Intermittent actuation attenuates fibrotic behaviour of myofibroblasts

Niamh A Ward; Shirley Hanley; Ruth Tarpey; Lucien H J Schreiber; Joanne O'Dwyer; Ellen T Roche; Garry P Duffy; Eimear B Dolan

doi:10.1016/j.actbio.2023.11.017

Intermittent actuation attenuates fibrotic behaviour of myofibroblasts

Acta Biomater. 2024 Jan 1:173:80-92. doi: 10.1016/j.actbio.2023.11.017. Epub 2023 Nov 14.

Authors

Niamh A Ward¹, Shirley Hanley², Ruth Tarpey³, Lucien H J Schreiber³, Joanne O'Dwyer⁴, Ellen T Roche⁵, Garry P Duffy⁶, Eimear B Dolan⁷

Affiliations

¹ Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Galway, Galway, Ireland.
² Flow Cytometry Core Facility, University of Galway, Galway, Ireland.
³ Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Galway, Galway, Ireland; Anatomy and Regenerative Medicine Institute (REMEDI), School of Medicine, University of Galway, Galway, Ireland.
⁴ Anatomy and Regenerative Medicine Institute (REMEDI), School of Medicine, University of Galway, Galway, Ireland.
⁵ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA.
⁶ Anatomy and Regenerative Medicine Institute (REMEDI), School of Medicine, University of Galway, Galway, Ireland; Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin, Dublin, Ireland; CÚRAM, Centre for Research in Medical Devices, University of Galway, Galway, Ireland.
⁷ Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Galway, Galway, Ireland; CÚRAM, Centre for Research in Medical Devices, University of Galway, Galway, Ireland. Electronic address: eimear.dolan@universityofgalway.ie.

PMID: 37967693
DOI: 10.1016/j.actbio.2023.11.017

Abstract

The foreign body response (FBR) to implanted materials culminates in the deposition of a hypo-permeable, collagen rich fibrotic capsule by myofibroblast cells at the implant site. The fibrotic capsule can be deleterious to the function of some medical implants as it can isolate the implant from the host environment. Modulation of fibrotic capsule formation has been achieved using intermittent actuation of drug delivery implants, however the mechanisms underlying this response are not well understood. Here, we use analytical, computational, and in vitro models to understand the response of human myofibroblasts (WPMY-1 stromal cell line) to intermittent actuation using soft robotics and investigate how actuation can alter the secretion of collagen and pro/anti-inflammatory cytokines by these cells. Our findings suggest that there is a mechanical loading threshold that can modulate the fibrotic behaviour of myofibroblasts, by reducing the secretion of soluble collagen, transforming growth factor beta-1 and interleukin 1-beta, and upregulating the anti-inflammatory interleukin-10. By improving our understanding of how cells involved in the FBR respond to mechanical actuation, we can harness this technology to improve functional outcomes for a wide range of implanted medical device applications including drug delivery and cell encapsulation platforms. STATEMENT OF SIGNIFICANCE: A major barrier to the successful clinical translation of many implantable medical devices is the foreign body response (FBR) and resultant deposition of a hypo-permeable fibrotic capsule (FC) around the implant. Perturbation of the implant site using intermittent actuation (IA) of soft-robotic implants has previously been shown to modulate the FBR and reduce FC thickness. However, the mechanisms of action underlying this response were largely unknown. Here, we investigate how IA can alter the activity of myofibroblast cells, and ultimately suggest that there is a mechanical loading threshold within which their fibrotic behaviour can be modulated. These findings can be harnessed to improve functional outcomes for a wide range of medical implants, particularly drug delivery and cell encapsulation devices.

Keywords: Collagen; Fibrosis; Foreign body response; Mechanical loading; Myofibroblast.

MeSH terms

Anti-Inflammatory Agents
Collagen / metabolism
Collagen / pharmacology
Fibrosis
Foreign Bodies* / pathology
Foreign-Body Reaction* / pathology
Humans
Myofibroblasts / metabolism

Substances

Anti-Inflammatory Agents
Collagen