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

Nature Biomedical Engineering volume 4, pages 814–826 (2020)Cite this article

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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.

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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.

References

  1. Towards advanced cell therapies. Nat. Biomed. Eng. 2, 339–340 (2018).

  2. Sedlmayer, F., Aubel, D. & Fussenegger, M. Synthetic gene circuits for the detection, elimination and prevention of disease. Nat. Biomed. Eng. 2, 399–415 (2018).

    CAS  PubMed  Google Scholar 

  3. Aijaz, A. et al. Biomanufacturing for clinically advanced cell therapies. Nat. Biomed. Eng. 2, 362–376 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Xie, M. et al. β-cell-mimetic designer cells provide closed-loop glycemic control. Science 354, 1296–1301 (2016).

    CAS  PubMed  Google Scholar 

  5. Kojima, R. et al. Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment. Nat. Commun. 9, 5066 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Power, A. T. et al. Carrier cell-based delivery of an oncolytic virus circumvents antiviral immunity. Mol. Ther. 15, 123–130 (2007).

    CAS  PubMed  Google Scholar 

  7. Chassin, H. et al. Sensing and responding to allergic response cytokines through a genetically encoded circuit. Nat. Commun. 8, 1101 (2017).

    PubMed  PubMed Central  Google Scholar 

  8. Pagliuca, F. W. et al. Generation of functional human pancreatic β cells in vitro. Cell 159, 428–439 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Millman, J. R. et al. Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nat. Commun. 7, 11463 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Desai, T. & Shea, L. D. Advances in islet encapsulation technologies. Nat. Rev. Drug Discov. 16, 338–350 (2017).

    CAS  PubMed  Google Scholar 

  11. Wood, K. J., Issa, F. & Hester, J. Understanding stem cell immunogenicity in therapeutic applications. Trends Immunol. 37, 5–16 (2016).

    CAS  PubMed  Google Scholar 

  12. Phelps, E. A. et al. Maleimide cross-linked bioactive PEG hydrogel exhibits improved reaction kinetics and cross-linking for cell encapsulation and in situ delivery. Adv. Mater. 24, 64–70 (2012).

    CAS  PubMed  Google Scholar 

  13. An, D. et al. Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes. Proc. Natl Acad. Sci. USA 115, E263–E272 (2018).

    CAS  PubMed  Google Scholar 

  14. An, D. et al. Developing robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) for cell therapies. Biomaterials 37, 40–48 (2015).

    CAS  PubMed  Google Scholar 

  15. Weir, G. C. Islet encapsulation: advances and obstacles. Diabetologia 56, 1458–1461 (2013).

    CAS  PubMed  Google Scholar 

  16. Hwa, A. J. & Weir, G. C. Transplantation of macroencapsulated insulin-producing cells. Curr. Diab. Rep. 18, 50 (2018).

    PubMed  Google Scholar 

  17. Colton, C. K. in Principles of Tissue Engineering 543–562 (Academic Press, 2014).

  18. Nyitray, C. E. et al. Polycaprolactone thin-film micro- and nanoporous cell-encapsulation devices. ACS Nano 9, 5675–5682 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chang, R. et al. Nanoporous immunoprotective device for stem-cell-derived β-cell replacement therapy. ACS Nano 11, 7747–7757 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kumagai-Braesch, M. et al. The TheraCyte device protects against islet allograft rejection in immunized hosts. Cell Transplant. 22, 1137–1146 (2013).

    PubMed  Google Scholar 

  21. Pedraza, E., Coronel, M. M., Fraker, C. A., Ricordi, C. & Stabler, C. L. Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials. Proc. Natl Acad. Sci. USA 109, 4245–4250 (2012).

    CAS  PubMed  Google Scholar 

  22. Paul, C. D., Mistriotis, P. & Konstantopoulos, K. Cancer cell motility: lessons from migration in confined spaces. Nat. Rev. Cancer 17, 131–140 (2017).

