Timed Epithelial Overlay Preserves Defect Closure While Suppressing Fibrotic Remodeling in Wound Microtissues

Area of Science:

• Biomedical Engineering
• Wound Healing Research
• Tissue Engineering

Background:

• Re-epithelialization is crucial for restoring skin barrier function and modulating fibroblast activity during wound healing.
• The precise role of epithelial coverage in balancing closure efficiency with scar-like fibrotic remodeling remains incompletely understood.

Purpose of the Study:

• To investigate how epithelial coverage timing influences fibroblast-driven wound closure and fibrotic remodeling.
• To establish a quantitative model for assessing epithelial regulation of wound healing dynamics.

Main Methods:

• Development of a tension-bearing NIH-3T3-collagen microtissue model with elastic scaffolds and a 500 μm circular microdefect.
• Application of MDCK epithelial overlay at different time points postwounding (immediate vs. 48 hours).
• Quantification of defect closure, microtissue contraction, fibroblast proliferation, myofibroblast differentiation, and fibronectin accumulation.

Main Results:

• Immediate epithelial overlay inhibited contraction-driven closure and suppressed wound edge proliferation.
• Delayed epithelial overlay (48 hours) preserved rapid closure, attenuated microtissue compaction, and reduced myofibroblast differentiation and fibronectin accumulation.
• Delayed overlay maintained fibroblast repopulation and effective epithelial coverage, attenuating remodeling gradients.

Conclusions:

• An optimal postwounding epithelial loading window exists that balances closure efficiency with reduced scar-like remodeling.
• Epithelial-derived signals, potentially including prostaglandin E2, play a role in modulating fibroblast activity.
• This engineered 3D wound model provides a platform for optimizing epithelial-assisted wound therapies and antifibrotic interventions.