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Hiroyuki Ijima Last modified date:2018.09.29

Professor / Molecular and Biochemical Systems Engineering
Department of Chemical Engineering
Faculty of Engineering


Graduate School
Undergraduate School


E-Mail
Homepage
http://www.chem-eng.kyushu-u.ac.jp/lab8/
Phone
092-802-2748
Fax
092-802-2748
Academic Degree
Doctor of Engineering
Country of degree conferring institution (Overseas)
No
Field of Specialization
Biochemical Engineering, Medical Engineering, Bioreactor, Biomaterial, Liver Tissue Engineering
Total Priod of education and research career in the foreign country
01years00months
Research
Research Interests
  • Development of hybrid-type artificial liver support system
    keyword : Hybrid-type artificial liver, Hepatocytes organoid, Hepatic failure rat model, Liver regeneration, High density culture, Bioreactor
    1990.07We developed a novel bioreactor and application system to patients. The bioreactor realized an induction of self organoid fomation and optimization of microenvironment for cell functions by using chemical engineering protocols. Furthermore, we succesfully developed hepatic failure animal model for estimating the performance of the artificial liver system..
  • Development of functional substratum and system for animal cell culture
    keyword : Animal cell culture, Culture substratum, Useful biological material, Bioreactor, Hydroxyl apatite, RGD, High density culture, Mass culture
    1997.04Macroporous hydroxyapatite culture substratum and packed-bed type bioreactor were developed. We suceeded mass production of colony stimulating factor using this system. Now, we focused optimization of this system and improvement of geometry, porosity and strength of the substratum..
  • Development of hybrid-type artificial kidney
    keyword : Hybrid-type artificial kidney, Renal proximal tubule cell, MDR, Active transport, RGD
    2002.05~2006.03We focused to develop a hybrid artificial kidney with renal proximal tubule cells immobilized on adhesive synthetic RGD peptide. Immobilized cells express the selective active transport of drugs in vitro culture using transwell. Furthermore, RGD-immobilized hollow fiber module was developed. Extracorporeal circulation system equipped hepotocyte-immobilized module and renal proximal tubule cells immobilized module was developed. Blood purification effect of severe hepatic failure rat induced by acetaminophen can be expressed by using this system..
  • Development of tissue-engineered liver
    keyword : Liver tissue engineering, Regenerative medicine, Angiogenesis, Scaffold, Cytokine, Hepatocytes organoid, Functional biomaterials
    2002.05.
  • Development of a cell function simulator
    keyword : Drug metabolism simylator, Hepatocytes organoid, cell function, bioreactor,
    2004.04.
  • Development of high density mass production procedd of ES cell-derived functional cells
    keyword : ES cell, High density culture, mass production, bioreactor, culture system, maintenance of undifferentiated condition, differentiation, functional cell
    2004.11.
Academic Activities
Books
1. Hiroshi Mizumoto, Nana Shirakigawa, Hiroyuki Ijima, Current Status and New Challenges of the Artificial Liver, Wiley, DOI:10.1002/9781119296034, 2018.02, The liver is the main metabolic organ in vivo. Therefore, severe liver dysfunction results in serious diseases with high mortality rates. Since Starzl et al. reported the first liver transplantation in a human in 1963, orthotropic liver transplantation has evolved by improving quality control, immune inhibition, and infection prevention of the donor’s liver. As the result, liver transplantation became the most effective treatment for severe liver failure in patients, causing many lives to be saved. According to data from 2016, the number of patients waiting for liver transplantation in the USA was 14 540 and 7841 patients received liver transplantation. However, 1240 patients died waiting for liver transplantation (United Network for Organ Sharing (UNOS). Available from: https://optn.transplant.hrsa.gov/data/view‐data‐reports/). In other words, donor shortage is a severe problem.
Therefore, an artificial liver (also called an artificial liver support system) can be expected to be a temporary substitute while a patient awaits transplantation. Furthermore, it has the potential to eliminate the need for liver transplantation by promoting liver regeneration and functional recovery. The necessary alternative function for treating liver failure is removal of toxins in blood. Based on this view point, the development of the artificial liver was considered to begin from Abel’s report in 1914. He performed dialysis with colloid membranes (Abel et al., 1914). However, practical development and many reports have been produced since the 1950s (Kiley et al., 1958), about a half century after the first report. Hemodialysis with
various types of membrane and hemoperfusion by using charcoal or synthetic resin has been carried out. These are classified as non‐biological (non‐bio) artificial livers. On the other hand, bioartificial livers (BAL) aim to compensate for the essential liver function by using biological components including whole livers or liver cells. The early clinical studies of BAL systems included cross‐hetero‐hemodialysis using xenogeneic animals or livers (Kimoto et al., 1959, Ozawa et al. 1982), extracorporeal liver perfusion (Eiseman et al., 1965, Sen et al., 1966), and an extracorporeal bioreactor with suspension hepatocytes (Matsumura et al., 1987). However, the outcome of these classical treatments was not satisfactory enough to save the patients’ lives.
