Hepatic tissue engineering: from transplantation to customized cell‐based liver directed therapies from the laboratory

Abstract

Today, liver transplantation is still the only curative treatment for liver failure due to end-stage liver diseases. Donor organ shortage, high cost and the need of immunosuppressive medications are still the major limitations in the field of liver transplantation. Thus, alternative innovative cell-based liver directed therapies, for example, liver tissue engineering, are under investigation with the aim that in future an artificial liver tissue could be created and be used for the replacement of the liver function in patients. Using cells instead of organs in this setting should permit (i) expansion of cells in an in vitro phase, (ii) genetic or immunological manipulation of cells for transplantation, (iii) tissue typing and cryopreservation in a cell bank and (iv) the ex vivo genetic modification of patient's own cells prior to re-implantation. Function and differentiation of liver cells are influenced by the three-dimensional organ architecture. The use of polymeric matrices permits the three-dimensional formation of a neo tissue and specific stimulation by adequate modification of the matrix surface, which might be essential for appropriate differentiation of transplanted cells. In addition, culturing hepatocytes on three-dimensional matrices permits culture in a flow bioreactor system with increased function and survival of the cultured cells. Based on bioreactor technology, bioartificial liver devices (BAL) are developed for extracorporeal liver support. Although BALs improved clinical and metabolic conditions, increased patient survival rates have not been proven yet. For intracorporeal liver replacement, a concept that combines tissue engineering using three-dimensional, highly porous matrices with cell transplantation could be useful. In such a concept, whole liver mass transplantation, long-term engraftment and function as well as correction of a metabolic defect in animal models could be achieved with a principally reversible procedure. Future studies have to investigate which environmental conditions and transplantation system would be most suitable for the development of artificial functional liver tissue including blood supply for a potential use in a clinical setting.

Maintenance of Human Hepatocyte FunctionIn Vitroby Liver-Derived Extracellular Matrix Gels

“…The medium was aspirated and PHHs were incubated with 2.5 mM NH 4 Cl in HMM for two hours at 378C. The conditioned medium was collected and the concentration of ammonia nitrogen was measured using a commercially available kit (Wako Pure Chemical Industries, Tokyo, Japan).…”

“…3 Tissue engineering and regenerative medicine (TE&RM) approaches for the reconstruction of functional liver tissue are being widely investigated and typically involve the use of cells, scaffolds, and bioactive factors. [3][4][5][6] The present study is predicated upon the hypothesis that the scaffold or substrate upon which hepatocytes are seeded is a critical determinant of cell phenotype and function.…”

Construction of a Portal Implantable Functional Tissue-Engineered Liver Using Perfusion-Decellularized Matrix and Hepatocytes in Rats

“…Ohashi et al developed a method to engineer a uniform, continuous sheet of Although BALs improve clinical and metabolic conditions, increased patient survival rates have not yet been hepatic tissue in a scaffold-independent manner using isolated primary hepatocytes (18). All of the above techproven (5,24). For intracorporeal liver replacement, transplantation of isolated liver cells desirable.…”

Liver Regeneration and Bioengineering - The Emergence of Whole Organ Scaffolds

“…In the last two decades innumerous strategies for the culture of adult hepatocytes in combination with several types of 3D, highly porous polymeric matrices have been attempted (45)(46)(47)(48)(49). However, in the absence of vasculature, restriction in cell growth and function is common due to the limitations in nutrient and oxygen diffusion.…”