Inhibiting Fibrotic Encapsulation of Body Implants by Targeting Mechanical Activation of Profibrotic TGF-β1

Noskovicova, Nina (1), Van Putten, Sander (1), Koehler, Anne (1, 2), Bank, Ruud (2), Hinz, Boris (1)

(1) Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada

(2) Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Background: The clinical performance of reconstructive silicone implants is compromised by foreign body reactions (FBRs). FBRs culminate in formation and contraction of fibrotic collagen tissue by α-SMA-expressing myofibroblasts contributing to implant failure. TGF-β1 is a key driver of fibrosis and secreted into the matrix in complex with the latent TGF-β1 peptide (LAP). Cell pulling on LAP via αv integrins mechanically activates TGF-β1 in context of a resistant matrix. Mechanical stress also controls the binding strength of integrins to their matrix ligands. The mechanisms and integrins activating TGF-β1 in FBRs are unknown.

Hypothesis: The stiff surface of silicone implants enhances activation of αv integrin and TGF-β1.

Objective: Inhibit activation and binding of αv integrin to reduce TGF-β1 activation and fibrotic encapsulation of bio-implants.

Methods: Silicone implants and osmotic pumps releasing the αv integrin-specific inhibitor CWHM12 were implanted subcutaneously in transgenic mice, expressing GFP and RFP under the control of the Col1α and α-SMA promoters, respectively. Implants were excised, and fibrotic capsules analyzed for thickness, collagen content, and myofibroblasts recruitment using immunohistochemistry. For in vitro studies, stiffness-tunable implant silicones were coated with recombinant LAP and used as substrates for fibroblasts. Integrin activation and recruitment to these surfaces was quantified as a function of stiffness.

Results: Blocking αv integrins with CWHM12 significantly reduced fibrotic capsule thickness, collagen deposition, and myofibroblast accumulation in vivo and reduced force transmission to LAP and TGF-β1 activation in vitro. Reducing extracellular and intracellular stress resulted in the decreased recruitment of the latent TGF-β1-activating integrin αvβ1 to the implant material.

Conclusion: Mechanical activation by stiffness silicone bio-implants enhances integrin αv binding to and activation of latent TGF-β1. Active TGF-β1 drives implant encapsulation by stiff scar tissue, amplifying the process.

Significance: Blocking αv integrin binding with CWHM12 or using soft silicone material both decrease the fibrotic response to bio-implants.