Designing a Murine Model of the Foreign Body Reaction
Jagannath Padmanabhan, PhD, Zachary A. Stern-Buchbinder, MS, Teruyuki Dohi, MD, PhD, Peter Than, MD, Geoffrey C. Gurtner, MD, FACS.
Stanford University School of Medicine, Stanford, CA, USA.
PURPOSE: Biomedical implants such as pacemakers, breast implants, artificial joints, and biosensors have vastly improved quality of life for patients worldwide. Over time, implant performance can be compromised by a fibrotic response known as the foreign body reaction (FBR). The FBR varies in severity with the most serious presentation, referred to here as “Hyper FBR”, involving formation of a proteinaceous capsule leading to implant rejection and failure, often requiring invasive and expensive device removal or replacement procedures. Hyper FBR-mediated implant failure remains the primary challenge in improving biomedical device function and longevity in patients. Development of an animal model that mimics severe FBR could be used to identify which factors give rise to this exaggerated response and to identify cellular and molecular targets for prophylaxis and therapy. Our lab has previously shown that applied mechanical stress can increase the severity of fibrotic reaction during wound healing by activation of mechanotransduction pathways. Here we hypothesized that application of mechanical stress by vibration of motorized implants might induce hyper FBR.
METHODS: We manufactured cylindrical polydimethylsiloxane (PDMS) implants which could be adapted to house small, prefabricated coin motors. The coin motors can be powered using an external battery to induce vibration of PDMS implants in situ. These vibration-enabled implants were implanted in the subcutaneous space of WT C57/BL6 mice. Non-vibrating PDMS implants were used as controls. Beginning on post-operative day 4, mice with vibration-enabled implants were sedated and their implants vibrated 1 hour daily for 8 days. Subsequently, mice from each group were euthanized at 2-week and 4-week endpoints, and implants were resected en-bloc with surrounding capsule and tissue intact. Fibrotic tissue surrounding the implants was analyzed using: 1. immunohistochemistry to analyze tissue fibrosis, 2. mass spectrometry to analyze protein content of FBR capsules, and 3. single-cell RNA sequencing to identify cells that mediate hyper FBR. Additionally, patient-derived FBR capsules from explanted biomedical devices were analyzed for validation of the animal model.
RESULTS: Histological analyses of tissue around the implants sections revealed that mechanical vibration of PDMS implants leads to an increased fibrotic reaction. At the 2-week timepoint, tissue surrounding control implants was predominantly granulation tissue, characterized by an early inflammatory response with increased vascularization. In contrast, tissue surrounding vibration-enabled implants displayed a more mature collagenous capsule formation. Additionally, analysis of trichrome-stained tissue sections revealed a significant increase in average collagen density around vibration-enabled implants as compared to controls. Comparison of FBR capsules from mice and humans revealed that the vibration-enabled implants in mice more closely resembled the tissue architecture of human FBR capsules than controls.
CONCLUSION: Our data suggests that this novel Hyper FBR mouse model may approximate clinical implant encapsulation and rejection seen in human patients. We are currently investigating specific mechanotransduction pathways activated during hyper FBR, which could serve as potential targets for therapy. Further research may lead to the development of specialized treatments which attenuate FBR and prolong optimal function of biomedical implants.
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