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The liver is located in the upper right-hand portion of the intestinal cavity. The liver consists of two main lobes, both of which are made up of millions of hepatocytes organized in the form of thousands of lobules. These lobules are connected to small ducts that connect with larger ducts to ultimately form the hepatic duct. The livers main two functions are to regulate chemical levels in the blood (e.g. amino acids, glucose, iron, etc.) and excrete bile which is necessary for digestion of fats. Chronic liver disease is marked by the gradual destruction of liver tissue over time and the gradual increase in scar tissue to replace that dysfunctional liver tissue. This causes an insufficient filtering of the bodys blood. It is the 12th leading cause of death in the United States, according to NIDDKa and eventually leads to transplant surgery [4]. The complex geometries in livers make liver tissue engineering difficult, but attainable and necessary to address the low numbers of donors. One treatment option for patients in liver failure is a bioartificial liver system; although, Masaya Iwamuro and his group in Japan have acknowledged the difficulties that bioartificial liver systems have with immunological rejection of the functional hepatocytes inside the system. This study focused on testing the feasibility of a bioartificial liver system with induced pluripotent stem cells (iPSCs) instead of the functional hepatocytes used currently. These iPSCs were bought from Riken Cell Bank, but were originally harvested from mice. The iPSCs were seeded onto mouse embryo fibroblasts on gelatin coated plates and allowed to grow in a CellMax Hollow Fiber Bioreactor System which is a flow based system with a 3D space for in-vitro cell culture and 0.2m pore diameter membranes. This construct was allowed to grow for 7 days. Researchers found that iPSCs had differentiated into hepatocytes and were producing albumin and urea after 7 days of cultivation proving iPSCs to be a promising option for bioartificial liver systems for patients with liver failure [1]. According to Natasha Forster and her team in Australia, current cell-based treatment alternatives to organ transplantation for liver failure are inadequate due to hepatocytes tendencies to dedifferentiate and die. In order to address this issue, they investigated the use of liver progenitor cells (LPCs) because they are more robust and easier to culture. They harvested these LPCs from adult TAT GRE LacZ transgenic mice livers. They cultured the LPCs in a Matrigel suspension (scaffold) in an in-vivo mouse chamber model. The chamber was located in a heavily vascularized adipose region in the groin of the mice and was composed of silicone tubing. The study was set up as follows: 4 groups of 4 mice, 2 groups on a normal diet, 2 groups on a diet inducing liver failure, 2 groups that had direct suspension of LPCs in Matrigel, 2 groups that had suspension of LPC spheroids cultured 1 week prior in Matrigel. All four groups were cultured for 4 weeks. After 4 weeks, researchers discovered that all four groups had remaining LPCs, some of which had differentiated into hepatocytes. The groups that experienced suspension of LPC spheroids in the Matrigel demonstrated greater LPC-survival. This model of LPC in-vivo culture is a promising alternative for Cirrhosis[2]. As addressed above, whole-organ liver tissue engineering is necessary to address the low numbers of donors. Soto-Gutierrez and his group have proposed exactly this solution. This group isolated rat hepatocytes as well as entire rat livers. They used the harvested rat liver and exposed it to a series of enzymatic, chemical, and mechanical methods in order to decellularize the scaffold. The decellularized liver protein scaffold was suspended in media in a cast acrylic reservoir that is a part of a flow based bioreactor system that also includes a peristaltic pump and bubble trap. The bioreactor system was placed in an incubator that allowed for an environment of 37 C and 5% CO2 to be maintained. Once suspended, researchers investigated three different seeding methods as follows: (1) 5 injections into different lobes at 2ml/min for 40min, (2) 1 injection into the reservoir chamber at 2mL/min for 40min, and (3) multiple injections 10-15min apart directly into the perfusion system at 2mL/min for 40min. This group successfully documented the use of a decellularized liver scaffold, its ability to support functional hepatocytes, and its potential use as an alternative to transplantation. There are many different approaches to tissue engineering a liver as well as similarities. All three groups used small rodents for their cell sources and were attempting to address patients in end stage liver failure. Additionally, Forster and Iwamuro used cells that had some level of pluripotentcy due to their robust characteristics. All groups had significantly different bioreactor systems and cultivation methods ranging from in-vitro to in-vivo systems and 40min to 4week cultivation. Additionally, Iwamuros group was addressing a bioartificial liver system while Forster and Soto-Gutierrez were addressing more traditional tissue engineering replacement methods. The most important next step the field of tissue engineered livers needs to make next is a progression to larger animal models to demonstrate its ability to be effective on a larger scale. Additionally, groups need to focus on making constructs that can execute all of the livers many functions.

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Works Cited [1] Iwamuro, Masaya, Hidenori Shiraha, Shuhei Nakaji, Masumi Furutani, Naoya Kobayashi, Akinobu Takaki, and Kazuhide Yamamoto. "A Preliminary Study for Constructing a Bioartificial Liver Device with Induced Pluripotent Stem Cell-derived Hepatocytes." Biomedical Engineering Online 11.93 (2012): n. pag. Biomedical Engineering Online. Web. 2 Dec. 2013. <http://www.biomedicalengineering-online.com/content/11/1/93>. [2] Forster, Natasha, MD, Jason A. Palmer, BSc, George Yeoh, PhD, Wei-Chen Ong, MD, Geraldine M. Mitchell, PhD, John Slavin, MBBS FRCPA, Janina Tirnitz-Parker, PhD, and Wayne A. Morrison, MD BS. "Expansion and Hepatocytic Differentiation of Liver Progenitor Cells InVivo Using a Vascularized Tissue Engineering Chamber in Mice." Tissue Engineering 17.3 (2011): 359-66. Gale Cengage Academic OneFile. Web. 2 Dec. 2013. <http://go.galegroup.com.ezproxy.lib.calpoly.edu/ps/retrieve.do?sgHitCountType=None&sort=R ELEVANCE&inPS=true&prodId=AONE&userGroupName=calpolyw_csu&tabID=T002&searc hId=R1&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchFor mtPosition=1&contentSet=GALE%7CA251459379&&docId=GALE|A251459379&docType= GALE&role=>. [3] Soto-Gutierrez, Alejandro, MD PhD, Li Zhang, MD MS, Chris Medberry, BS, Ken Fukumitsu, MD PhD, Danver Faulk, BS, Hongbin Jiang, MD, Janet Reing, MS, Roberto Gramignoli, PhD, Junji Komori, MD PhD, Mark Ross, PhD, Masaki Nagaya, MD PhD, Eric Lagasse, PhD, Donna Stoiz, PhD, Stephen C. Strom, PhD, Ira J. Fox, MD, and Stephen F. Badylak, DVM PhD MD. "A Whole-Organ Regenerative Medicine Approach for Liver Replacement." Tissue Engineering 17.6 (2011): 677-86. Gale Cengage Academic OneFile. Web. 2 Dec. 2013. <http://go.galegroup.com.ezproxy.lib.calpoly.edu/ps/retrieve.do?sgHitCountType=None&sort=R ELEVANCE&inPS=true&prodId=AONE&userGroupName=calpolyw_csu&tabID=T002&searc hId=R2&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchFor mtPosition=1&contentSet=GALE%7CA259751849&&docId=GALE|A259751849&docType= GALE&role=>. [4] Wexner Medical Center. "The Liver: Anatomy and Functions." The Liver: Anatomy and Functions. The Ohio State University, n.d. Web. 30 Nov. 2013.

a) National Institute of Diabetes and Digestive and Kidney Diseases

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