Prevention of the foreign body response to implantable medical devices by inflammasome inhibition

Damiano G. Barone; Alejandro Carnicer-Lombarte; Panagiotis Tourlomousis; Russell S. Hamilton; Malwina Prater; Alexandra L. Rutz; Ivan B. Dimov; George G. Malliaras; Stephanie P. Lacour; Avril A.B. Robertson; Kristian Franze; James W. Fawcett; Clare E. Bryant

doi:10.1073/pnas.2115857119

Prevention of the foreign body response to implantable medical devices by inflammasome inhibition

Damiano G. Barone (Co-first Author), Alejandro Carnicer-Lombarte (Co-first Author), Panagiotis Tourlomousis, Russell S. Hamilton, Malwina Prater, Alexandra L. Rutz, Ivan B. Dimov, George G. Malliaras, Stephanie P. Lacour, Avril A.B. Robertson, Kristian Franze, James W. Fawcett^*, Clare E. Bryant^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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Abstract

Fibrotic scarring secondary to the foreign body reaction (FBR) generates a physical barrier obstructing the functional interaction of implantable medical devices with the host tissue. The mechanistic basis of the FBR is poorly understood, restricting the current therapeutic options to prevent it. Here, we show that in a peripheral nerve injury-implant model (NI) the FBR has a dysregulated innate immune profile recruiting M1-like activated macrophages, immature macrophages, activated dendritic cells, and immature dendritic cells compared with nerve injury alone, which recruits predominantly M2-like macrophages. The gene signature of the FBR shows increased myofibroblast activity, explaining why collagen and scarring are present, but also up-regulation of inflammasome constituents. Local delivery of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome inhibitor MCC950, through its incorporation into the silicone coating of implants, reduced the inflammation and fibrosis associated with both NI and subcutaneous implantable devices. In the NI model, MCC950 did not affect neuronal repair. Inhibition of the NLRP3 inflammasome may, therefore, be a promising therapeutic approach to prevent the FBR, hence prolonging the functional lifespan of implantable medical devices and neural implants. Copyright © 2022 the Author(s).

Original language	English
Article number	e2115857119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	12
Online published	17 Mar 2022
DOIs	https://doi.org/10.1073/pnas.2115857119
Publication status	Published - 22 Mar 2022
Externally published	Yes

Funding

Part of the RNA-seq work was performed with the Genomics and Transcriptomics Core, which is funded by the UK Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_00014/5) and a Wellcome Trust Major Award (208363/Z/17/Z), and with guidance from Marcella Ma, whom we wish to thank. C.E.B. was supported by a Wellcome Trust Investigator Award (108045/Z/15/Z). This work was also supported by the UK Wellcome Trust (Translational Medicine and Therapeutics PhD Programme Fellowship 109511/Z/15/Z to D.G.B.), UK Health Education England and National Institute for Health Research (HEE/NIHR Integrated Clinical Academic Program Clinical Lectureship CL-2019-14-004 to D.G.B.), UK MRC and Sackler Foundation (Doctoral Training Grant RG70550 to A.C.-L.), Engineering and Physical Sciences Research Council Cambridge NanoDTC (EP/L015978/1), Centre for Trophoblast Research (M.P. and R.S.H.), Whitaker International Scholars Program (A.L.R.), the European Commission?s Horizon 2020 (Marie Sklodowska-Curie Fellowship 797506 to A.L.R.), Bertarelli Foundation (S.P.L.), European Research Council (Consolidator Award 772426 to K.F.), UK Biotechnology and Biological Sciences Research Council (Research Grant BB/N006402/1 to K.F.), and Alexander von Humboldt Foundation (Humboldt Professorship to K.F.). This research was funded in whole, or in part, by the Wellcome Trust (Grants 109511/Z/15/Z and 108045/Z/15/Z).

Research Keywords

Foreign body reaction
MCC950
Neural interfaces
NLRP3 inflammasome

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This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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Barone, D. G., Carnicer-Lombarte, A., Tourlomousis, P., Hamilton, R. S., Prater, M., Rutz, A. L., Dimov, I. B., Malliaras, G. G., Lacour, S. P., Robertson, A. A. B., Franze, K., Fawcett, J. W., & Bryant, C. E. (2022). Prevention of the foreign body response to implantable medical devices by inflammasome inhibition. Proceedings of the National Academy of Sciences of the United States of America, 119(12), Article e2115857119. https://doi.org/10.1073/pnas.2115857119

