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Rac2 Signaling Mediates Pathologic Foreign Body Response To Implanted Devices
Dharshan Sivaraj, BS, Jagannath Padmanabhan, PhD, Kellen Chen, PhD, Dominic Henn, MD, Hudson C. Kussie, BS, Melissa C. Leeolou, BS, Artem A. Trotsyuk, BS, David P. Perrault, MD, Janos A. Barrera, MD, Michael Januszyk, MD, Geoffrey C. Gurtner, MD.
Stanford University School of Medicine, Stanford, CA, USA.

PURPOSE:
Implanted medical devices, including breast implants, pacemakers, neurostimulators, and orthopedic protheses, are associated with more than $100 billion in annual global health care expenditures. However, between 10% and 30% of these devices fail prematurely. In most cases, implant failure occurs due to a phenomenon termed the foreign body response (FBR). FBR begins as a wound healing response to the trauma created from the insertion of a foreign object. A continued presence of the implant exacerbates this response, resulting in the formation of a collagenous fibrous capsule around the implanted object. This process eventually leads to device malfunction as well as distortion of the surrounding tissues. Currently, there are no FDA-approved therapies that effectively prevent debilitating fibrotic capsule formation and the resulting functional complications around biomedical devices.
METHODS: We compared human breast implant tissue and a novel murine model of FBR (mechanically stimulating implant or MSI model) to identify the key signaling pathways associated with pathological FBR. Subsequently, we utilized pathway analyses to identify potential molecular targets that are central to the signaling associated with pathological FBR. Finally, we employed small molecule inhibitors of mechanotransduction signaling in our mouse model as a proof of concept for a pharmacological strategy to target FBR and analyzed its effect on FBR capsule formation using immunostaining and histopathology.
RESULTS: We first identified that Rac2, a hematopoietic-specific Rho-GTPase, was differentially upregulated in Baker IV compared to Baker I breast implant capsule tissue. Additionally, single cell sequencing of murine capsule tissue from our MSI model of FBR revealed significant differences in the activation of Rac2 and associated inflammatory markers relative to standard murine implants. Finally, we demonstrated that pharmacologically blocking Rac2 signaling in our MSI model significantly reduced the degree of FBR capsule formation as measured by decreased capsule thickness, collagen deposition, and myofibroblast activation.
CONCLUSION: Our results highlight the important role of Rac2 as a mediator of pathologic foreign body response in both mice and humans. We demonstrate that pharmacological inhibition of Rac2 could potentially serve as an effective therapy to reduce FBR in patients receiving biomedical implants, thereby increasing patient quality of life and reducing implant failure rates. Further, these findings provide novel insights into the molecular mechanisms underlying fibrotic responses to implanted devices.


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