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July 22, 2020

3D printing and iPS cells regenerate nerves in rat

The Ikeya Laboratory shows how transplanting scaffoldless conduits made by 3D printing of their iPS cell-derived mesenchymal stem cells recovers nerve loss in rats.

A new material consisting of iPS cell products and manufactured using 3D bioprinting shows impressive healing effects in nerve damage. The laboratory of CiRA Associate Professor Makoto Ikeya, in collaboration with Associate Professor Ryosuke Ikeguchi at the Orthopedic Surgery, Kyoto University Hospital, reports in Scientific Reports that conduits made of iMSCs, which are mesenchymal stem cells (MSCs) made from iPS cells, regenerate damaged peripheral nerves when grafted at the damaged site. Notably, these conduits had an extraordinary capacity to vascularize the damaged site, which could explain the better results compared with standard nerve graft material. With further development, this new biotechnology promises to become a safer and more effective product for nerve regeneration.

Peripheral nerve damage can lead to a loss of movement or sensation. Normally the damage itself is not life threatening but could put the patient at risk due to an unawareness of position, such as walking on icy or uneven surfaces, or of the environment, such as extreme heat or cold. Nerve grafts from other parts of the patient's body are commonly used to repair the damage. The grafted nerve does not itself replace the damaged nerve but acts as a conduit for new nerve tissue to grow. However, sometimes this autograft treatment is not an option.

"There are many reasons why we cannot do nerve autografts. Risk of neuromas. Mismatched caliber size. The extra surgical incision," explains Ikeya.

Nerves from donors can be used instead, but that involves patient-donor matching, which is not always feasible. Engineers have produced scaffolds made of artificial materials as alternatives, but these materials risk infection.

Stem cells, on the other hand, promise a resource for producing natural biomaterials as a conduit.

With 3D bioprinting, Ikeya considered whether his lab's iMSC technology could be used.

"3D bioprinting has made nerve conduits out of fibroblasts, but the fibroblasts are not very stable or homogenous. With iMSCs, we can control the quality and quantity for them to secrete regenerative factors," he says.

Another advantage of iMSCs is that they have stem cell properties, meaning that they can take diverse cellular properties when transplanted to the damaged site, including that of glial cells, which have neuroprotective effects.

To test the effectiveness of their iMSC conduit, the researchers grafted it into rats with nerve damage. Comparisons with standard silicone scaffolds used in nerve grafting showed the iMSC conduit outperformed in every metric including nerve size and functional behavior. One reason was its stability; cells did not die of necrosis, a concern when using biomaterials.

One reason could be that the conduit showed indications of good vascularization. The ability to promote blood flow would also enable the conduit to feed the damaged area regenerative factors. Consistently, the conduit expressed genes associated with neurogenesis and angiogenesis.

3D bioprinting fibroblasts and even other MSCs have been used for nerve grafts before. However, Ikeya explains, the use of iPS cells makes for a purer product.

"The innovation is the use of iMSCs. Other groups have used MSCs, but we want to show that iPS cells can make a higher quality product," he says.

*Funding for the project came from the Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Japan Science and Technology, Takeda Pharmaceuticals, Cyfuse and the iPS Cell Research Fund.

Paper Details
  • Journal: Scientific Reports
  • Title: Pro-angiogenic scaffold-free Bio three-dimensional conduit developed from human induced pluripotent stem cell-derived mesenchymal stem cells promotes peripheral nerve regeneration
  • Authors: Sadaki Mitsuzawa1*, Chengzhu Zhao2*, Ryosuke Ikeguchi1**, Tomoki Aoyama3, Daisuke Kamiya2,4, Maki Ando1, Hisataka Takeuchi1, Shizuka Akieda5, Koichi Nakayama6, Shuichi Matsuda1 and Makoto Ikeya2,4**
    * These authors contributed equally to this work
    ** Authors in correspondence
  • Author Affiliations:
    1. Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    2. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    3. Department of Physical Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    4. Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan
    5. Cyfuse Biomedical K.K., Tokyo, Japan
    6. Department of Regenerative Medicine and Biomedical Engineering, Faculty of Medicine, Saga University, Saga, Japan
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