J. Padmanabhan1, T. Dohi1, Z. A. Stern-Buchbinder1, P. A. Than1, A. Trotsyuk1, S. H. Kwon1, Z. Maan1, G. C. Gurtner1 1Stanford University,Surgery,Palo Alto, CA, USA
Introduction.
Biomedical implants such as pacemakers, breast implants, and biosensors are employed to improve the quality of life for millions of patients worldwide. Implant performance and longevity is primarily limited by foreign body reaction (FBR), which is a fibrotic reaction characterized by accumulation of cells, proteins, and other biological materials at the implant-tissue interface. Severe FBR leads to formation of thick, collagen-rich FBR capsules, poor implant-tissue integration and implant rejection. We have previously shown that severe fibrosis during wound healing, a process closely related to FBR, is mediated by mechanical force (mechanotransduction). The role of mechanotransduction in FBR severity is not clear since currently used animal models do not recapitulate the mechanical environment around biomedical implants in humans. Moreover, which specific cellular subpopulations are involved and how mechanical cues activate these cells remain unknown.
Methods.
We developed a novel surgical model to study mechanically-induced severe FBR in mice. Briefly, we manufactured cylindrical silicone implants which could be adapted to house small, prefabricated coin motors that can be powered using an external battery to induce implant vibration. Vibration-enabled implants and control silicone implants were implanted subcutaneously in mice for 2 and 4 weeks. Beginning on post-operative day 4, mice with vibration-enabled implants were sedated and their implants vibrated 1 hour daily for 8 days. FBR capsules from the murine models were compared to human FBR tissue using immunohistochemistry to validate the improved murine model.
Further, FBR tissue from the improved murine model were analyzed using single cell sequencing (scRNA-seq) and proteomics analyses to identify critical mechanotransduction pathways that mediate FBR. Finally, we collected and analyzed various biomedical implants (pacemakers, chest batteries etc.) explanted from human patients to confirm the findings.
Results.
The mechanical environment around biomedical implants in humans can be recreated in mice by using vibration-enabled silicone implants. This is an improved and easily reproducible model, which elicits human-like FBR to model silicone biomaterials in mice. We employed this improved model to study the role of mechanotransduction in adverse implant-tissue interactions. scRNA-seq identified unique clusters of cells that highly express the IQGAP1/Rho-GTPase pathway, are upregulated in FBR. Comparative protein analyses of FBR capsules and control subcutaneous tissue confirmed the above findings. Additionally, IQGAP1/Rho-GTPase pathway components were detected at both transcript and protein levels in human FBR tissue, further corroborating the animal data.
Conclusions.
IQGAP1/Rho-GTPase pathway is a promising target for therapies aimed at reducing FBR. Further studies are underway to confirm these findings and develop therapeutic strategies to limit FBR.