A wireless, battery-free device enables oxygen generation and immune protection of therapeutic xenotransplants in vivo
Contributed by Robert Langer; received July 13, 2023; accepted August 10, 2023; reviewed by Sharon Gerecht and David Putnam
Significance
Cell therapies for protein replacement result in functional cures for patients with chronic, life-threatening conditions such as Type 1 Diabetes (T1D), but their development has been limited by challenges in maintaining transplanted cell viability in vivo. Attack from host immune tissue and low oxygen levels represent two major causes of failure. This work addresses both challenges through an immune-isolating device that houses and oxygenates transplanted cells in vivo. The device oxygenates cells via electrolytic water vapor splitting inside the body, obviating the need for pumps and fluid handling mechanisms. The device is battery-free and relies on wireless energy harvesting, addressing challenges associated with battery recharging, size, and toxicity, potentially allowing for long-lived cell therapies in subcutaneous sites.
Abstract
The immune isolation of cells within devices has the potential to enable long-term protein replacement and functional cures for a range of diseases, without requiring immune suppressive therapy. However, a lack of vasculature and the formation of fibrotic capsules around cell immune-isolating devices limits oxygen availability, leading to hypoxia and cell death in vivo. This is particularly problematic for pancreatic islet cells that have high O2 requirements. Here, we combine bioelectronics with encapsulated cell therapies to develop the first wireless, battery-free oxygen-generating immune-isolating device (O2-Macrodevice) for the oxygenation and immune isolation of cells in vivo. The system relies on electrochemical water splitting based on a water-vapor reactant feed, sustained by wireless power harvesting based on a flexible resonant inductive coupling circuit. As such, the device does not require pumping, refilling, or ports for recharging and does not generate potentially toxic side products. Through systematic in vitro studies with primary cell lines and cell lines engineered to secrete protein, we demonstrate device performance in preventing hypoxia in ambient oxygen concentrations as low as 0.5%. Importantly, this device has shown the potential to enable subcutaneous (SC) survival of encapsulated islet cells, in vivo in awake, freely moving, immune-competent animals. Islet transplantation in Type I Diabetes represents an important application space, and 1-mo studies in immune-competent animals with SC implants show that the O2-Macrodevice allows for survival and function of islets at high densities (~1,000 islets/cm2) in vivo without immune suppression and induces normoglycemia in diabetic animals.
Data, Materials, and Software Availability
All study data are included in the article and/or supporting information.
Acknowledgments
This work was funded by the Juvenile Diabetes Research Foundation (JDRF), (grant 3-SRA-2022-1098-S-B), the Leona M. and Harry B. Helmsley Charitable trust (2102-04997) and the NIH (NIH R01EB031992). S.R.K gratefully acknowledges funding from the JDRF (postdoctoral fellowship 3-PDF-2022-1138-A-N) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB-NIH) (K99EB032427). S.B. acknowledges funding from the NIBIB-NIH (K99EB025254). We thank Dr. Philipp Gutruf for insightful discussions. Device fabrication and assembly was partly performed at MIT.Nano, and we acknowledge the contributions of MIT.Nano staff members Dennis Ward, Donal Jamieson, and Kurt Broderick in helping refine our fabrication processes and in maintaining essential equipment. Finally, we thank the Joslin Diabetes Center for providing us isolated rat islets that we used in the studies described here.
Author contributions
S.R.K., M.A.B., S.B., R.L., and D.G.A. designed research; S.R.K., C.L., M.A.B., N.K., B.W., L.O., A.F., R.L., and D.G.A. performed research; S.R.K., C.L., M.A.B., N.K., R.L., and D.G.A. analyzed data; and S.R.K., R.L., and D.G.A. wrote the paper.
Competing interests
S.R.K, M.A.B, S.B, N.K, R.L., and D.G.A are inventors on a patent application relevant to the technology described in the above work. D.G.A is on the Scientific advisory board of Sigilon Therapeutics, a biotechnology company based in Cambridge, MA, that develops antifibrotic materials for microencapsulated cell-based therapies. R.L. receives licensing fees (to patents in which he was an inventor on) from, invested in, consults (or was on Scientific Advisory Boards or Boards of Directors) for, lectured (and received a fee), or conducts sponsored research at MIT for which he was not paid for a large number of entities. A full list can be found in SI Appendix.
Supporting Information
Appendix 01 (PDF)
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Movie S1.
180x speed video of continuous wireless, battery‒free oxygen and hydrogen generation from O2‒Macrodevice in deionized water.
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- 24.20 MB
Movie S2.
180x speed video of pulsed mode wireless battery‒free oxygen and hydrogen generation from O2‒Macrodevice in deionized water, operated at a duty cycle of 50%.
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- 24.40 MB
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Copyright
Copyright © 2023 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Data, Materials, and Software Availability
All study data are included in the article and/or supporting information.
Submission history
Received: July 13, 2023
Accepted: August 10, 2023
Published online: September 22, 2023
Published in issue: October 3, 2023
Keywords
Acknowledgments
This work was funded by the Juvenile Diabetes Research Foundation (JDRF), (grant 3-SRA-2022-1098-S-B), the Leona M. and Harry B. Helmsley Charitable trust (2102-04997) and the NIH (NIH R01EB031992). S.R.K gratefully acknowledges funding from the JDRF (postdoctoral fellowship 3-PDF-2022-1138-A-N) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB-NIH) (K99EB032427). S.B. acknowledges funding from the NIBIB-NIH (K99EB025254). We thank Dr. Philipp Gutruf for insightful discussions. Device fabrication and assembly was partly performed at MIT.Nano, and we acknowledge the contributions of MIT.Nano staff members Dennis Ward, Donal Jamieson, and Kurt Broderick in helping refine our fabrication processes and in maintaining essential equipment. Finally, we thank the Joslin Diabetes Center for providing us isolated rat islets that we used in the studies described here.
Author contributions
S.R.K., M.A.B., S.B., R.L., and D.G.A. designed research; S.R.K., C.L., M.A.B., N.K., B.W., L.O., A.F., R.L., and D.G.A. performed research; S.R.K., C.L., M.A.B., N.K., R.L., and D.G.A. analyzed data; and S.R.K., R.L., and D.G.A. wrote the paper.
Competing interests
S.R.K, M.A.B, S.B, N.K, R.L., and D.G.A are inventors on a patent application relevant to the technology described in the above work. D.G.A is on the Scientific advisory board of Sigilon Therapeutics, a biotechnology company based in Cambridge, MA, that develops antifibrotic materials for microencapsulated cell-based therapies. R.L. receives licensing fees (to patents in which he was an inventor on) from, invested in, consults (or was on Scientific Advisory Boards or Boards of Directors) for, lectured (and received a fee), or conducts sponsored research at MIT for which he was not paid for a large number of entities. A full list can be found in SI Appendix.
Notes
Reviewers: S.G., Duke University; and D.P., Cornell University.
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