ReviewToward engineering of vascularized three-dimensional liver tissue equivalents possessing a clinically significant mass
Section snippets
Hepatocyte-based therapies for liver failures
Liver is the center of the various metabolisms in humans. The functions are those such as metabolisms of sugars, proteins/amino acids and lipids, detoxification of exogenous chemicals, production of bile acids, and storing of various other essential chemicals such as vitamins or irons. Therefore, its failure often results in a fatal threat to our life. Even at present, the ultimate treatment for such fatal liver failure is orthotropic liver transplantation of donor livers, incurring the
Classification of the approaches
To design liver tissue equivalent from engineering point of view, we need to consider both the actual structure of the liver and the current feasibility of various technologies. Fig. 2 shows the schematic illustration of the macro- to micro-structure of the liver [22]. The 3D blood flow network is well arranged so that each hepatocyte can actively exhibit metabolic functions. The hepatic portal vein supplies various ingested nutrients or toxic chemicals from the small intestine and the hepatic
Advantages and drawbacks of 3D culture
As discussed above, 3D culture of hepatocyte are necessary in obtaining high cell density and are also advantageous in obtaining enhanced hepatic functions, on the condition that oxygen and nutrients are satisfactorily supplied to all the cells in the entire 3D structure. The possible mechanisms for the 3D effects from the biological point of view is categorized into the three as follows [52]: enhanced cell-to-cell contact that makes them recognize they are in in vivo mimicking cellular
Necessity of oxygen carriers for rearing large liver tissues
As far as we target at development of liver tissue equivalents possessing clinically significant mass, 500 cm3, we need to pay attention to the oxygen supply in such larger scale as well as in micro-scale. The first reason is the very low oxygen solubility in culture medium, 2 × 10−7 mol-O2/mL-culture medium under 21% O2 in the gas phase, which is about 1/70 that of blood. The second reason is that culture medium should be perfused at less than a certain flow rate that gives a physiological shear
Maximizing spontaneous tissue organization both in vitro and in vivo
A study in 1960 pointed out the fact that a confluent hepatocytes monolayer cultured in a usual static condition is usually put an extremely anaerobic condition [115]. This can easily be predicted from the Fick's First law, simple oxygen diffusion through the culture medium layers and the oxygen consumption of the hepatocyte monolayer beneath the culture medium. However, there has been almost no research that tried complete removal of this oxygen limitation and in vitro realization of aerobic
Conclusive remark and expected roles of biochemical engineers
Toward engineering of liver tissue equivalents possessing a clinically significant mass (500 cm3) and per-volume-based functionalities comparable to those of in vivo liver tissue, we proposed a possible road map showing the first proof-of-concept stage using pigs where the fundamental methodology for development of 3D vascularized tissue equivalents is to be established and the second human clinical stage based on the same methodology but using human liver cells (Fig. 1). Related important
Acknowledgement
The results introduced in this review as our works were partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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Cited by (0)
- 1
Current address: Okami Chemical Industry Co. Ltd., Emba 78, Makishima-cho, Uji-shi, Kyoto 611-0041, Japan.
- 2
Current address: International Clinical Research Center, Research Institute, International Medical Center of Japan, Toyama 1-21-1, Shinjuku-ku, Tokyo 162-8655, Japan.