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Development of a 3D subcutaneous construct containing insulin-producing beta cells using bioprinting

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Abstract

Type 1 diabetes is caused by insulin deficiency due to the loss of beta cells in the islets of Langerhans. In severe cases, islet transplantation into the portal vein is performed. However, due to the loss of transplanted islets and the failure of islet function, the 5-year insulin independence rate of these patients is < 50%. In this study, we developed a long-term, insulin-secreting, 3D-bioprinted construct implanted subcutaneously with the aim of preventing islet loss. The bioprinted construct was fabricated by the multi-layer bioprinting of beta-cell (mouse insulinoma-6: MIN-6)-encapsulated alginate bioink and poly(caprolactone) biodegradable polymer. A glucose response assay revealed that the bioprinted constructs proliferated and released insulin normally during the 4-week in vitro period. Bioprinted MIN-6 generated clusters with a diameter of 100–200 µm, similar to the original pancreatic islets in the construct. In an in vivo study using type 1 diabetes mice, animals implanted with bioprinted constructs showed three times higher insulin secretion and controlled glucose levels at 8 weeks after implantation. Because the implanted, bioprinted constructs had a positive effect on insulin secretion in the experimental animals, the survival rate of the implanted group (75%) was three times higher than that of the non-implanted group (25%). The results suggest that the proposed, 3D-bioprinted, subcutaneous construct can be a better alternative to portal vein islet transplantation.

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Acknowledgements

This research was supported by the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (No. HH21C0011), and Gachon University Gil Medical Center (No. FRD 2021-02).

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Authors and Affiliations

  1. Department of Molecular Medicine, College of Medicine, Gachon University, 155, Gaetbeol-ro, Yeonsu-ku, Incheon, Republic of Korea

    Chi B. Ahn, Ji-Hyun Lee & Jin W. Lee

  2. Department of Health Sciences and Technology, GAIHST, Gachon University, 155, Gaetbeol-ro, Yeonsu-ku, Incheon, Republic of Korea

    Joo H. Kim, Tae H. Kim & Jin W. Lee

  3. College of Pharmacy, Gachon University, 191, Hambangmoe-ro, Yeonsu-ku, Incheon, Republic of Korea

    Hee-Sook Jun

  4. Department Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, College of Medicine, Gachon University, 21, Namdong-daero 774 beon-gil, Namdong-gu, Incheon, Republic of Korea

    Kuk H. Son

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  1. Chi B. Ahn
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Contributions

CBA, JHL, KHS, and JWL contributed to conceptualization; CBA and JHL were involved in validation; JHK, THK, and HSJ contributed to formal analysis; KHS and JWL were involved in writing—original draft, and project administration. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Kuk H. Son or Jin W. Lee.

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The authors declare that they have no conflict of interest.

Ethical approval

The animal study protocol was approved by the Animal Subjects Committee of Gachon University (Approval number: LCDI-2018-0057). The institutional guidelines for the care and use of laboratory animals were followed.

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Chi B. Ahn and Ji-Hyun Lee have contributed equally to this work.

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Ahn, C.B., Lee, JH., Kim, J.H. et al. Development of a 3D subcutaneous construct containing insulin-producing beta cells using bioprinting. Bio-des. Manuf. 5, 265–276 (2022). https://doi.org/10.1007/s42242-021-00178-9

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