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A retrievable implant for the long-term encapsulation and survival of therapeutic xenogeneic cells

Abstract

The long-term function of transplanted therapeutic cells typically requires systemic immune suppression. Here, we show that a retrievable implant comprising a silicone reservoir and a porous polymeric membrane protects human cells encapsulated in it after implant transplantation in the intraperitoneal space of immunocompetent mice. Membranes with pores 1 µm in diameter allowed host macrophages to migrate into the device without the loss of transplanted cells, whereas membranes with pore sizes <0.8 µm prevented their infiltration by immune cells. A synthetic polymer coating prevented fibrosis and was necessary for the long-term function of the device. For >130 days, the device supported human cells engineered to secrete erythropoietin in immunocompetent mice, as well as transgenic human cells carrying an inducible gene circuit for the on-demand secretion of erythropoietin. Pancreatic islets from rats encapsulated in the device and implanted in diabetic mice restored normoglycaemia in the mice for over 75 days. The biocompatible device provides a retrievable solution for the transplantation of engineered cells in the absence of immunosuppression.

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Fig. 1: Overview of an implantable macrodevice and its pre-clinical development.
Fig. 2: Membrane pore size regulates immune cell infiltration and survival of xenografts in BALB/c mice.
Fig. 3: A biocompatible surface coating minimized foreign body reaction and prevents device failure in C57BL/6 mice.
Fig. 4: THPT coating reduces cellular buildup on the implanted devices.
Fig. 5: Long-term delivery of EPO in C57BL/6 mice in a sustained or on-demand manner, using coated macrodevices encapsulating HEKepo cells.
Fig. 6: Efficacy of the coated macrodevice encapsulating rat islets in curing STZ-induced diabetic C57BL/6 mice.

Data availability

The main data supporting the findings in this study are available within the paper and its Supplementary Information. The raw and analysed datasets are too numerous to be readily shared publicly. Source data for the figures are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by a JDRF grant (2-SRA-2019-714-S-B) and Leona M. and Harry B. Helmsley Charitable Trust Foundation Grant (2017PG-T1D027) to D.G.A. and R.L. S.B. was supported by the National Institutes of Health and NIBIB (K99EB025254) and a JDRF Postdoctoral Fellowship (PDF-2015-90-A-N). L.R.V. and A.F. were supported by the NSF Graduate Research Fellowship Program. S.J. was supported by the Mazumdar-Shaw oncology fellowship. O.V. was supported by a DOD/CDMRP postdoctoral fellowship (W81XWH-13-1-0215). D.L.G. is supported by the National Institutes of Health (UC4 DK104218). We acknowledge S. K. Aresta-Dasilva, C. Landry and A. Nguyen for assistance with the animal experiments. We also acknowledge S. Hrvatin for discussions. This work was supported in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute. We thank the Koch Institute Swanson Biotechnology Center for technical support (specifically the Histology, Proteomics and Flow Cytometry core facilities). We also acknowledge the use of resources at the W. M. Keck Biological Imaging Facility and the Genomics core at the Whitehead Institute. This work was performed in part at the Center for Nanoscale Systems, a member of the National Nanotechnology Coordinated Infrastructure network, which is supported by the National Science Foundation under NSF award number 1541959. The Center for Nanoscale Systems is part of Harvard University.

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S.B. and D.G.A. conceived the device, designed the study and wrote the manuscript. S.B., L.R.V., D.T., S.J., C.M., A.W., A.F., Y.T. and C.B. conducted the experiments. V.Y. helped to develop the surface modification method. J.H.-L. and G.C.W. isolated the rat islets and provided technical expertise. O.V., D.L.G. and R.L. provided conceptual advice and technical support. D.G.A. and R.L. supervised the study. All authors discussed the results and commented on the manuscript.

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Correspondence to Daniel G. Anderson.

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Competing interests

D.G.A., R.L. and O.V. are founding scientists of Sigilon Therapeutics—a biotechnology company based in Cambridge, Massachusetts, United States that produces anti-fibrotic materials for cell-based therapies. For a list of entities with which R.L. is involved, compensated or uncompensated, see https://www.dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0.

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Bose, S., Volpatti, L.R., Thiono, D. et al. A retrievable implant for the long-term encapsulation and survival of therapeutic xenogeneic cells. Nat Biomed Eng 4, 814–826 (2020). https://doi.org/10.1038/s41551-020-0538-5

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