BioEngine: One Step Closer to Artificial Liver Device

As the title suggests, this article looks into the developments of BioEngine, a firm focusing upon the development of artificial liver technology. In particular, the company is trying to create support structures that will allow specialized cells to "grow and function outside of an actual organ". Back in 2007, the company hoped to get FDA clearance to perform its first human trials within two years. I did a little bit a research on the company's website, but I did not find any information confirming whether or not BioEngine actually got its approval. However, it appeared as if the website had not been updated in a long time.

The goal of BioEngine is to create "three-dimensional structures that could provide a foothold for human cells" and to then commercialize the technology. The first few prototypes failed, but after completely starting from the scratch, the new designs are starting to show some promise. There are several challenges that engineers must overcome when designing these structures. First off, the cells must be really close to blood vessels in order to exchange nutrients and toxins. As a result, the vessels must branch into ever smaller vessels via a mechanism that does not cause the blood to clot. Researchers originally created channels with flat edges, and this method did not work. BioEngine then teamed up with ExOne, and with their expertise, they created a structure with rounded out grooves, allowing the blood to flow smoothly.



Conceptually, this idea seems to have a lot of promise, but I am not entirely convinced that it will functionally work. The article discusses the challenges of blood clotting, but I think that there are far more serious questions that need to be answered. What kind of cells will they put into the device? Will these cells be able to successfully function within this artificial environment? If an individual's liver is missing a specific function, adding a "simple" one cell type artificial liver seems like a good solution. Given all of the research, I think that this therapy will be incredibly expensive, and it only help a certain sub-population of those with liver disease. Regardless, I found the article very interesting, and I think that it taking a good step towards the production of a truly artificial liver.

-John

Wade Roush, Xconomy, 9/20/07
http://www.xconomy.com/2007/09/20/bioengine-one-step-closer-to-artificial-liver-device/

Researchers Aim To Cut Future Need for Liver Transplants

Several years ago, a group of scientists headed by James Ross at the University of Edinburgh discovered primitive liver cells that have the potential to differentiate and repair a damaged liver. Their hope is that theses cell will be able to provide an alternative treatment to liver transplantation because these cells can mature into different cell types both in and out of the body. Some researchers believe that these cells potentially lie dormant within the liver itself. If found, surgeons could then transfer the undifferentiated cells to locations within the damaged liver in order to repair the organ.

This potential treatment is remarkably similar to the liver's natural healing process. The liver repairs itself through three primary mechanisms. First of all, prior research has shown that mature liver cells inherently divide quickly in response to damage. Secondly, some liver repair results from stems cells circulating in the blood stream. The body recruits these cells from the body, and they differentiate to form new liver cells. The third type of liver repair involves the cell type described in this article. This mechanism only responds when the liver undergoes a significant amount of damage. In response, a specific population of primitive liver cells begins to divide and differentiate. Scientists hope to use this last method in order to develop a new treatment for liver failure. Consequently, the origin and cause of the third mechanism will be play an important role in future research.

So far, there have been several reoccurring themes within the development of artificial livers. It is fact that liver transplants are incredibly expensive, and to complicate matters, there are far too few donors. Researchers are currently looking into several mechanical, extra-corporeal liver alternatives, but none of them are cost effective. As a result, there is strong pressure to develop a new treatment because liver failure is currently a fatal disease. This theoretical technique of harnessing primitive liver cells conceptually overlaps with ideas from regenerative medicine and stem cell technology. In this case, the stem cells can potentially be retrieved from the body itself, and subsequently, doctors will simply be activating the body's natural healing response. My guess is that this method would be substantially cheaper than many of the other artificial liver alternative, and as a result, it has a lot of potential.

-John

No author given, Science Daily, 07/07/06
http://www.sciencedaily.com/releases/2006/07/060706175049.htm

Artificial liver support at present and in the future

This article discusses and summarizes the current as well as future treatments for liver failure. Currently, liver failure is a fatal disease with significantly high mortality rate, and the primary solution involves a liver transplant. This method has numerous complications, and there is a continuous shortage of available organs. The authors suggest that plasma exchange and continuous hemodiafiltration are currently the two most potential treatments for the disease, but they are still a long ways off from the ideal solution. In the best case scenerio, bioartificial liver support, gene therapy and regenerative medicine will lead to the development of a functional artificial liver.

