A New Way to Test Drugs: in Mice With Human Livers

By Joseph Castro | July 12, 2011 5:15 pm

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What’s the News: While mice are a major tool for biomedical research, they’re not always useful for testing the toxicity of pharmaceutical drugs because their livers don’t react to drugs the same way that human livers do. But in a new study, published in the journal PNAS, scientists at MIT have gotten around this issue by implanting mice with miniature, humanized livers. Researchers may be able to use the artificial organs to help create drugs for diseases like hepatitis C, which mice don’t normally contract, and improve the development of other drugs. “In the near term, we envision using these mice alongside existing toxicology models to help make the drug development pipeline safer and more efficient,” said MIT biomedical engineer Alice Chen (via LiveScience).

How the Heck:

  • The MIT team first developed tissue scaffolds that are the same size, shape, and texture of contact lenses. In the scaffolds, the researchers combined human liver cells (hepatocytes), which quickly lose their function after being removed from the body, with other mouse and human cells for nutrients and support.
  • After the researchers implanted the scaffolds into the mice’s abdominal cavities, it took the artificial livers about a week to fully integrate into the animals. The researchers did not remove the mice’s existing livers. The scaffold gel is able to partially protect the foreign cells from the mice’s immune systems, giving researchers weeks to test drugs on the humanized livers.
  • The team tested the artificial livers by injecting the rodents with the compounds coumarin and debrisoquine, which mice and humans break down differently. The mice produced the same metabolites—breakdown products—that humans do.

What’s the Context:

  • Scientists created “chimeric” livers last year by repairing damaged livers in mice with human liver cells. An issue with this method is that it takes months for the chimeric livers to form.
  • Additionally, this technique requires that the mice have weakened immune systems, so that their bodies don’t immediately reject the human cells; this limits the use of the chimeric livers in studying certain diseases, according to an article from MIT.

The Future Holds: The researchers are now studying how the artificial livers respond to other drugs whose human metabolites are known. They are also working on developing humanized livers that are even smaller.

(via Nature)

Image: Wikimedia Commons/Rama

CATEGORIZED UNDER: Health & Medicine
  • Professor Pranab Kumar Bhattacharya MD(cal) FIc Path Professor and Head of Pathology; Calcutta school of Tropical medicine CR Avenue Kolkata-73 West Bengal; India

    Title-Stem cells can be used to generate a new hepatocytes for transplantation in Liver failure
    Professor Pranab Kumar Bhattacharya MD(cal) FIc Path Professor and Head of Pathology; Calcutta school of Tropical medicine CR Avenue Kolkata-73 West Bengal; India