    CAS  PubMed  Google Scholar 

  23. Anderson, J. M., Rodriguez, A. & Chang, D. T. Foreign body reaction to biomaterials. Semin. Immunol. 20, 86–100 (2008).

    CAS  PubMed  Google Scholar 

  24. Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34, 345–352 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Vegas, A. J. et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived β-cells in immune-competent mice. Nat. Med. 22, 306–311 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bochenek, M. A. et al. Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat. Biomed. Eng. 2, 810–821 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Pullen, L. C. Stem cell-derived pancreatic progenitor cells have now been transplanted into patients: report from IPITA 2018. Am. J. Transplant. 18, 1581–1582 (2018).

    PubMed  Google Scholar 

  28. Mahou, R., Zhang, D. K. Y., Vlahos, A. E. & Sefton, M. V. Injectable and inherently vascularizing semi-interpenetrating polymer network for delivering cells to the subcutaneous space. Biomaterials 131, 27–35 (2017).

    CAS  PubMed  Google Scholar 

  29. Weaver, J. D. et al. Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation. Biomaterials 172, 54–65 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ludwig, B. et al. Transplantation of human islets without immunosuppression. Proc. Natl Acad. Sci. USA 110, 19054–19058 (2013).

    CAS  PubMed  Google Scholar 

  31. Whyte, W. et al. Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir. Nat. Biomed. Eng. 2, 416–428 (2018).

    CAS  PubMed  Google Scholar 

  32. Lee, K. S. & Ram, R. J. Plastic–PDMS bonding for high pressure hydrolytically stable active microfluidics. Lab Chip 9, 1618–1624 (2009).

    CAS  PubMed  Google Scholar 

  33. Lovett, M., Lee, K., Edwards, A. & Kaplan, D. L. Vascularization strategies for tissue engineering. Tissue Eng. Part B Rev. 15, 353–370 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mendelsohn, A. & Desai, T. Inorganic nanoporous membranes for immunoisolated cell-based drug delivery. Adv. Exp. Med. Biol. 670, 104–125 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Scalea, J., Hanecamp, I., Robson, S. C. & Yamada, K. T-cell-mediated immunological barriers to xenotransplantation. Xenotransplantation 19, 23–30 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. Leader, B., Baca, Q. J. & Golan, D. E. Protein therapeutics: a summary and pharmacological classification. Nat. Rev. Drug Discov. 7, 21–39 (2008).

    CAS  PubMed  Google Scholar 

  37. Lee, D. E., Son, W., Ha, B. J., Oh, M. S. & Yoo, O. J. The prolonged half-lives of new erythropoietin derivatives via peptide addition. Biochem. Biophys. Res. Commun. 339, 380–385 (2006).

    CAS  PubMed  Google Scholar 

  38. Régulier, E., Schneider, B. L., Déglon, N., Beuzard, Y. & Aebischer, P. Continuous delivery of human and mouse erythropoietin in mice by genetically engineered polymer encapsulated myoblasts. Gene Ther. 5, 1014–1022 (1998).

    PubMed  Google Scholar 

  39. Schweicher, J., Nyitray, C. & Desai, T. A. Membranes to achieve immunoprotection of transplanted islets. Front. Biosci. 19, 49–76 (2014).

    Google Scholar 

  40. Chong, A. S., Alegre, M.-L., Miller, M. L. & Fairchild, R. L. Lessons and limits of mouse models. Cold Spring Harb. Perspect. Med. 3, a015495 (2013).

    PubMed  PubMed Central  Google Scholar 

  41. Tucker, S. P., Melsen, L. R. & Compans, R. W. Migration of polarized epithelial cells through permeable membrane substrates of defined pore size. Eur. J. Cell Biol. 58, 280–290 (1992).