The article takes a different perspective because the authors are from Japan. Since the Japanese health-care insurance program differs from that of the United States and Europe, Japanese researchers approach the treatment of end-stage liver diseases from a different angle. In Japan, it is illegal to run clinical trials with biological artificial livers. As a result, researchers focus on specific aspects of bioartificial liver development that do not use the liver itself.

There are many different techniques being researched to replace the liver's role in detoxification, metabolism, and regulation, but so far, none of the the controlled clinical trials have yielded the expected benefits. The bioartifical livers are both too complex and too expensive to be used as a regular treatment. Some of the blood purification techniques are becoming standard treatments, but they can only do so much. The conclusion of this article is that a significant amount of research still needs to be done before society can benefit from an affordable and functional artificial liver.

-John

Kazuhiko Onodera, Journal of Artificial Organs, 4/14/06
http://www.springerlink.com/content/rk22478g36373872/fulltext.pdf

Artificial Liver May Extend Lives (June 2, 2009)

This article provides an accurate representation of the current progress and uses of the artificial liver, or Extracorporeal Liver Assist Device (ELAD). According to the article, artificial livers have been in trials since the 1960’s, but have had little success. Problems have arisen due to complications such as the difficulty in creating chemicals essential to metabolism and blood clotting. However, with the advances in technology and the ability to grow human cells in culture and then implant these immortalized hepatocytes onto some type of synthetic material, ELADs have overcome many of the earlier issues. Due to this technology and increased success rates, the population eligible to be put on the ELAD has expanded. Now, there are more hospitals around the U.S. that are offering this therapy to acute liver failure patients as part of clinical trials. Thus far, the results of ELAD are very promising and “thirty day transplant survival rates were statistically higher in the ELAD group compared to the control,” which consisted of standard therapy. If clinical trials continue going well, the use of ELAD will expand even more, and may become a standard procedure for acute liver failure patients in a few years.

This progress in liver treatment will most likely prolong life by assisting people who have liver failure until a transplant can be received. While the ELAD itself is not sufficient to sustain life for a long period of time, scientists are hoping that while on ELAD, livers will be able to regenerate and gain back normal function. This would not only save a person’s life, but will also eliminate the need for a transplant.

-Mark

Belinda Mager, Bio-Medicine, 6/2/09

http://www.bio-medicine.org/medicine-news-1/Artificial-liver-may-extend-lives-47650-2/

Doctors test latest attempt at artificial liver (February 2, 2009)

Back in February 1999, a trial was put into place to test the ELAD (an Extracorporeal Liver Assist Device.) As of 2009, ten years later, the ELAD has still not been implemented in our health care system. This article, published ten years after the first testing trial, states that doctors are again experimenting with the device and trying to get hospitals to utilize the machine. The article emphasizes that although this device will not replace a damaged kidney, it could buy enough time for for the damaged liver to recover on its own or sustain itself until a kidney replacement is available.

This experiment is, hopefully, the last quest to implement the use of a device that could temporarily take over some of the liver’s jobs when it is failing or damaged. It’s amazing how this device was designed in 1999 and even after ten years the device is not widely used even though it has proved its efficacy several times. In 2002, a patient named Kevin Fitzmaurice began to emerge from a coma after a day of using the liver assist device. Had Kevin not gotten on the ELAD support, he would have died before the arrival of his donated kidney. Kevin’s case is one of the primary reasons the ELAD has been brought back into testing.

However, now that doctors are trying to get hospitals to use this device, it has been under close scrutiny primarily because of the $30,000 price tag. 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. I think these standards the FDA has placed on the device are extremely reasonable, especially given the current health care situation and debate. There are many illnesses and diseases that plague this world and, of course, acute liver failure is one of them. However, there’s no point in investing large amounts of money and time in a complicated artificial liver device that won’t prove any more effective than the already existent treatments. Considering the large price tag this treatment comes with, this device should prove strong efficacy. Spending thousands upon thousands of dollars on biotechnology that doesn't prove significant efficacy, is, in my opinion, futile when there are other significant health issues that need to be addressed.

