such as hemodialysis, hemofiltration, and hemoperfusion have been improved. In the 1980s, emerging technologies such as hemodiafiltration adsorption, hemodiafiltration, and plasma exchange increased the efficiency of blood purification and were widely applied. Research on non-biological artificial livers continued to deepen and become more perfect. At the same time, a new generation of biological artificial livers appeared, with subsequent research focusing on long-term cultivation of liver cells, functional maintenance, design of bioreactors, cryopreservation and resuscitation of liver cells, etc.

To date, significant research and development progress has been made in both hepatocyte sources and bioreactors. Porcine hepatocytes, tumor-derived hepatocyte lines, immortalized hepatocyte strains, liver stem cells, transdifferentiated stem cells, etc., have been successively used as cell sources; hollow fiber bioreactors, flat plate single-layer bioreactors, packed fluidized bed bioreactors and other devices have been invented; oxygen supply and temperature control have been added to the reactors to improve hepatocyte activity. Technologies such as nanotechnology and microfluidics have been introduced into reactor design, and their performance has been continuously improved and optimized.

With a series of in vitro devices, various treatment technologies are derived by utilizing principles such as ultrafiltration, adsorption, osmosis, diffusion, and filtration.

Non-biological artificial liver is currently the most widely used artificial liver treatment model in clinical practice, developed from blood purification. It includes plasma exchange, hemoperfusion, albumin dialysis, as well as combined blood purification methods with hemodialysis and hemofiltration.

The Report lists seven mainstream non-biological artificial liver technologies and summarizes their technical characteristics, precautions, advantages, and disadvantages. For more detailed content, please refer to the full report.

The single-mode has simple functions and limited efficacy, while the combined mode often better meets patients' multi-dimensional treatment needs in clinical practice.

The selection of artificial liver models requires personalized treatment based on a comprehensive range of factors including the patient's cause, condition, stage of illness, actual equipment conditions, plasma reserves, family wishes, economic situation, etc. The artificial liver treatment model has gradually evolved from the initial single-method treatment to a combination of different methods. Combined non-biological artificial livers utilize their respective advantages for functional complementarity, breaking through the limitations of traditional treatments and better meeting clinical needs. Currently, the most common combination model in China is based on PE (Perfusion-Embodiment).

The Report analyzes five combination models and details their clinical application characteristics from multiple dimensions. For more detailed content, please refer to the full report.

Currently, the most clinically prevalent artificial liver support systems include the Molecular Adsorption Recirculation System (MARS system) in Europe and America, and Li-NBAL (Li's Non-Biological Artificial Liver) invented by the team led by Academician Li Lanjuan in China.

The Report takes these two non-biological artificial livers as examples and conducts an in-depth analysis of non-biological artificial liver products from dimensions such as application status and system principles. For more detailed content, please refer to the full report.

Non-biological artificial livers play a positive role in the treatment of liver failure, but there are still many difficulties that need to be resolved in clinical application.

The 'Report' summarizes the challenges faced in the clinical application of non-biological artificial livers. Starting from four key elements: plasma supply, treatment modalities, timing of treatment, and clinical efficacy, it points out that there are unmet therapeutic needs in the field of artificial liver therapy. At the same time, to a certain extent, these difficulties have also driven the rapid development of biological artificial liver technology. For more detailed content, please refer to the full report.

Biological artificial liver provides a new solution for the treatment of liver failure. Hepatocyte source and bioreactor are the two core elements of biological artificial liver.

Compared with traditional physical artificial livers, bioartificial livers have significant advantages and can solve many pain points in the treatment of liver failure.The Report further summarizes the clinical application advantages of bioartificial livers and analyzes the key development elements of core components such as hepatocyte sources and bioreactors.

An ideal hepatocyte source needs to meet the requirements of excellent liver function, sufficient hepatocyte quantity, and safety. The performance of a bioreactor is directly related to the therapeutic effect and safety of an artificial liver support system. An ideal reactor requires a reasonable design and highly biocompatible materials to ensure the functioning of the hepatocyte source and the safety of patient treatment.

Based on this, the Report summarizes four key characteristics that it needs to possess:

Source: Analysis by Frost & Sullivan

The scientific community is working towards developing practical liver cell sources, with ongoing research delving deeper into various types of liver cell sources, including animal-derived liver cells, primary human liver cells, tumor-derived liver cells, liver cell-derived liver cells, transdifferentiated liver cells, and immortalized liver cells.

The Report analyzes and summarizes the development progress and scientific research achievements of various types of hepatocyte sources. It also compares hepatocytes from different sources, considering multiple dimensions such as liver function, proliferation ability, and accessibility. For more detailed content, please refer to the full report.

Source: Analysis by Frost & Sullivan

Currently, there are mainly four types of bioreactors: hollow fiber type, perfused bed/stent type, plate type, and microcapsule suspension type.

The Report subsequently provides an intuitive summary and induction of the working principles of these four types of reactors, as well as their advantages and disadvantages during operation. For more detailed content, please refer to the full report.

Most products of bioartificial livers are in the research and development stage, with some pioneering companies having already started industrialization.

In the field of bioartificial liver, technology globally is currently in the research and development stage, with no related products on the market.The Report summarizes multiple ongoing artificial liver systems at home and abroad, systematically organizing them by type of artificial liver, cell source, reactor type, research institution, and project progress.