Based on these backgrounds, the artificial liver has been developed and has become an effective treatment in clinical use. In this chapter, the current status and the future vision of non‐bio and bioartificial livers are reviewed. Furthermore, tissue‐ and organ‐engineered livers are introduced as a new stream of liver failure treatments. Finally, the future vision of liver failure treatment is summarized..
Papers
1. Shintaro Nakamura, Takafumi Kubo, Hiroyuki Ijima, Heparin-conjugated gelatin as a growth factor immobilization scaffold, Journal of Bioscience and Bioengineering, 10.1016/j.jbiosc.2012.11.011, 115, 5, 562-567, 2013.05, Tissue engineering requires growth factors, cells and a scaffold to permit effective tissue regeneration. This study aimed to develop a scaffold with a focus on immobilizing growth factors within gelatin. We focused on the extracellular matrix and developed a heparin-conjugated gelatin (Hep-gela). Conjugation was confirmed using the alcian blue assay and x-ray diffraction patterns. The mechanical strength and stability of the Hep-gela gel in protease solution were improved compared with collagen gel. Hep-gela was able to immobilize vascular endothelial growth factor (VEGF) even in the presence of albumin, with an efficiency of 54.2%. Immobilized VEGF promoted proliferation of human umbilical vein endothelial cells. Hep-gela-immobilized VEGF maintained its native biological activity. In summary, Hep-gela has the potential to become an effective material in the field of regenerative medicine..
2. Yung-Te Hou, Hiroyuki Ijima, Nana Shirakigawa, Takayuki Takei, Koei Kawakami, Development of growth factor-immobilizable material for hepatocyte transplantation, Biochemical Engineering Journal, http://dx.doi.org/10.1016/j.bej.2012.09.007, 69, 172-181, 2012.12, Growth factor (GF)-immobilizable materials were developed as a practical hepatocyte transplantation method for reconstructing a tissue-like structure in liver tissue engineering. Two GF-immobilizable scaffolds, namely single hepatocyte-embedded, heparin-immobilized, collagen-gel-filled polyurethane foam, and hepatocyte spheroid-embedded, heparin-immobilized, collagen-gel-filled polyurethane foam were developed by covalently incorporating heparin into collagen gel, using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide for hepatocyte transplantation. Seventy percent partial hepatectomy (PH) was performed at the same time after hepatocyte transplantation. Angiogenesis efficiency and viability of transplanted cells are discussed in terms of normalized hemoglobin content, nuclear density and histological observations after transplantation. In summary, the normalized hemoglobin content and viability of transplanted cells were higher in GF-immobilized scaffolds with PH pretreatment than in the other scaffolds with/without PH pretreatment. These materials have the potential for in vivo hepatocyte transplantation, as GFs released from remnant liver were easily incorporated into the heparin-immobilized collagen gel system. These GF–heparin complexes may promote the survival of embedded cells. Furthermore, the transplantation of spheroids promoted increased angiogenesis compared with hepatocytes, and resulted in sufficient vascularization for cell survival..
3. Nana Shirakigawa, Hiroyuki Ijima, and Takayuki Takei, Decellularized liver as a practical scaffold with a vascular network template for liver tissue engineering, Journal of Bioscience and Bioengineering, 10.1016/j.jbiosc.2012.05.022 , 114, 5, 546-551, 2012.11, The construction of a functional liver-tissue equivalent using tissue engineering is a very important goal because the liver is a central organ in the body. However, the construction of functional organ-scale liver tissue is impossible because it requires a high-density blood vessel network. In this study, we focused on decellularization technology to solve this problem. Decellularized liver tissue with a fine vascular tree network template was obtained using Triton X-100. The distance between each vascular structure was less than 1 mm. Endothelialization of the blood vessel network with human umbilical vein endothelial cells (HUVECs) was successfully performed without any leakage of HUVECs to the outside of the vessel structure. Furthermore, hepatocytes/spheroids could be located around the blood vessel structure. This study indicates that decellularized liver tissue is a potential scaffold for creating a practical liver tissue using tissue engineering technology..
4. Yung-Te Hou, Hiroyuki Ijima, Takayuki Takei, Koei Kawakami, Growth factor/heparin-immobilized collagen gel system enhances viability of transplanted hepatocytes and induces angiogenesis, Journal of Bioscience and Bioengineering, 10.1016/j.jbiosc.2011.05.003, 112, 3, 265-272, 2011.09.
5. Hiroyuki Ijima, Yung-Te Hou, Takayuki Takei, Development of hepatocyte-embedded hydrogel-filled macroporous scaffold cultures using transglutaminase, Biochemical Engineering Journal, 10.1016/j.bej.2010.09.003, 52, 276-281, 2010.11.
6. Yung-Te Hou, Hiroyuki Ijima, Shunichi Matsumoto, Takafumi Kubo, Takayuki Takei, Shinji Sakai, and Koei Kawakami, Effect of a hepatocyte growth factor/heparin-immobilized collagen system on albumin synthesis and spheroid formation by hepatocytes, Journal of Bioscience and Bioengineering, doi:10.1016/j.jbiosc.2010.01.016, 110, 2, 208-216, 2010.08.
7. Hiroyuki Ijima, Practical and functional culture technologies for primary hepatocytes, Biochemical Engineering Journal, 10.1016/j.bej.2009.10.003, 48, 3, 332-336, Vol.48, No.3, pp.332-336, 2010.02.
8. Hiroyuki Ijima, Hiroshi Mizumoto, Kohji Nakazawa, Toshihisa Kajiwara, Taku Matsushita, Kazumori Funatsu, Hepatocyte growth factor and epidermal growth factor promote spheroid formation in polyurethane foam/hepatocyte culture and improve expression and maintenance of albumin production, Biochemical Engineering Journal, 10.1016/j.bej.2009.06.012, 47, 1-3, 19-26, Vol.47, No.1-3, pp.19-26, 2009.12.