-Andrea

No author given, Associated Press (MSNBC), 2/2/09
http://www.msnbc.msn.com/id/28981937/#storyContinued

World’s First Artificial Human Liver Grown in Lab (October 31, 2006)

This article, published three years ago in October 2006, reveals that two British scientists were able to grow the world’s first artificial liver from stem cells. Using blood taken from babies’ umbilical cords just minutes after birth, the scientists were able to create tissue the size of a small coin that replicates the functions of a liver.

This scientific breakthrough can lead to significant benefits for humanity within the next several years. The article states that within two years the mini liver can be used to test new drugs, reducing the number of animal experiments and providing results based on a human rather than an animal liver. Within five years, pieces of the artificial liver could be used to repair livers damaged by injury, disease, and alcohol abuse. And in fifteen years' time, whole functioning livers could be grown in the lab and then be transplanted into the body.

This experiment could be seen as an excellent advancement in the field of tissue engineering. It’s great to see that within the next couple of years, an the artificial liver created in the lab could be used to directly benefits people’s health. Having this work be transferred from the lab to the operating table would result in significant health benefits for those suffering from a failing kidney.

This experiment has also proven groundbreaking proof that stem cell research can be done in a more ethically acceptable manner. It’s great to see an experiment that could be beneficial to the eventual reduction of human suffering without all the politically motivated debates that sometimes hinder great discoveries. If scientists are able to derive stem cells from umbilical cords, then more stem cell research should be conducted using this source. Tissue engineering and stem cell research are amazing scientific and medical breakthroughs. Omitting the constant ethical debate surrounding stem cell research, by utilizing the daily discard of millions of umbilical cords, could result in the implementation of such research in our health care system.

-Andrea

Bill Christensen, Live Science, 10/31/06
http://www.livescience.com/health/061031_artif_liver.html

HepaLife Artificial Liver Shows Promise (February 11, 2008)

Similar to dialysis where the function of the failed kidney is replaced by the dialysis machine, HepaMate functions as a bioartificial liver system. HepaLife, a biotech company in Boston, developed an artificial liver that showed positive results of tests that PICM-19 cells inside the bioreactor could function as an external liver. The PICM-19 cells are unique in their ability to maintain liver function by synthesizing 80% of ammonia present in urea and producing a significant amount of area. Both are processes that show promise of substantial clinical applications. PICM-19 cells, which are pig embryonic liver stem cells, are remarkably able to sustain these abilities while displaying characterisitics representative of human liver cells.

I found this article on MedGadget, an internet journal of medical technologies. It is actually the same press release taken from HepaLife's website, which suggests to me that there might be a financial partnership between MedGadget and HepaLife. Currently, the HepaMate is in Phase III of the clinical trials.

Despite all of these positive results, I am still skeptical of the bioartificial liver system that HepaLife is developing. There are a few questions that arise in my mind when using pig embryonic liver stem cells. How are they able to control the pig embryonic liver stem cells proliferation and differentiation in order to sustain functionality? How can they prevent a porcine viral infection from transferring to human tissues and possible creating a pandemic? Have animal rights' advocates not protested the use of pig embryonic liver stem cells in the HepaMate system? The clinical studies show that there is a definite benefit for patients with acute liver failure, but will it make a big enough difference to assist those with chronic liver failure and need a transplant? Do the benefits of the bioartificial liver system outweigh the costs? Will this technology be able to be made as available as renal dialysis machines at centers and in homes?

I don't know how to answer any of these questions, but the health care debate will have a huge impact on many of them. In the United States, liver failure is not as high a priority as kidney failure, but hopefully reforms such as expanding coverage for immunosuppressive drugs and insurance companies working to cover costs for renal dialysis will be applied to a treatment such as the bioartificial liver system as well.

-Robin

No author given, MedGadget, 2/11/08
http://medgadget.com/archives/2008/02/hepalife_artificial_liver_shows_promise.html

Biological Extracorporeal Liver Assist Devices: A minireview (January 13, 2005)

This article reviews the growth of Biological Extracorporeal Liver Assist Devices (ELAD) as an alternative to traditional organ transplantation that has been the primary method of treating chronic liver failure in past decades. However, due to the decreasing number of organ donors, high costs, high morbidity and the need to be on lifelong immunosuppressive drugs, research in ELADs could yield wider applications of the ELAD to the general public.

