For the first time, a real pathogen has instigated a real disease process in an artificial organ, and scientists are really, really pleased. As far as scientists are concerned, the whole point of an artificial organ—in this case, a liver-on-a-chip platform—is to simulate a real organ’s physiology, and that includes pathophysiology. By using an artificial liver to model the interactions between human tissue and an infectious agent—in this case, hepatitis B—scientists based at Imperial College London have opened a new front in disease research and, potentially, the development of new drugs.
“This is the first time that organ-on-a-chip technology has been used to test viral infections,” said Marcus Dorner, Ph.D., a researcher at Imperial's School of Public Health. “Our work represents the next frontier in the use of this technology. We hope it will ultimately drive down the cost and time associated with clinical trials, which will benefit patients in the long run.”
Hepatitis B virus (HPV) is currently incurable and affects over 257 million people worldwide. Development of a cure has been slow because there is no model system in which to test potential therapies.
However, the Imperial team showed that liver-on-a-chip technology originally developed at MIT, the University of Oxford, and biotechnology company CN Bio Innovations could be infected with hepatitis B virus. Details of this work appeared February 14 in the journal Nature Communications, in an article entitled “3D Microfluidic Liver Cultures as a Physiological Preclinical Tool for Hepatitis B Virus Infection.”
“Here, we describe a 3D microfluidic primary human hepatocyte system permissive to HBV infection, which can be maintained for at least 40 days,” wrote the article’s authors. “This system enables the recapitulation of all steps of the HBV life cycle, including the replication of patient-derived HBV and the maintenance of HBV cccDNA [covalently closed, circular DNA].”
Essentially, the scientists demonstrated that their liver-on-chip platform could be infected with HBV at physiological levels, and that it responded to the virus much like a real human liver, exhibiting immune cell activation and other markers of infection.
“We show that innate immune and cytokine responses following infection with HBV mimic those observed in HBV-infected patients, thus allowing the dissection of pathways important for immune evasion and validation of biomarkers,” the authors continued. “Additionally, we demonstrate that the co-culture of PHH [primary human hepatocytes] with other nonparenchymal cells enables the identification of the cellular origin of immune effectors.”
By uncovering the virus's intricate means of evading inbuilt immune responses, the liver-on-a-chip platform provides information that could be exploited for future drug development.
Although this technology is in its early stages, the researchers suggest that it might eventually enable patients to have access to new types of personalized medicine. Rather than using generic cell lines, doctors in the future could potentially use cells from an actual patient and test how they would react to certain drugs for their infection, which may make treatments more targeted and effective.
“Once we begin testing viruses and bacteria on other artificial organs,” noted Dr. Dorner, “the next steps could be to test drug interaction with the pathogens within the organ-on-chip environment.”
Organs-on-chips house live human cells on scaffolds that are physiologically, mechanically, and structurally similar to the emulated organ. Drugs or viruses are passed through the cells via tubes that simulate blood flow through the body. The living cells used in tests last much longer on the chip than in traditional laboratory methods, and require lower infection doses compared to traditionally used model systems.
Besides organs-on-chips for the liver, there are organs-on-chips for the heart, kidneys, and lungs. These artificial organs, the authors say, might all be useful in studying how tissues interact with pathogens, which would help researchers better understand the mechanisms of infectious disease. Artificial organs, then, could lead to new drugs and treatments for diseases that affect different organs.