Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid...

Area of Science:

• Biomedical Engineering
• Immunology
• Cellular Mechanobiology

Background:

• Small animal models inadequately replicate the human foreign-body response (FBR) to implanted materials.
• The FBR's severity in humans is not fully explained by implant chemistry or mechanical properties alone.

Purpose of the Study:

• To investigate the role of physical forces and mechanotransduction in the human FBR.
• To identify molecular mechanisms driving the human FBR that are absent in small animal models.
• To develop a more accurate preclinical model for studying human FBR to implants.

Main Methods:

• Utilized allometric scaling principles to analyze force-dependent FBR.
• Investigated immune-cell-specific RAC2 mechanotransduction signaling pathways.
• Induced human-like FBR in mice using vibrating silicone implants to apply human-tissue-scale forces.

Main Results:

• Implant surface forces, increasing exponentially with body size, drive the FBR.
• Human FBR is mediated by RAC2 signaling in immune cells, irrespective of implant material properties.
• Elevated extrinsic forces in mice activated RAC2 signaling in myeloid cells, mimicking human FBR.
• Pharmacological or genetic inhibition of RAC2 significantly reduced FBR in mice.

Conclusions:

• Allometric scaling of forces explains differences in FBR between humans and small animals.
• RAC2 mechanotransduction is a critical, conserved pathway in the human FBR.
• Findings have significant implications for the design and safety assessment of medical implants.