Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells

Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by im...

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Published in:	Nature biomedical engineering Vol. 7; no. 11; pp. 1419 - 1436
Main Authors:	Padmanabhan, Jagannath, Chen, Kellen, Sivaraj, Dharshan, Henn, Dominic, Kuehlmann, Britta A., Kussie, Hudson C., Zhao, Eric T., Kahn, Anum, Bonham, Clark A., Dohi, Teruyuki, Beck, Thomas C., Trotsyuk, Artem A., Stern-Buchbinder, Zachary A., Than, Peter A., Hosseini, Hadi S., Barrera, Janos A., Magbual, Noah J., Leeolou, Melissa C., Fischer, Katharina S., Tigchelaar, Seth S., Lin, John Q., Perrault, David P., Borrelli, Mimi R., Kwon, Sun Hyung, Maan, Zeshaan N., Dunn, James C. Y., Nazerali, Rahim, Januszyk, Michael, Prantl, Lukas, Gurtner, Geoffrey C.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-11-2023 Nature Publishing Group
Subjects:	13/1 13/106 13/107 13/51 692/308/575 692/4017 Animals Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Body size Foreign-Body Reaction Humans Implants Mechanical properties Mechanotransduction Mechanotransduction, Cellular Mice Myeloid cells Myeloid Cells - pathology Prostheses and Implants Rac2 protein Signal Transduction Silicones Transplants & implants
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Summary:	Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellular and tissue levels can be induced in mice via the application of human-tissue-scale forces through a vibrating silicone implant. FBRs to such elevated extrinsic forces in the mice were also mediated by the activation of Rac2 signalling in a subpopulation of mechanoresponsive myeloid cells, which could be substantially reduced via the pharmacological or genetic inhibition of Rac2 . Our findings provide an explanation for the stark differences in FBRs observed in small animals and humans, and have implications for the design and safety of implantable devices. Elevated extrinsic tissue-scale forces can drive pathological foreign-body responses to implants, mediated by the Rac2 -mediated activation of a subpopulation of mechanoresponsive myeloid cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2157-846X 2157-846X
DOI:	10.1038/s41551-023-01091-5