A scary figure from the article is that up to 90% of patients with FHF (fulminant hepatic failure) develop irreversible neurologic damage, multiple organ failure, or sepsis while waiting for a liver transplant. The liver does have the ability to regenerate and repair, but this ability is impaired after liver damage. Recently, the artificial liver development has advanced with the use of live hepatocytes and new biomaterials. Similar to the collagen of the heart being used as a scaffold for stem cells to grow, hepatocytes cooperate with the biomaterials to act as a functioning artificial liver.

Most studies in the field targeted blood detoxification and used techniques like hemodialysis and plasma exchange. None of these were shown to improve patient survival. The extracorporeal liver (ELAD) assist device was developed that used whole blood perfusion through a bioreactor with a human hepatoblastoma cell line. A study noted no significant effect on disease outcome. Another device developed in Germany is the modular extracorporeal liver system (MELS). It had a multicompartment bioreactor and capillary systems to perform functions such as cell oxygenation and carbon dioxide removal. The MELS system uses human liver cells harvested from organs unsuitable for transplant. Surprisingly, it maintained hepatocyte functions for longer than 2 months and a clinical study is in progress.

The authors themselves have created a hybrid BAL system, HepatAssist System, using cryopreserved porcine hepatocytes that is the first cell-based device in a phase II/III clinical trial and has been successful in treating acute liver failure and bridging patients until transplantation.

I am concerned of the possibilty of viral infection from pig to human tissues. There are also concerns about how and where hepatocytes are harvested from, storage, and how many hepatocytes are adequate for liver function. The variability in the different models are based on these factors as well as the actual materials used for the hollow fibers and bioreactor. With the health care reform, there is a possibility that more funding will be provided for this research in order to find a device that can be used as a basic model for all companies. Granted there would be increased competition between different companies to build the first successfully FDA-approved model, but once it is created they could cooperate in order to increase efficiency of the original design and make the artificial liver more accessible as a public option for acute and chronic liver failure

-Robin

Nozomu Sugiyama, Transplantation Reviews, July 2001

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B75B4-4F7S93K-2&_user=489286&_coverDate=07%2F31%2F2001&_alid=1121603733&_rdoc=1&_fmt=high&_orig=search&_cdi=12972&_sort=r&_st=4&_docanchor=&_ct=2&_acct=C000022678&_version=1&_urlVersion=0&_userid=489286&md5=c56c779b6061ce7dd9ef94a9bc81e274

Hybrid Bioartificial Liver (February 19, 2004)

There are approximately 1-2 million deaths worldwide every year resulting from liver failure. As of November 6, 2009, the Organ Procurement and Transplantation Network listed 15, 911 candidates on the waiting list for a liver in the United States. However, only 4, 644 liver donors were listed (4, 490 deceased and 154 living). Clearly, there is a huge need for a device that can help alleviate such a wide divide.

The treatment of liver failure using the hybrid bioartificial liver (BAL) support device is a relatively new technology stemming from the increasingly poor outcomes in acute liver failure and the limited number of organs for transplantation. Currently, BAL is used as a bridge until liver transplantation is available or until liver regeneration is complete and has also been successful in treating acute liver failure. The bioartificial liver support system combines a biological component (hepatocytes) with a synthetic component (biomaterial).

The article glosses over various cells that could be used as the biological component, gives a brief summary of a few systems on the market, and introduces the discovery of immortalized human hepatocytes lines as a source of creating hepatocytes and the BAL device being worked on. The debate with what kind of cells can be used to create hepatocytes is one that resonates with the class lecture on organ transplantation. Human embryonic stem cells, somatic stem cells, differentiated tissue cells, and cells from tissues of animal species (primarily pig) are all potential sources for creating hepatocytes. With human embryonic stem cells, the problem is difficulty to control the pluripotency of the cells and their ability to proliferate leads to the question of the patient maybe developing cancer down the road. Somatic stem cells and differentiated tissue cells have high costs and the yield is not enough to be worthwhile.

