J. P. Yasmeh1, H. Kussie1, A. M. Alsharif1, E. McKenna1, M. Granoski1, A. Hostler1, K. Fischer1, M. Jafri1, G. Gurtner1, K. Chen1 1University Of Arizona, Surgery, Tucson, AZ, USA
Introduction: After device implantation, an immunological inflammatory response triggers the foreign body response (FBR) and fibrotic capsule formation. We have recently demonstrated that immune cell specific Rac mechanotransduction signaling may be the primary driver of the long term, pathological FBR in humans. However, our understanding of human FBR is limited to chronic, long term time points, as clinical devices are typically implanted in humans for many years prior to removal. How an FBR initially forms during acute time periods following implantation is not well understood.
Methods: We used our previously published (Padmanabhan et al., 2023, accepted in Nat Biomed Eng) polydimethylsiloxane (PDMS) mechanically stimulated implants (MSIs) to generate human-like FBR. These MSIs were comprised of Sylgard 184 PDMS (7.5 mm radius; 4 mm height), encapsulated coin motors to generate vibration, and were implanted using a modified Seldinger method into 15 male C57/BL6 mice. Implants were connected to external 3V batteries to initiate mechanical stimulation through vibration for an hour a day. 5 mice received saline injections (vehicle) and no mechanical stimulation (control); 5 received saline with mechanical stimulation (MSI); 5 received mechanical simulation with 5mg/kg NSC Rac inhibitor (RI) (MSI+RI). After one week, implants were explanted, and FBR tissue was analyzed using hematoxylin and eosin, trichrome, and picrosirius red staining combined with ImageJ, Matlab, CurveAlign, and CTfire.
Results: Control FBR tissue had an average capsule thickness of 124.2µm. Acute mechanical stimulation significantly increased the average capsule thickness by 2.3-fold to 284.8µm (p=0.0285). Histological ECM analysis with Picrosirius Red showed that acute mechanical stimulation triggered significantly longer (p=0.038), wider (p=0.007), and more aligned (p=0.015) collagen fibers compared to control capsules. Conversely, disruption of mechanical signaling with early Rac inhibition significantly reduced average thicknesses by about half to 133.8µm (p=0.0298), which was also not significantly different from controls.
Conclusion: While much is unknown about the early development of capsular development, our results demonstrate that intervention during these early time points may still have significant effects on acute FBR thickness. Mechanical stimulation at early time points triggered an immediately thickening of FBR tissue with increased fibrotic tissue architecture, and pharmacological disruption reduced the capsule thickness. These findings could potentially inform future clinical trials to build in primary efficacy endpoints at earlier stages instead of waiting for chronic, yearlong time points. These potential immediate effects will allow us to develop therapeutics more quickly for FBR to reduce device failure, improving patient outcomes and quality of life.