Header

UZH-Logo

Maintenance Infos

Mechanical stimulation induces rapid fibroblast proliferation and accelerates the early maturation of human skin substitutes


Wahlsten, Adam; Rütsche, Dominic; Nanni, Monica; Giampietro, Costanza; Biedermann, Thomas; Reichmann, Ernst; Mazza, Edoardo (2021). Mechanical stimulation induces rapid fibroblast proliferation and accelerates the early maturation of human skin substitutes. Biomaterials, 273:120779.

Abstract

The clinical treatment of large, full-thickness skin injuries with tissue-engineered autologous dermo-epidermal skin substitutes is an emerging alternative to split-thickness skin grafting. However, their production requires about one month of in vitro cell and tissue culture, which is a significant drawback for the treatment of patients with severe skin defects. With the aim to reduce the production time, we developed a new dynamic bioreactor setup that applies cyclic biaxial tension to collagen hydrogels for skin tissue engineering. By reliably controlling the time history of mechanical loading, the dynamic culturing results in a three-fold increase in collagen hydrogel stiffness and stimulates the embedded fibroblasts to enter the cell cycle. As a result, the number of fibroblasts is increased by 75% compared to under corresponding static culturing. Enhanced fibroblast proliferation promotes expression of dermal extracellular matrix proteins, keratinocyte proliferation, and the early establishment of the epidermis. The time required for early tissue maturation can therefore be reduced by one week. Analysis of the separate effects of cyclic loading, matrix stiffening, and interstitial fluid flow indicates that cyclic deformation is the dominant biophysical factor determining fibroblast proliferation, while tissue stiffening plays a lesser role. Local differences in the direction of deformation (in-plane equibiaxial vs. uniaxial strain) influence fibroblast orientation but not proliferation, nor the resulting tissue properties. Importantly, dynamic culturing does not activate fibroblast differentiation into myofibroblasts. The present work demonstrates that control of mechanobiological cues can be very effective in driving cell response toward a shorter production time for human skin substitutes.

Abstract

The clinical treatment of large, full-thickness skin injuries with tissue-engineered autologous dermo-epidermal skin substitutes is an emerging alternative to split-thickness skin grafting. However, their production requires about one month of in vitro cell and tissue culture, which is a significant drawback for the treatment of patients with severe skin defects. With the aim to reduce the production time, we developed a new dynamic bioreactor setup that applies cyclic biaxial tension to collagen hydrogels for skin tissue engineering. By reliably controlling the time history of mechanical loading, the dynamic culturing results in a three-fold increase in collagen hydrogel stiffness and stimulates the embedded fibroblasts to enter the cell cycle. As a result, the number of fibroblasts is increased by 75% compared to under corresponding static culturing. Enhanced fibroblast proliferation promotes expression of dermal extracellular matrix proteins, keratinocyte proliferation, and the early establishment of the epidermis. The time required for early tissue maturation can therefore be reduced by one week. Analysis of the separate effects of cyclic loading, matrix stiffening, and interstitial fluid flow indicates that cyclic deformation is the dominant biophysical factor determining fibroblast proliferation, while tissue stiffening plays a lesser role. Local differences in the direction of deformation (in-plane equibiaxial vs. uniaxial strain) influence fibroblast orientation but not proliferation, nor the resulting tissue properties. Importantly, dynamic culturing does not activate fibroblast differentiation into myofibroblasts. The present work demonstrates that control of mechanobiological cues can be very effective in driving cell response toward a shorter production time for human skin substitutes.

Statistics

Citations

Dimensions.ai Metrics
3 citations in Web of Science®
1 citation in Scopus®
Google Scholar™

Altmetrics

Downloads

10 downloads since deposited on 16 Jun 2021
10 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Clinic for Surgery
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Biophysics
Physical Sciences > Bioengineering
Physical Sciences > Ceramics and Composites
Physical Sciences > Biomaterials
Physical Sciences > Mechanics of Materials
Uncontrolled Keywords:Biophysics, Mechanics of Materials, Bioengineering, Biomaterials, Ceramics and Composites
Language:English
Date:1 June 2021
Deposited On:16 Jun 2021 10:30
Last Modified:17 Jun 2021 20:00
Publisher:Elsevier
ISSN:0142-9612
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.biomaterials.2021.120779
PubMed ID:33932701

Download

Hybrid Open Access

Download PDF  'Mechanical stimulation induces rapid fibroblast proliferation and accelerates the early maturation of human skin substitutes'.
Preview
Content: Published Version
Filetype: PDF
Size: 11MB
View at publisher
Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)