Breeding transgenic pigs for porcine hepatocytes is a viable option, but their compatibility with humans is not 100%, they have the potential to infect human tissues with porcine endogenous retrovirus (PERV), and animal rights advocates protest the breeding of transgenic pigs. A type of system available, HepatAssist System (Figure 1), a BAL support system that uses porcine hepatocytes (based on 1997 Demetriou study). As of 2004 when the article was published, Phase II and III had already been completed and the clinical study is still ongoing. What was remarkable to me was that it required 9 billion frozen porcine hepatocytes!

The authors of the article discuss the process by which they are able to reversibly immortalize human hepatocytes. First, immortalized genes are proliferated in vitro until the desired number is reached. Then, the genes needed are removed by selection markers and finally, reversion occurs to generate human hepatocytes. The entire reaction would actually be applicable to a large scale at a low cost. This technology has great implications in furthering the development of a BAL because hepatocyte cell lines can possibly de-differentiate and lose their hepatocyte ability.

This is definitely a huge step in establishing the biological component of the BAL. However, I think that clinical studies will still be necessary and it will also be important to device the synthetic component that will work well with the human hepatocyte cell lines. The BAL support system design is similar to that in renal dialysis with the same principle of counter-current blood flow over a semipermeable membrane with functioning hepatocytes on the other side. Thus, the synthetic component must contain fibers of a material that can maximize the liver's excretory and metabolic functions. With regard to the current health care debate, the reform currently includes measures to help those with chronic diseases, which includes chronic liver failure. I am uncertain whether this will include increased funding for research into a BAL device, but I am hopeful that this is a step in the right direction.

-Robin

Naoya Kobayashi, Journal of Artificial Organs, 2/19/04
http://www.springerlink.com/content/hqva24y20gcjcn07/

Developments in Bioartificial Liver Research (July 2000)

“Developments in Bioartificial Liver Research” is a review article from 2000 that discusses the progress made in artificial liver technology up to that date. Its focus is on Bioartificial Livers (BALs), and their potential for helping individuals waiting for liver transplants. According to the paper, there are three requirements for a successful BAL: “(1) a viable and highly functional hepatocyte cell line, (2) a suitable bioreactor environment and peripheral control system, and (3) an effective extracorporeal circulatory system to incorporate an artificial liver system.” The article also discusses some of the issues that need to be dealt with to have a successful and lasting BAL. Many of the issues mentioned in 2000 are still relevant today when trying to develop a functional bioartificial liver. One of the major problems is trying to find hepatocytes suitable for BAL systems. These hepatocytes can be derived from animal cell lines or human cell lines. As learned in class, xenogenic transplantations, whether in the form of cells or whole organs, present numerous complications. Porcine hepatic cells are often used, but issues such as hetoroimmunity and infection often arise. Ideally, human hepatic cells would be used, but this is more complicated due to legal restrictions and a lack of sources. In 2000, a promising endeavor was implanting human hepatic genes into animal cells. This would take care of the proliferation issue, as well as some heteroimmunity problems. As seen today, this method has provided many benefits and is more commonly used than in the year 2000. With regard to these cell lines, the most important factor is that these cells should be able to proliferate for a prolonged period of time, minimize immune response, and produce the necessary proteins and chemicals that normal hepatocytes would. The article then discusses the three dimensional bioreactor consisting of the liver cells and a hollow fiber system through which the blood plasma is delivered. The bioreactor functions to eliminate toxins and deliver liver specific proteins into the blood stream. At the time of this article, the three dimensional bioreactor was in its earliest production and trial stages. Now, it is the accepted type of bioreactor that is most effective in performing liver functions compared to the 2D bioreactor system. In addition to the bioreactor component that this article focuses on, other aspects of the liver assist device are equally as important such as the anticoagulant, the plasma separator, and the oxygenator, among other parts. As mentioned before, the expanded use of such bioartificial liver systems would have a direct impact on healthcare costs. It is also interesting to think about whether such temporary treatment should be provided to all those suffering liver failure via Medicaid, similar to end stage renal disease and kidney dialysis. This article indicates that the year 2000 marks a significant progression in bioartificial liver technology. It is around this time that biotechnologists prioritized the efficacy and success of the production of liver cell related proteins in addition to detoxification of the blood.

