Hepatic Tissue Engineering Using Scaffolds: State of the Art
Ph.D., Department of Embryology and Stem Cells, Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran, P.O. Box: 19615-1177, Tel: +98 21 22432020, Fax: +98 21 22432021, E-mail: email@example.com
Department of Embryology and Stem Cells, Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR , Tehran, Iran
Severe hepatic failure accounts for many deaths and raises medical costs each year worldwide. Currently, liver transplantation is the most common therapeutic option for patients with end-stage chronic liver disease. Due to decrease in the number of organ donors, many in need of transplantation continue to remain on the waiting list. Hepatic Tissue Engineering is a step toward alleviating the need for organ donors. Regenerative medicine and tissue engineering require two complementary key ingredients as follows: 1) biologically compatible scaffolds that can be readily adopted by the body system without harm, and 2) suitable cells including various stem cells or primary cells that effectively replace the damaged tissues without adverse consequences. Yet many challenges must be overcome such as scaffold choice, cell source and immunological barriers. Today, hepatogenic differentiation of stem cells has created trust and promise for use of these cells in hepatic tissue engineering and liver replacement. However, using suitable scaffolds is an important key to achieving the necessary functions required for hepatic replacement. In recent years, different scaffolds have been used for liver tissue engineering. In this review, we have presented different concepts in using cell /scaffold constructs to guide hepatic tissue engineering.
Every year, the number of patients needing a hepatic transplant increases. Many of those in need of a transplant have suffered from full hepatic failure caused by disease, genetic complications or adverse drug reactions. Cur-rently, there are many people waiting to have a liver transplant. However, there are not enough organ donors.
At the moment, there are about 700 patients waiting to have a liver transplant in Iran, but the number of liver donors is less than 200. At present, liver transplantation is the only therapeutic option for patients with end-stage chronic liver disease and severe liver failure.
However, the efficacy of liver transplantation is limited by the shortage of available organ donors, risk of rejection, infections, and other complications caused by the lifelong immunosuppression (1).
Tissue engineering proves to be a tem-porary treatment for patients suffering from hepatic failure (2). For successful tissue regen-eration, the cells constituting tissues to be re-generated are necessary. Considering the pro-liferation activity and differentiation potential of cells, stem cells are practically promising. Self-renewal is a unique property of stem cells that gives multi-potential differentiation ability to them.
Today, there are different studies showing hepatogenic differentiation capacity of the stem cells (3-5). However, the challenge re-mains to develop robust protocols, to generate functional hepatocytes from stem cells suit-able for the transplantation.
A complementary key ingredient in regen-erative medicine and tissue engineering is to make a use of biologically compatible scaf-folds that can be readily adopted by the body system without harm (6). Advances in polymer chemistry have facilitated the engineering of synthetic matrices that can be precisely ma-nipulated with regard to physical and mechan-ical characteristics. This review has presented some directions that the field of liver tissue engineering is heading.
The liver is a highly metabolic, complex array of vasculature, endothelial cells and parenchymal cells that performs many func-tions in the body. The bulk of the liver is primarily composed of parenchymal cells such as hepatocytes, hepatocyte precursor cells (oval cells or Ito cells), stellate cells, kuppfer cells, epithelial cells, sinusoidal epi-thelial cells, biliary epithelial cells and fibro-blasts (7). Hepatocytes constitute approximate-ly 70% of the cellular population of the liver and perform major metabolic functions such as plasma protein synthesis and transport, xenobiotic metabolism, glucose homeostasis, urea synthesis, and ketogenesis (8). Thus, hepatocytes used for tissue engineering pur-poses must be able to perform these basic functions.
In the field of hepatic tissue engineering, choosing cell type and cell source is important because it is necessary to choose cells that demonstrate the particular phenotype of interest. The various cell types that have been studied include stem cells, hematopoietic cells, oval progenitor cell and mature hepato-cytes (9-11). Deciding which cell type to use is dictated by the need and desire for the cells to perform in a predicted manner, exhibiting certain characteristics.
Hepatic progenitor cells found within the liver have already begun to differentiate, but still have several options before becoming destined to a specific cell line. These cells will not necessary become mature hepato-cytes, but may in fact differentiate into other functional cells of the liver, such as bile duct cells (12,13). Hepatic progenitor cells are often distinguished as primary or small hepatocytes. Mature hepatocytes can be obtained either from the perfusion of an intact or resectioned liver or from an established cell line.
Currently, primary mature hepatocytes, the most common cellular component in current liver tissue engineering, do not replicate suffi-ciently in vitro to meet the requirements of clinical use an
With the recent advances in the field of hepatic tissue engineering, there is much promise of working towards an implantable whole organ. Many new polymers are being developed that respond to thermal changes, release imbedded or attached growth factors and other mediators, and have degradation characteristics and properties that is ideal for growth, viability, and attachment. An optimal polymer is being developed based on desired characteristics. Recently, electrospun nano-fibrous scaffolds showed great promise and potential for liver tissue engineering.
Many other factors are being studied that contribute to cell growth and differentiation. However, further studies need to be per-formed for the development of a bioartificial liver system.
With the growth of the tissue-engineering field, many ethical considerations must be recognized. Determining which cell source is safest for patients, which cells should be used, whether they are embryonic stem cells, oval progenitors or adult stem cells, and how the cells should be stored and cultured are im-portant issues to take into consideration.
Hepatic tissue engineering is an ever ex-panding field encompassing and including new areas of study. Because of its multidis-ciplinary nature, it is important for clinicians, basic scientists and engineers to collaborate and explore all areas of possibilities. With each new advance in the field of tissue engin-eering, a step towards an implantable liver is realized. Even though the goal of creating an entire implantable organ has not yet been reached, the progress towards this goal is proving to be fruitful to all those involved, mainly the patients who will benefit from the advancements being made.