    CAS  PubMed  Google Scholar 

  42. Bryers, J. D., Giachelli, C. M. & Ratner, B. D. Engineering biomaterials to integrate and heal: the biocompatibility paradigm shifts. Biotechnol. Bioeng. 109, 1898–1911 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Whyte, W. et al. Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir. Nat. Biomed. Eng. 2, 416–428 (2018).

    CAS  PubMed  Google Scholar 

  44. Zhang, L. et al. Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. Nat. Biotechnol. 31, 553–556 (2013).

    CAS  PubMed  Google Scholar 

  45. Smith, R. S. et al. Vascular catheters with a nonleaching poly-sulfobetaine surface modification reduce thrombus formation and microbial attachment. Sci. Transl. Med. 4, 153ra132 (2012).

    PubMed  Google Scholar 

  46. Xie, X. et al. Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer. Nat. Biomed. Eng. 2, 894–906 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Jin, X., Yuan, J. & Shen, J. Zwitterionic polymer brushes via dopamine-initiated ATRP from PET sheets for improving hemocompatible and antifouling properties. Colloids Surf. B Biointerfaces 145, 275–284 (2016).

    CAS  PubMed  Google Scholar 

  48. Veiseh, O. et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat. Mater. 14, 643–651 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Tireli, M. et al. Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole. Beilstein J. Org. Chem. 13, 2352–2363 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Régulier, E., Schneider, B. L., Déglon, N., Beuzard, Y. & Aebischer, P. Continuous delivery of human and mouse erythropoietin in mice by genetically engineered polymer encapsulated myoblasts. Gene Ther. 5, 1014–1022 (1998).

    PubMed  Google Scholar 

  51. Sommer, B. et al. Long-term doxycycline-regulated secretion of erythropoietin by encapsulated myoblasts. Mol. Ther. 6, 155–161 (2002).

    CAS  PubMed  Google Scholar 

  52. Weber, L. M. & Anseth, K. S. Hydrogel encapsulation environments functionalized with extracellular matrix interactions increase islet insulin secretion. Matrix Biol. 27, 667–673 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Suzuki, K. et al. Function and survival of macroencapsulated syngeneic islets transplanted into streptozocin-diabetic mice. Transplantation 66, 21–28 (1998).

    CAS  PubMed  Google Scholar 

  54. Neufeld, T. et al. The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs. PLoS ONE 8, e70150 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Salehi, S. & Reed, E. F. The divergent roles of macrophages in solid organ transplantation. Curr. Opin. Organ Transpl. 20, 446–453 (2015).

    CAS  Google Scholar 

  56. Morris, D. L. Minireview: emerging concepts in islet macrophage biology in type 2 diabetes. Mol. Endocrinol. 29, 946–962 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kang, J. W. et al. Combined confocal Raman and quantitative phase microscopy system for biomedical diagnosis. Biomed. Opt. Express 2, 2484–2492 (2011).

    PubMed  PubMed Central  Google Scholar 

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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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Author notes

  1. Siddharth Jhunjhunwala

    Present address: Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India

  2. Omid Veiseh

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

  3. These authors contributed equally: Lisa R. Volpatti, Devina Thiono.

Authors and Affiliations

  1. David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Suman Bose, Lisa R. Volpatti, Devina Thiono, Volkan Yesilyurt, Collin McGladrigan, Yaoyu Tang, Amanda Facklam, Siddharth Jhunjhunwala, Omid Veiseh, Chandrabali Bhattacharya, Robert Langer & Daniel G. Anderson

  2. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Lisa R. Volpatti, Amy Wang, Robert Langer & Daniel G. Anderson

  3. Department of Anesthesiology, Boston Children’s Hospital, Boston, MA, USA

    Devina Thiono, Volkan Yesilyurt, Collin McGladrigan, Yaoyu Tang, Robert Langer & Daniel G. Anderson

  4. Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, MA, USA

    Jennifer Hollister-Lock & Gordon C. Weir

  5. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Dale L. Greiner

  6. Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer & Daniel G. Anderson

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Contributions

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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