In terms of the application types of bioreactors, hollow fiber bioreactors possess good immune barrier functions and material transport capabilities, making them the most widely used bioreactors at present. In terms of the type of cell source, most of the systems under research in China use human hepatocytes, while overseas projects mostly use porcine hepatocytes or liver cancer cells.

For more detailed content, please refer to the full report.

Source: Analysis by Frost & Sullivan

ELAD from Vital therapies, USA^®It is currently the bioartificial liver system with the most clinical cases, accumulating a large amount of clinical data and research results. The Report reviews ELAD^®The system's previous clinical explorations include three phase III clinical trials conducted at multiple trial sites globally, namely in China from 2006 to 2007, in the United States, Europe, and Australia from 2013 to 2015, and in the United States and Europe from 2016 to 2018. The clinical significance of reproducing these historical data is reemphasized.

• HepAssis2^®system

Source: Analysis by Frost & Sullivan

Biological artificial liver is a composite device that combines medical technology with cell therapy, possessing both technical and product attributes. There are also two regulatory models coexisting: one as medical technology regulation, and the other as regulation of drug-device combinations. The clinical treatment application of biological artificial liver is gradually becoming standardized, and the review and approval mechanism is increasingly perfecting itself.

The Report provides an in-depth review and analysis of the audit approval process. For more detailed content, please refer to the full report.

Source: Analysis by Frost & Sullivan

From upstream suppliers, midstream manufacturers to downstream end channels of bioartificial liver,The Report has sorted out the participants in the industrial chain and further analyzed the many barriers they face in the development process of the industry. For more detailed content, please refer to the full report.

The biologic artificial liver industry is driven by multiple favorable factors. The Report provides an in-depth interpretation from three perspectives: treatment demand, technological innovation, and policy benefits, revealing the driving forces behind the development of the biologic artificial liver industry.

Based on the current market situation and development dynamics, the 'Report' conducts a professional analysis and prediction of the future development of the bioartificial liver industry, and makes the following prospects:

1) There are significant individual differences among patients with liver failure, and an era of personalized and precise artificial liver treatment for patients may be upon us;

2) The business model of bioartificial liver is gradually being established, and the construction of a complete supporting blood purification center will promote the healthy development of the industry;

(3) The accessibility of bioartificial liver products has increased, benefiting more patients after penetration rates improve, and the market will continue to expand;

4) The industrialization process of bioartificial livers is accelerating, and the demand downstream of the industry is expanding, which will effectively drive the progress of upstream industries.

The influx of capital will boost the clinical transformation of bioartificial liver technology and accelerate its industrialization pace.

The Report summarizes the financing progress of several biologic artificial liver companies in recent years.Currently, companies that are at the forefront of financing progress include Tonggan Medical Sciences and Micro-Zhi Zhuo Biotechnology.For more detailed content, please refer to the full report.

Wuhan Tonggan Medical Technology Co., Ltd. was established in 2013 and is a leading enterprise in the industrialization of bioartificial liver technology in China. The company's main business revolves around the development of medical devices, bio-new materials, drugs, and other series products related to bioartificial liver, as well as the promotion of bioartificial liver treatment technologies. The company has developed a new HepAssis2 model.^®As the world's first bioprosthetic liver treatment technology to enter commercialization, in the future, the company will collaborate with multiple enterprises and research institutions on the bioprosthetic liver project, aiming to develop towards a full industrial chain that includes basic research & development, medical technology services, medical device consumables, and bio-high-value materials, accelerating the industrialization process of bio-artificial livers.

Shanghai Weizhijiao Biotechnology Co., Ltd. was established in 2015. The company possesses internationally leading cell differentiation and production technologies and is a new biopharmaceutical technology company focusing on severe liver diseases and cell therapy. The Hepacure bioartificial liver under development by the company is dedicated to providing better clinical solutions for patients with liver failure.

Guangdong Qianhui Biotechnology Co., Ltd. was established in 2011 and is a high-tech enterprise dedicated to the research, development, and production of biotechnological technologies such as "composite bioartificial liver" and organoids. Currently, it possesses a full-dimensional bioartificial liver technology solution and a product pipeline related to artificial livers, gradually forming an industrialization pattern with one center, two cities, and two bases.

Shanghai Sailive Biotechnology Co., Ltd. was established in 2013 and is located in the Zhangjiang High-tech Core Park. The company has built a new generation of bioartificial liver system ALiver™, focusing on providing novel cell therapy solutions for patients with liver diseases, and is committed to becoming a leader in the international field of liver disease cell therapy.

Shandong Yiruite Biotechnology Co., Ltd. was established in 2019, headquartered within the Zhangjin Comprehensive Bonded Zone (Shandong, China). The company is dedicated to the research and treatment of liver diseases. Its ELAD bioartificial liver is currently the world's leading extracorporeal liver-assisted treatment device. It also has an integrated cell bioreactor industrialization center within the bonded zone.

Guanhao Biotechnology Co., Ltd. was established in 1999 and is located in Guangzhou. The company continues to expand its business in the fields of biomaterials, cell stem cells, pharmaceuticals, as well as advanced medical technology and products. The wholly-owned subsidiary, Beihao Research Institute, relies on Professor Deng Hongkui's CiPS and EPS technologies from Peking University to conduct research on bioartificial liver cell therapy technology.