**Liver Regeneration and Bioengineering – The Emergence of Whole Organ Scaffolds**

Pedro M. Baptista, Dipen Vyas and Shay Soker *Wake Forest University Health Sciences, Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA*

#### **1. Introduction**

240 Liver Regeneration

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> Every year an estimated two million people die of advanced liver disease. The World Health Organization estimates that over six hundred and fifty million people worldwide are affected by some form of liver disease, including thirty million Americans. On a worldwide base, the bleak cenario of one to two million deaths are accounted to liver related diseases annually. From all the countries, China has the world's largest population of Hepatitis B patients (approx. 120 million) with five hundred thousand people dying of the liver disease every year(1, 2). In the US alone, there are around five hundred thousand critical episodes of liver problems every year requiring hospitalization with a huge burden to the patients and an enormous cost to the health care system. In the European Union and United States of America alone, over eighty one thousand and twenty six thousand people died of chronic liver disease in 2006, respectively(1, 3). For these patients, liver transplantation is currently the only therapy proven to extend survival for end-stage liver disease, as it is also the only treatment for severe acute liver failure and the some forms of inborn errors of metabolism. However, the waiting list for liver transplants is extensive and many on the list will not receive an organ due to a dramatic shortage of donors or not being eligible(1).

> A good example of this is that in 2007 there were nearly seventeen thousand individuals on the US waiting list for a liver transplant. Only 30% of those in need were transplanted. The average waiting time was more than 400 days. The same year, about one thousand and three hundred people died while waiting for a suitable donor with no available medical option for saving their life. Also, for those patients with fulminant hepatic failure, a severe liver disease with 60-90% mortality, depending on the cause, only 10% received a transplant. Nevertheless, liver transplantation still has a relatively high mortality of 30-40% at 5-8 years with 65% of the deaths occurring in the first 6 months. In addition, patients who have undergone transplantation have to use lifelong immunosuppressive therapy, with sometimes severe side effects(4).

> The etiologies of end-stage chronic liver disease that lead to transplantation are numerous and ~80% of people in the liver transplant waiting list have as primary diagnosis a cirrhotic liver. Fortunately, some of the causes of the disease are nowadays preventable. A good example is the successful vaccination programs in many countries in the world against Hepatitis B virus that have considerably reduced the incidence of chronic carriers and viral

Liver Regeneration and Bioengineering – The Emergence of Whole Organ Scaffolds 243

In addition to the previously mentioned four special case exceptions, a transplant center can apply for a MELD exception for a patient whose medical urgency is not reflected by the

The implementation of more fair and efficient allocation systems, improvement in the immunosupressive regimens, and the increase of living donation have all helped to increase overall patient survival and graft survival in the past decade in the United States. The number of livers transplanted also increased to a all time high in 2006, with a marked decrease on the waiting time for liver transplantation after MELD implementation,

An example of the impact of these improvements is the increase of 6% (86% in 2007) and 16% (87% in 2007) of the unadjusted 1-year graft survival for deceased donor and living donor liver recipients between 1998 and 2007, respectively. These accounts also for an improvement of 3% (89% in 2007) and 11% (91% in 2007) of the unadjusted 1-year patient survival for deceased donor and living donor liver recipients for the same period, respectively(7). However, these numbers decrease significantly for the 5-year patient survival. In 2007 it was 74% and 79% for deceased donor and living donor liver recipients, respectively. These numbers decrease even further for the 10-year patient survival, where in 2007 we had 61% and 71% patient survival for deceased donor and living donor liver recipients, respectively. One important note is that patient survival was higher than graft survival ~5%, because of the opportunity for repeat liver transplantation in the event of graft failure(8).

These numbers highlight the need for novel therapies that can increase patient survival, as well as lower costs to the health care systems. Tolerance research and its clinical induction is a good example of this. The identification of molecular signatures in tolerant patients in whom immunosuppression could be stopped, and induction of tolerance, through lymphocyte depletion or T lymphocyte co-stimulation blockade, are the most advanced

In the past few decades, due to scarcity of donors, extracorporeal liver support devices have been developed to support the failing liver resulting from different complications. These devices were created initially for the management of patients waiting for a suitable donor for orthotopic liver transplantation. Recent advances in the design of these devices allow now utilizing them in the recovery of the native liver from an acute injury. Thus, these devices can either bridge the patients to liver transplantation or can fully avoid the need for it (10). Liver support devices can be broadly classified into two classes: artificial liver (AL) devices and bioartificial (BAL) devices. The artificial support devices are designed to detoxify the blood or plasma via different methods like hemodialysis, hemofiltration, hemodiafiltration, hemadsorption, plasmapheresis, plasma fractionation and albumin dialysis (10, 11). Bioartificial support devices are targeted towards providing essential metabolic and synthetic functions of liver along with removal of toxins. BAL devices generally utilize primary hepatocytes or hepatoma cell lines incorporated into a bioreactor system to perform the essential liver functions (12). Here, we will discuss the operating principles of several artificial and bioartificial support systems which have been or are

approaches to reduce complications of immunosuppression(9).

MELD score(6).

especially for the sickest patients.

**3. Bioartificil liver devices** 

currently used in clinical trials.

induced cirrhosis(5). Regrettably, close to 20% of the livers transplanted in the USA and 30% in Europe have a preventable underlying cause, alcoholic liver disease. Also ~45% of deaths due to liver cirrhosis in the USA are related with alcohol abuse(1, 3, 4). Patients with pathologies like hepatic cancer, congenital malformations and metabolic diseases, and acute hepatic necrosis compose the remaining percentage of the list.