-Mark

Seishi Nagamori, Journal of Gastroenterology, 7/07/00

http://www.springerlink.com/content/5edyeq1qb4f46cj9/

Trial begins for the first artificial liver device using human cells (February 25, 1999)

Physicians at the University of Chicago Hospitals began clinical testing of the first artificial liver device that uses cells from humans rather than pigs. Vitagen Inc. of La Jolla, California has designed ELAD (Extracorporeal Liver Assist Device) to serve as a temporary liver support for patients suffering form acute liver failure. The device has two goals: 1.) to support the patient through a brief period of liver failure, protecting the organs for up to 10 days, giving the damaged liver time to recover without transplantation; 2.) to extend the patients ability to survive until a suitable liver transplant is available.

The system separates the plasma from the cellular components of the blood. The device pumps the patient's plasma through cell-filled cartridges. The cartridges put the plasma in contact with millions of liver cells, which should function much like a normal liver. The treated plasma is filtered and re-mixed with the cellular components of the blood, and put back into the patient.




The trial will involve 24 patients. Six patients will receive standard therapy plus treatment with the ELAD Artificial Liver. Eighteen patients will be divided randomly--nine to receive treatment with ELAD and nine to receive standard therapy.

Seven years prior to this breakthrough trial, baboon and pig livers made their way into the human body to assist patients suffering from liver failure. To me, the ELAD represents a significant advance in the quest to lessen the amount of deaths caused by liver-related diseases. The article states that there are 12,000 people currently waiting for a liver transplant and less than 4,500 viable livers donated each year. With an obvious lack of available organ donors, the ELAD could serve as a fantastic option for when a liver fails or when a viable liver fails to reach a patient for transplantation.

There have been biotechnological breakthroughs in artificial assist devices for the heart, lungs, and kidneys. However, the liver as seen no such devices even after xenogeneic transplantation was met with rejection and no permanent artificial liver. The ELAD, with its use of human cells, could possibly be more able to imitate the function of a human liver. Perhaps this device will be what the failed liver has been waiting for.

-Andrea

No author given, UChicago Medical Center, 2/25/99
http://www.uchospitals.edu/news/1999/19990225-elad.html

Artificial Liver Used After Removal of Organ (May 19, 1993)

This article gives insight into the progress of technological advances in the field of artificial livers. Published in 1993, the case mentioned in this article was one of the first in the field of medicine where a bioartificial liver ‘kept a patient alive after her own failing liver was removed.” While the bioartificial liver used at the time was a crude product compared to those used today, it fulfilled its role of keeping the patient alive until the transplant arrived 14 hours later. At the time, very few other artificial livers were employed, and the few that were resulted in death. Today, there are have been numerous cases where people are put on bioartificial livers (BALs). This method of keeping a patient alive or out of a coma as they wait for a transplant has become more common. Companies have developed more advanced bioartificial livers that may use human liver cells instead of porcine liver cells, reducing rejection from the host. At the same time that this article points out progress in artificial liver technology, it also emphasizes the fact that there is still no permanent artificial liver. BALs are solely meant to temporarily keep the patient alive until a transplant from another human arrives. This is why they are referred to as "bridging" mechanisms.

While there is no permanent liver transplant available, BALs can be beneficial when the issue of health care costs arise. The purpose of BALs are to support liver function, which leads to the possibility that the native liver will heal and ultimately rid the need of requiring a transplant for many individuals. This would save the healthcare industry a large amount of money while improving rates of recovery from liver failure as well. However, this cannot be proven. There is also the opposite possibility that BALs would increase healthcare costs. BALs are another product and if it becomes a universally accepted method for all individuals waiting for transplants, it would mean that hospitals would have to purchase more and patients would have to pay more. The bottom line is, BALs will definitely influence healthcare costs. Whether or not it will be beneficial to costs is the question.

-Mark

No author given, New York Times, 5/19/93

http://www.nytimes.com/1993/05/19/health/artificial-liver-used-after-removal-of-organ.html?scp=3&sq=artificial%20liver&st=cse