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title = "Prevention of the foreign body response to implantable medical devices by inflammasome inhibition",

abstract = "Fibrotic scarring secondary to the foreign body reaction (FBR) generates a physical barrier obstructing the functional interaction of implantable medical devices with the host tissue. The mechanistic basis of the FBR is poorly understood, restricting the current therapeutic options to prevent it. Here, we show that in a peripheral nerve injury-implant model (NI) the FBR has a dysregulated innate immune profile recruiting M1-like activated macrophages, immature macrophages, activated dendritic cells, and immature dendritic cells compared with nerve injury alone, which recruits predominantly M2-like macrophages. The gene signature of the FBR shows increased myofibroblast activity, explaining why collagen and scarring are present, but also up-regulation of inflammasome constituents. Local delivery of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome inhibitor MCC950, through its incorporation into the silicone coating of implants, reduced the inflammation and fibrosis associated with both NI and subcutaneous implantable devices. In the NI model, MCC950 did not affect neuronal repair. Inhibition of the NLRP3 inflammasome may, therefore, be a promising therapeutic approach to prevent the FBR, hence prolonging the functional lifespan of implantable medical devices and neural implants. Copyright {\textcopyright} 2022 the Author(s).",

keywords = "Foreign body reaction, MCC950, Neural interfaces, NLRP3 inflammasome",

author = "Barone, {Damiano G.} and Alejandro Carnicer-Lombarte and Panagiotis Tourlomousis and Hamilton, {Russell S.} and Malwina Prater and Rutz, {Alexandra L.} and Dimov, {Ivan B.} and Malliaras, {George G.} and Lacour, {Stephanie P.} and Robertson, {Avril A.B.} and Kristian Franze and Fawcett, {James W.} and Bryant, {Clare E.}",

year = "2022",

month = mar,

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doi = "10.1073/pnas.2115857119",

language = "English",

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Barone, DG, Carnicer-Lombarte, A, Tourlomousis, P, Hamilton, RS, Prater, M, Rutz, AL, Dimov, IB, Malliaras, GG, Lacour, SP, Robertson, AAB, Franze, K, Fawcett, JW & Bryant, CE 2022, 'Prevention of the foreign body response to implantable medical devices by inflammasome inhibition', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 12, e2115857119. https://doi.org/10.1073/pnas.2115857119

Prevention of the foreign body response to implantable medical devices by inflammasome inhibition. / Barone, Damiano G. (Co-first Author); Carnicer-Lombarte, Alejandro (Co-first Author); Tourlomousis, Panagiotis et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 12, e2115857119, 22.03.2022.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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T1 - Prevention of the foreign body response to implantable medical devices by inflammasome inhibition

AU - Barone, Damiano G.

AU - Carnicer-Lombarte, Alejandro

AU - Tourlomousis, Panagiotis

AU - Hamilton, Russell S.

AU - Prater, Malwina

AU - Rutz, Alexandra L.

AU - Dimov, Ivan B.

AU - Malliaras, George G.

AU - Lacour, Stephanie P.

AU - Robertson, Avril A.B.

AU - Franze, Kristian

AU - Fawcett, James W.

AU - Bryant, Clare E.

PY - 2022/3/22

Y1 - 2022/3/22

N2 - Fibrotic scarring secondary to the foreign body reaction (FBR) generates a physical barrier obstructing the functional interaction of implantable medical devices with the host tissue. The mechanistic basis of the FBR is poorly understood, restricting the current therapeutic options to prevent it. Here, we show that in a peripheral nerve injury-implant model (NI) the FBR has a dysregulated innate immune profile recruiting M1-like activated macrophages, immature macrophages, activated dendritic cells, and immature dendritic cells compared with nerve injury alone, which recruits predominantly M2-like macrophages. The gene signature of the FBR shows increased myofibroblast activity, explaining why collagen and scarring are present, but also up-regulation of inflammasome constituents. Local delivery of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome inhibitor MCC950, through its incorporation into the silicone coating of implants, reduced the inflammation and fibrosis associated with both NI and subcutaneous implantable devices. In the NI model, MCC950 did not affect neuronal repair. Inhibition of the NLRP3 inflammasome may, therefore, be a promising therapeutic approach to prevent the FBR, hence prolonging the functional lifespan of implantable medical devices and neural implants. Copyright © 2022 the Author(s).

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KW - Foreign body reaction

KW - MCC950

KW - Neural interfaces

KW - NLRP3 inflammasome

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JO - Proceedings of the National Academy of Sciences of the United States of America

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Prevention of the foreign body response to implantable medical devices by inflammasome inhibition

Abstract

Funding

Research Keywords

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