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Periodontal Ligament Group

Periodontal Tissue Regenerative Therapy with Periodontal Ligament-derived Cell Sheets

　We have started the clinical trial named "Periodontal Regeneration with Autologous Periodontal Ligament Cell Sheets" for which the Minister of Health, Labour and Welfare gave its approval on January 4, 2011. Specifically, we are producing autologous periodontal ligament cell sheets by aseptically harvesting and cultivating periodontal ligament cells in a cell processing center (CPC). We then test the cell sheets to see if they maintain the same quality as periodontal ligament cells, and we also test to ensure that the cells are safe and free from viruses and germs.

　After verifying the effectiveness and safety of the cell sheets, we will transplant them into the areas affected by periodontal disease. Over the next two years, we plan to conduct clinical tests on 10 human subjects. As we have a high incidence of periodontal diseases in Japan, development of a fundamental therapy is much hoped for. Therefore we wish to establish methods to treat severe periodontal diseases (which are regarded as very hard to cure) using this cell-sheet-engineering-based therapy. Moreover, to expand the range of indications, it is essential that we verify the efficacy of our work through translational research; therefore our group is carrying out the basic research in parallel with the clinical trial. At the level of animal experiments, we have been exploring and studying the effectiveness of cell sheet on a wide range of canine periodontal defect models. In order to find the optimal cell source, we autografted onto 4 dogs three kinds of cells: bone-marrowderived mesenchymal stem cells, alveolar periosteal cells, and periodontal ligament cells. We then compared the different regenerated tissues and observed a significant regeneration of periodontal tissue, including nerve tissue, in the group treated with periodontal ligament cells. In experimenting at the cellular level, we are investigating the human periodontal ligament cell's multipotency, as well as its immunomodulatory and trophic functions to benefit other cells, aiming to carry out research that considers also the other uses of this treatment which could be employed in the future. Specifically, we are carrying out analysis of the Wnt-related gene expression during osteoinduction; conducting research on the maintenance of stemness; and third, we are developing a minimally invasive cell-harvest method. In addition, regarding the application of cell sheet engineering, we aim to explore its effects on bone augmentation around dental implants, and through its application we also seek to establish an epithelial-mesenchymal interaction model of the tooth development.

Fig.1：
Transplantation of periodental ligament-derived cell sheets

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Fig.2：
A Typical Work Scene in the CPC
A pair of researchers working in the clean room wearing double-layered gowns. One works on producing cell sheets and the other records the operation, while confirming with each other.

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Researcher Introduction

Institute of Advanced BioMedical Engineering and Science,
Associate Professor　　Takanori IWATA

Takanori IWATA　 Isao Ishikawa, now has 7 members, consisting of 4 staff and 3 graduate students. We cover everything dealing with the research from conducting basic experiments to clinical trials and on through to translational research, which bridges both these areas. So far we have had to face many challenges including such unaccustomed work as preparing various application forms, conducting safety tests, as well as cell cultivation, which requires wearing double-layered gowns in the cell processing center. Nevertheless, this resulted in our obtaining approval from the Ministry of Health, Labour and Welfare at the start of 2011 to conduct our clinical trials. Though we are at the beginning of our research, we have built up a capable system in which six of us can carry out the work in the CPC. We will continue to drive safely the clinical test forward and evaluate the effectiveness of this therapy.

 

Achievements

  • Tsumanuma Y, Iwata T, Washio K, Yoshida T, Yamada A, Takagi R, Ohno T, Lin K, Yamato M, Ishikawa I, Okano T, Izumi Y. Comparison of different tissue-derived stem cell sheets for periodontal regeneration in a canine 1-wall defect model. Biomaterials. 2011;32(25):5819 - 25.
  • Washio K, Iwata T, Mizutani M, Ando T, Yamato M, Okano T, Ishikawa I. Assessment of cell sheets derived from human periodontal ligament cells: a pre-clinical study. Cell Tissue Res. 010;341(3):397- 404.
  • Iwata T, Yamato M, Zhang Z, Mukobata S, Washio K, Ando T, Feijen J, Okano T, Ishikawa I. Validation of human periodontal ligament-derived cells as a reliable source for cytotherapeutic use. J Clin Periodontol. 2010;37(12):1088 - 99.
  • Ishikawa I, Iwata T, Washio K, Okano T, Nagasawa T, Iwasaki K, Ando T. Cell sheet engineering and other novel cell-based approaches to periodontal regeneration. Periodontol 2000. 2009;51:220 - 38.
  • Iwata T, Yamato M, Tsuchioka H, Takagi R, Mukobata S, Washio K, Okano T, Ishikawa I. Periodontal regeneration with multilayered periodontal ligament-derived cell sheets in a canine model. Biomaterials. 2009;30(14):2716 - 23.