Abstract

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type 1 diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in rodent models of diabetes; however, humans transplanted with equivalent microsphere formulations have experienced only transient islet graft function owing to a vigorous foreign-body response (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing in non-human primate (NHP) models of seven alginate formulations that were efficacious in rodents, including three that led to transient islet graft function in clinical trials. All formulations elicited significant FBR and PFO 1 month post implantation; however, three chemically modified, immune-modulating alginate formulations elicited a reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency.

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Acknowledgements

This work was supported jointly by the Chicago Diabetes Project and the JDRF and the Leona M. and Harry B. Helmsley Charitable Trust (grant number 3-SRA-2014-285-M-R (R.L. and D.G.A.)), the US National Institutes of Health (grant numbers DK091526 (J.O.) EB000244 (R.L.), EB000351 (R.L.), DE013023 (R.L.), CA151884 (R.L.) and UC4DK104218 (D.L.G.)), and through a gift from the Tayebati Family Foundation (D.G.A. and R.L.). This work was also supported by the Slovak Research and Development Agency under contract number APVV-14-858 (I.L.). O.V. was supported by JDRF and Department of Defense Congressionally Directed Medical Research Program (DOD/CDMRP) postdoctoral fellowships (grant numbers 3-2013-178 and W81XWH-13-1-0215, respectively). J.C.D. was supported by a JDRF postdoctoral fellowship (grant number 3-PDF-2015-91-A-N). The authors acknowledge L. Halliday and the veterinary staff at the Biological Resource Laboratories at UIC for their assistance and technical support during the course of the studies. We thank R. Calafiore and G. Basta from the University of Perugia for producing the A-PLO-A spheres under current good manufacturing practice conditions at the University of Illinois at Chicago for the herein described experiments. We thank B. Tuch and his team at the Diabetes Transplant Unit, Prince of Wales Hospital, Sydney, Australia, for the production of the UPMVG-Ba2+ spheres and sharing his experience from the clinical trials in encapsulated islet transplant trials conducted in Sydney, Australia. We thank H. H. Tam for his advice on the statistical analysis of datasets.

Author information

Author notes

    • Omid Veiseh
    • , Jie Li
    •  & Karsten Olejnik

    Present address: Department of Bioengineering, Rice University, Houston, TX, USA

    • Arturo J. Vegas

    Present address: Chemistry Department, Boston University, Boston, MA, USA

    • James J. McGarrigle
    • , Douglas Isa
    •  & Sofia Ghani

    Present address: CellTrans Inc., Chicago, IL, USA

    • Mohammad Nourmohammadzadeh

    Present address: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA

    • Yuan Xing
    • , Yong Wang
    •  & Jose Oberholzer

    Present address: Department of Surgery and Biomedical Engineering, University of Virginia, Charlottesville, VA, USA

  1. These authors contributed equally to this work: Matthew A. Bochenek, Omid Veiseh.

Affiliations

  1. Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA

    • Matthew A. Bochenek
    • , James J. McGarrigle
    • , Meirigeng Qi
    • , Enza Marchese
    • , Mustafa Omami
    • , Joshua Mendoza-Elias
    • , Mohammad Nourmohammadzadeh
    • , Arshad Khan
    • , Chun-Chieh Yeh
    • , Yuan Xing
    • , Douglas Isa
    • , Sofia Ghani
    • , Yong Wang
    •  & Jose Oberholzer
  2. Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA

    • Matthew A. Bochenek
    • , Joshua Mendoza-Elias
    • , Mohammad Nourmohammadzadeh
    • , Yuan Xing
    • , Yong Wang
    •  & Jose Oberholzer
  3. David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Matthew A. Bochenek
    • , Omid Veiseh
    • , Arturo J. Vegas
    • , Joshua C. Doloff
    • , Jie Li
    • , Casey Landry
    • , Andrew R. Bader
    • , Karsten Olejnik
    • , Michael Chen
    • , Robert Langer
    •  & Daniel G. Anderson
  4. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Matthew A. Bochenek
    • , Omid Veiseh
    • , Arturo J. Vegas
    • , Joshua C. Doloff
    • , Jie Li
    • , Casey Landry
    • , Andrew R. Bader
    • , Karsten Olejnik
    • , Michael Chen
    • , Robert Langer
    •  & Daniel G. Anderson
  5. Department of Anesthesiology, Boston Children’s Hospital, Boston, MA, USA

    • Matthew A. Bochenek
    • , Omid Veiseh
    • , Arturo J. Vegas
    • , Joshua C. Doloff
    • , Jie Li
    • , Casey Landry
    • , Andrew R. Bader
    • , Karsten Olejnik
    • , Michael Chen
    • , Robert Langer
    •  & Daniel G. Anderson
  6. Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, MA, USA

    • Jennifer Hollister-Lock
    •  & Gordon C. Weir
  7. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    • Dale L. Greiner
  8. Department of Biotechnology and Food Sciences, Norwegian University of Science and Technology, Trondheim, Norway

    • Berit Løkensgard Strand
  9. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    • Anne Mari A. Rokstad
  10. Centre of Obesity, Clinic of Surgery, St. Olavs University Hospital, Trondheim, Norway

    • Anne Mari A. Rokstad
  11. Polymer Institute, Slovak Academy of Sciences, Bratislava, Slovakia

    • Igor Lacik
  12. Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA

    • Robert Langer
    •  & Daniel G. Anderson
  13. Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Robert Langer
    •  & Daniel G. Anderson
  14. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Robert Langer
    •  & Daniel G. Anderson
  15. Sigilon Therapeutics, Inc., Cambridge, MA, USA

    • Omid Veiseh
    • , Jie Li
    •  & Karsten Olejnik

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Contributions

M.A.B., O.V., A.J.V., J.J.M., D.G.A. and J.O. designed the experiments, analysed the data and wrote the manuscript. M.A.B., O.V., A.J.V., J.J.M., M.Q., E.M., M.O., J.C.D., J.M.-E., M.N., A.K., C.-C.Y., Y.X., D.I., S.G., J.L., C.L., A.R.B., K.O., M.C., Y.W. and J.O. performed experiments. J.H.-L., D.L.G., G.C.W., B.L.S., A.M.A.R., I.L. and R.L. provided conceptual advice and technical support. R.L., D.G.A. and J.O. supervised the study. All of the authors discussed the results and assisted in the preparation of the manuscript.

Competing interests

O.V., A.J.V., R.L., D.G.A. and J.O. are founding scientists of Sigilon Therapeutics, a biotech company based in Cambridge, MA, USA, that produces antifibrotic materials for cell-based therapies. J.O. is founder and President of CellTrans, a biotech company based in Chicago, IL, USA, for the transplantation of cell-based therapies.

Corresponding authors

Correspondence to Daniel G. Anderson or Jose Oberholzer.

Supplementary information

  1. Supplementary Information

    Supplementary figures and tables

  2. Reporting Summary

  3. Supplementary Video 1

    Non-invasive laparoscopic transplantation technique for hydrogel spheres into the bursa omentalis

  4. Supplementary Video 2

    Non-invasive laparoscopic retrieval of Z1-Y15 spheres containing allogeneic islets performed 1-month post-transplantation

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https://doi.org/10.1038/s41551-018-0275-1

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