    The current consensus in the field that organ transplantation is the primary treatment for chronic liver disease like cirrohosis of liver and acute liver failure. Presently, orthotopic liver transplantation (OLTx) is the only treatment that improves the survival rate in patients with ALF. Throughout the world, there is a significant shortage of organ donors like liver and donation of any organ depends on a persons’ motivation and will to donate his or her organ, even after his brain death and no laws in the country can force a person to donate his or her organ and not even of a corpus. The availability of an organ so depends on the local market system, though in some country like India , selling and buying of any organ is strictly prohibited by legislation. Not only are there not enough livers, but the surgery for liver transplant itself is traumatic, expensive, requires specially trained liver transplant team and these individuals who underwent liver transplant must live on immuno suppressants drugs for the rest of their lives which is again too costly. The success rate of Liver Transplant in India specially in Kolkata is also very low. Taken as a whole, the liver transplant solution is incredibly expensive with a low success rate and only helps a small number of people affected with liver disease. However, recent research into artificial livers shows many probably show promising developments.
    Biologic liver support methods are based on the use of XENOGENEIC livers or hepatocytes—parenchymatous cells of the liver—to support the failed human liver5. These methods exploit the functions of biological cells, namely detoxification, metabolism (biotransformation), and biosynthesis. The foundations of biologic liver support were laid in 1932 when Krebs and Henseleit demonstrated metabolic function in ex vivo samples of animal livers. More than two decades later, Otto et al became the first designers of an experimental animal extracorporeal ex vivo liver perfusion system. The first clinically applied biologic liver support, using a baboon liver, was reported in 1980. The contemporary era of biologic liver support began in 1975 when Wolf and Munkelt utilized isolated hepatocytes. During the past two decades, technologic advances in liver cell isolation and culture and improved biomaterials have formed the research base for the development of a variety of liver-assist devices. A number of problems have not yet been fully solved, which demand further laboratory and clinical research before a truly effective liver support device can be developed; including enhancement of the cultured hepatocytes’ preservation and longevity, and better understanding of the biology of liver cell function and injury.
    The first report of successful isolation of hepatocytes using collagenase perfusion dates back to 19698. Although a number of animal trials of hepatocyte transplantation have yielded encouraging results, evidence of long-term survival and function of transplanted human hepatocytes has been tantalizingly slow to come.1 Survival of isolated rat hepatocytes transplanted into the red pulp of the spleen was described in the late 1970s.2 This and subsequent experimental studies focused on transplantation of ectopic hepatocytes—cells transplanted to non hepatic body regions such as the peritoneum, lungs, fat pads, and subcutaneous tissue. A number of studies have demonstrated that, in fact, ectopic hepatocytes are functional and able to proliferate extensively.3,4
    The most successful transplantation of hepatocytes has been into the liver, where the engraftment causes transitory (2–3 hours) portal hypertension.4 The published literature suggests that transplanting 1–5% of liver mass might be sufficient to restore adequate functional activity and normal metabolic parameters to the failed liver.5 Evidence of the effectiveness of the transplanted hepatocytes is typically based on anecdotal case reports.6, 7, 8
    Contemporary bioartificial liver support systems aim to provide adequate functional organ replacement. This is potentially possible because perfusion through a sufficiently large number of hepatocytes could help to overcome liver failure and provide a safe bridge to OLT or recovery. This method is based on a biologic reactor containing a matrix supporting cultured cells. The patient’s blood flows through the reactor cartridge, plasma is ultra filtrated through the fibers into the cartridge’s extra capillary space, and comes into contact with the hepatic cells. The exchange of metabolites is dependent on cell viability and metabolism. Human cells (allogeneic), animal cells (xenogeneic), and cell lines from immortalized liver cells or tumor cells (HepG2cells) have been used.8 Xenogeneic cell lines carry greater immunologic and zoonotic risks. The strategy of providing an adequate mass of human liver cells is based on the immortalization and spontaneous or genetic manipulation of human hepatocyte cultures, so that the cells maintain the full repertoire of liver functions. The possible use of these cells for transplantation is hindered by the theoretical risk posed by the viral manipulation needed to derive the cells: the hepatocytes might rapidly lose liver-specific functions and die8 At present there are two types of biologic reactor in use, the Extracorporeal Liver Assist Device (ELAD, Vital Therapies, Inc., San Diego, CA) and the Bioartificial Liver (BAL, HepatAssist, Circe Biomedical, Lexington, MA), which can be distinguished on the basis of the cell source used for the bioreactors.
    The Extracorporeal Liver-Assist Device8
    Over the past two decades, researchers around the world have made significant progress in the creation of a functioning artificial liver. In particular, there have been many successes in engineering artificially grown liver cells that replicate the liver’s functions with designs functioning both inside and outside of the body. The extracorporeal liver assist device, or ELAD, is one such achievement. Connecting this machine to individuals with liver failure has allowed many individuals to survive long enough until an organ becomes available and has even been successful in treating acute liver failure . It also provides extra support to the liver, giving the organ time to regenerate itself. As ELAD undergoes more clinical trials, an increasing number of hospitals across the United States are beginning to offer it as a therapy for liver disease patients. The FDA is asking for three to 10 days of ELAD liver support to improve the 30-day survival that the similarly ill get with today’s standard supportive care.The ELAD system uses the C3A clone of the HepG2 cell line. Clinical testing of this system began in 1996 and indicated the need for better prognostic indices a recently published trial demonstrated how the ELAD was part of a successful bridge to OLT in five patients
    Patients are connected to the ELAD by standard dual-lumen hemodialysis catheters for central access; blood is drawn at a rate of 200 ml/min and pumped into a chamber containing ELAD cartridges (four cartridges are used for an adult patient and two for a child weighing less than 40 kg). Each of the cartridges contains approximately 100 g of C3A cells within the extracapillary space surrounding the hollow fibers. The ultrafiltrate passes through the lumen of the fibers, in which the biochemical transport occurs.
    ELAD is easily reproducible and its use is typically straightforward. The system’s current design provides greater metabolic activity, and incorporates an oxygenator and a glucose infusion pump to support the hepatocytes. The clinical safety results obtained so far have been encouraging. The limited number of patients treated so far does not, however, allow us to ascertain the device’s full safety profile and potential efficacy.
    At BioEngine, a rising firm in biotechnology, researchers created a similar device designed to function within the human body. This structure would theoretically provide a bio artificial scaffold for human liver cells to grow and function normally. In other aspects of the field, biologists have been able to grow artificial liver cells from embryonic stem cells, human hepatocytes, and porcine hepatocytes. Although these technological advances are large steps towards developing a solution to liver failure, scientists still have a long way to go, as there are many biological, ethical, and economic reasons that are hindering artificial liver development.