9. Hiroyuki Ijima, Takafumi Kubo, Yung-Te Hou, Primary rat hepatocytes form spheroids on hepatocyte growth factor/heparin-immobilized collagen film and maintain high albumin production, Biochemical Engineering Journal, 10.1016/j.bej.2009.05.017, 46, 2, 227-233, Vol.46, No.2, pp.227-233, 2009.10.
10. Hiroyuki IJIMA, Shohei KURODA, Koei KAWAKAMI, Degoxin transport by renal proximal tubule cells is enhanced on adhesive synthetic RGD peptide, The International Journal of Artificial Organs, Vol.30, No.1, pp.25-33, 2007.01.
11. Hiroyuki Ijima, Koei Kawakami, Promote a monolayer formation and highly express the ammonia metabolism of primary rat hepatocyte on a RGD-containing peptide coated polystyrene dish, Journal of Bioscience and Bioengineering, Vol.100, No.1, pp.62-66, 2005.07.
12. Shinji Sakai, Kenji Kawabata, Tsutomu Ono, Hiroyuki Ijima, Koei Kawami, Development of mammalian cell-enclosing subsieve-size agarose capsules (<100um) for cell therapy, Biomaterials, 10.1016/j.biomaterials.2004.11.043, 26, 23, 4786-4792, Vol.26, pp.4786-4792, 2005.01.
13. Koei Kawakami, Yoshihide Sera, Shinji Sakai, Tsutomu Ono, Hiroyuki Ijima, Development and Characterization of a Silica Monolith Immobilized Enzyme Micro-bioreactor, Industrial & Engineering Chemistry Research, 10.1021/ie049354f, 44, 1, 236-240, Vol.44, No.1, pp.236-240, 2005.01.
Presentations
1. Construction of Whole Organ Engineering, and Regenerative Medicine - Liver -, [URL].
2. Nana Shirakigawa, Hiroki Sakamoto, Cho Jaeyong, Daisuke Imai, Yo-ichi Yamashita, Ken Shirabe, Yoshihiko Maehara, Hiroyuki Ijima, Fundamental technology for the creation of whole liver engineering, and functional evaluation of recellularized liver, 2015 4th TERMIS World Congress (Tissue Engineering and Regenerative Medicine International Society), 2015.09, Technology for regenerative medicine based on tissue engineering is desired earnestly as an effective medical treatment for serious organ diseases. Especially, liver is a central organ for metabolism in our body and is complicated structure. Therefore, liver tissue engineering is one of the most important and difficult themes. However, formation of tissue-like structure with the thickness more than 1mm is still impossible, because oxygen consumption rate of hepatocytes is higher than the other organs’ cells. Scale-up and easy process development are required. For the realization, creation of whole liver engineering (WLE) consisting of cells, functional ECM and fine organ template will be indispensable.
Heparin-collagen conjugate and solubilized liver ECM were developed as growth factor-immobilizable materials. VEGF and HGF were immobilized on these functional materials (>90%). Hepatocytes on these materials well expressed various liver-specific functions in vitro. Hepatocytes or fetal liver cells (FLCs)-embedded functional gel was subcutaneously transplanted into rat. Angiogenesis and viability of hepatocytes were enhanced in the gel. Furthermore, transplanted FLCs form liver tissue-like structure with vascular network.
Organ-scale scaffold having a template of blood vessel network was obtained by decellularization with detergent. The fineness of the network was the same as original liver, evaluated by 3D-CT. Furthermore, endothelialization and expression of liver-specific function of hepatocytes were confirmed. Furthermore, recellularized liver well metabolize ammonia during blood circulation.
Based on the above-mentioned results, we expected that fundamental technology for the creation of WLE was developed.
Keywords: Whole organ engineering, Decellularized liver, Liver tissue engineering, Functional ECM.
3. Hiroyuki Ijima, Shintaro Nakamura, Jingia Ye, Nana Shirakigawa, Daisuke Imai, Yo-ichi Yamashita, Ken Shirabe, Yoshihiko Maehara, Fundamental technology for the creation of Whole Liver Engineering, TERMIS-AP 2014 (Tissue Engineering and Regenerative Medicine International Society, Asia-Pacific Annual Conference 2014), 2014.09, Technology for regenerative medicine based on tissue engineering is desired earnestly as an effective medical treatment for serious organ diseases. Especially, liver is a central organ for metabolism in our body and is complicated structure. Therefore, liver tissue engineering is one of the most important and difficult themes. However, formation of tissue-like structure with the thickness more than 1mm is still impossible, because oxygen consumption rate of hepatocytes is higher than the other organs’ cells. Development for upsizing and easy process is required. For the realization, creation of whole liver engineering (WLE) consisting of cells, functional ECM and fine organ template will be indispensable.
Heparin-collagen conjugate and solubilized liver ECM were developed as growth factor-immobilizable materials. VEGF and HGF were immobilized on these functional materials (>90%). Hepatocytes on these materials well expressed various liver-specific functions in vitro. Hepatocytes or fetal liver cells (FLCs)-embedded functional gel was subcutaneously transplanted into rat. Angiogenesis and viability of hepatocytes were enhanced in the gel. Furthermore, transplanted FLCs form liver tissue-like structure with vascular network.
Organ-scale scaffold having a template of blood vessel network was obtained by decellularization with detergent. The fineness of the network was the same as original liver, evaluated by 3D-CT. Furthermore, endothelialization and expression of liver-specific function of hepatocytes were confirmed. In other words, initial structure of WLE was successfully developed. Additionally, blood circulation system containing recellularized liver and functional evaluation system of the liver were developed.
Based on the above-mentioned results, fundamental technology for the creation of WLE was developed.

