Combination of ultra-purified stem cells with an in situ-forming bioresorbable gel enhances intervertebral disc regeneration
Daisuke Ukeba,
Katsuhisa Yamada,
Takashi Suyama,
Darren R. Lebl,
Takeru Tsujimoto,
Takayuki Nonoyama,
Hirokazu Sugino,
Norimasa Iwasaki,
Masatoki Watanabe,
Yumi Matsuzaki,
Hideki Sudo
Affiliations
Daisuke Ukeba
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
Katsuhisa Yamada
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
Takashi Suyama
PuREC/Bio-venture from Shimane University, Izumo, Shimane, Japan
Darren R. Lebl
Department of Orthopedic Surgery, Spine Service, Hospital for Special Surgery, New York, USA
Takeru Tsujimoto
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
Takayuki Nonoyama
Global Institution for Collaborative Research and Education, Global Station for Soft Matter, Hokkaido University, Sapporo, Hokkaido, Japan
Hirokazu Sugino
Department of Cancer Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
Norimasa Iwasaki
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
Masatoki Watanabe
Japan Tissue Engineering Co., Ltd. (J-TEC), Gamagori, Aichi, Japan
Yumi Matsuzaki
PuREC/Bio-venture from Shimane University, Izumo, Shimane, Japan
Hideki Sudo
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan; Department of Advanced Medicine for Spine and Spinal Cord Disorders, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo, Hokkaido 060-8638, Japan; Corresponding author at: Department of Advanced Medicine for Spine and Spinal Cord Disorders, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo, Hokkaido 060-8638, Japan.
Summary: Background: Lumbar intervertebral disc (IVD) herniations are associated with significant disability. Discectomy is the conventional treatment option for IVD herniations but causes a defect in the IVD, which has low self-repair ability, thereby representing a risk of further IVD degeneration. An acellular, bioresorbable, and good manufacturing practice (GMP)-compliant in situ-forming gel, which corrects discectomy-associated IVD defects and prevents further IVD degeneration had been developed. However, this acellular matrix-based strategy has certain limitations, particularly in elderly patients, whose tissues have low self-repair ability. The aim of this study was to investigate the therapeutic efficacy of using a combination of newly-developed, ultra-purified, GMP-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs) and the gel for IVD regeneration after discectomy in a sheep model of severe IVD degeneration. Methods: RECs and nucleus pulposus cells (NPCs) were co-cultured in the gel. In addition, RECs combined with the gel were implanted into IVDs following discectomy in sheep with degenerated IVDs. Findings: Gene expression of NPC markers, growth factors, and extracellular matrix increased significantly in the co-culture compared to that in each mono-culture. The REC and gel combination enhanced IVD regeneration after discectomy (up to 24 weeks) in the severe IVD degeneration sheep model. Interpretation: These findings demonstrate the translational potential of the combination of RECs with an in situ-forming gel for the treatment of herniations in degenerative human IVDs. Funding: Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd.