    The world’s first artificial liver had been grown from stem cells by British scientists in 2006. The resulting “mini-liver” is the size of a small coin; the same technique will be further developed to create a full-size liver. The mini-liver is useful as it is; within two years it can be used to test new drugs, reducing the number of animal experiments as well as providing results based on a human (rather than animal) liver. The stem cells used by Drs. McGucklin and Forraz in this research are gathered from umbilical cords (“cord blood”), seen by some as a more ethical alternative to stem cells created from human embryo. However Liver cells could be grown from Induced Skin stem cells or even bone marrow stem cells. The creation of efficient human liver cells requires a large amount of time, money, and resources, which adds to the overall costs of these therapies for a small yield of available cells. As a result, many of these therapies are not economically sound and cannot be available to the general public. Many scientists believe that developing more cost effective designs will be the focus of artificial liver research over the next decade. There is already an ongoing public debate on the ethical issues of using embryonic stem cells for research.. From a biological point of view, there are concerns of porcine cells possibly transferring viruses from pigs to humans. Addressing these concerns in these current technologies will allow for further progress within artificial liver research.
    1Chowdhury JR et al. (1998) Human hepatocyte transplantation: gene therapy and more? Pediatrics 102: 647–648 | Article | PubMed | ISI | ChemPort |
    2 Mito M et al. (1979) Studies on ectopic liver utilizing hepatocyte transplantation into the rat spleen. Transpl Proc 11: 585–591 | ChemPort |
    3.Darby H et al. (1986) Observations on rat spleen reticulum during the development of syngeneic hepatocellular implants. Br J Exp Pathol 67: 329–339 | PubMed | ChemPort |
    4.Selden AC et al. (1991) Further observations on the survival, proliferation and function of ectopically implanted syngeneic and allogeneic liver cells in rat spleen. Eur J Hepatol Gastroenterol 3: 607–611
    5. Selden C and Hodgson H (2004) Cellular therapies for liver replacement. Transpl Immunol 12: 273–288 | PubMed | ChemPort |
    6. Soriano H (2002) Liver cell transplantation: human applications in adults and children. In: Hepatocyte transplantation: proceedings of Falk Symposium 126 (Progress in Gastroenterology and Hepatology Part III) held in Hannover, Germany, October 2–3, 2001, 99–105 (Eds Gupta S et al.) Dordrecht, Boston, London: Kluwer Academic Publishers
    7. Strom SC et al. (1997) Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation 63: 559–569 | Article | PubMed | ISI | ChemPort |
    8. J Michael Millis* and Julian E Losanoff Technology Insight: liver support systems Nature Clinical Practice Gastroenterology & Hepatology (2005) 2, 398-405

  • Deepa Agarwal

    Thank you Professor Pranab Kumar Bhattacharya for shareing ur view regarding ARTIFICIAL LIVER.
    Artificial Liver can save many people but due to its transplantion cost everyone will be not benefit from this..as
    “artificial liver” in 2006 had been grown using stem cell by british Scientist..it can stop ethies on animal experiment..but how can cost be reduced so that it can reach to normal croud? Most of the needed people dont know about this technique..


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