Keywords: Whole organ engineering, Decellularized liver, Liver tissue engineering, Functional ECM.
4. Basic Study for Liver Tissue Engineering by Using Decellularized Organ.
5. Cell-embedded functional gel-filled scaffold culture for liver tissue engineering
Hiroyuki Ijima, Nana Shirakigawa, Yung-Te Hou, Shintaro Nakamura, Takayuki Takei, Koei Kawakami .
6. Organoid formation and the function expression of primary rat hepatocytes are improved by culturing with hepatocyte growth factor-immobilized culture substratum.
Membership in Academic Society
  • The Society of Chemical Engineers, Japan
  • Japanese Society for Artificial Organs
  • The Society for Biotechnology, Japan
  • The Japanese Society for Regenerative Medicine
  • The Japanese Society for Biomaterials
  • Japan Bioindustry Association
  • Japanese Society for Alternative to Animal Experiments
  • Japanese Association for Animal Cell Technology
Awards
  • Base structure consisting of an endothelialized vascular-tree network and hepatocytes for whole liver engineering
    (JBB Volume 116, Issue 6, December 2013, Pages 740-745)
Educational
Educational Activities
Biomaterials engineering

Bioprocess Engineering I

The second basics physical chemistry and practice

Fundamentals of bioengineering

The second/the third materials science engineering expriment

Cell Biology
Other Educational Activities
  • 2008.12.
Social
Professional and Outreach Activities
International collaboration for the development of cell chip using non-adhesive single cell culture technology .