Abstract
Impaired skin wound healing due to severe injury often leads to dysfunctional scar tissue formation as a result of excessive and persistent myofibroblast activation, characterised by the increased expression of α-smooth muscle actin (αSMA) and extracellular matrix (ECM) proteins. Yet, despite extensive research on impaired wound healing and the advancement in tissue-engineered skin substitutes, scar formation remains a significant clinical challenge. This study aimed to first investigate the effect of methacrylate gelatin (GelMA) biomaterial stiffness on human dermal fibroblast behaviour in order to then design a range of 3D-printed GelMA scaffolds with tuneable structural and mechanical properties and understand whether the introduction of pores and porosity would support fibroblast activity, while inhibiting myofibroblast-related gene and protein expression. Results demonstrated that increasing GelMA stiffness promotes myofibroblast activation through increased fibrosis-related gene and protein expression. However, the introduction of a porous architecture by 3D printing facilitated healthy fibroblast activity, while inhibiting myofibroblast activation. A significant reduction was observed in the gene and protein production of αSMA and the expression of ECM-related proteins, including fibronectin I and collagen III, across the range of porous 3D-printed GelMA scaffolds. These results show that the 3D-printed GelMA scaffolds have the potential to improve dermal skin healing, whilst inhibiting fibrosis and scar formation, therefore potentially offering a new treatment for skin repair.
Highlights
GelMA hydrogels have a significant effect on human dermal fibroblast behaviour, whereby increasing stiffness promotes myofibroblast activation through increased fibrosis-related gene and protein expression
While not optimal for myofibroblast inhibition, we used the same concentration of GelMA (10%) as the stiffest non-porous hydrogel and successfully developed a range of 3D-printed GelMA scaffolds with a tuneable porous architecture and porosity that facilitated fibroblast viability, proliferation and infiltration
We further demonstrated that the introduction of pores into the GelMA stiff hydrogel negates the effect of bulk GelMA hydrogel stiffness on myofibroblast activation, with reduced expression of α-smooth muscle actin (αSMA), fibronectin I (FN) and collagen III (Col III) observed within scaffold groups treated with TFG-β1
Summary
The skin is the largest organ of the human body, which forms an effective barrier against the external environment and protects the body from dehydration and environmental insults [1,2]. The skin wound-healing process begins immediately via a dynamic series of physiological events to repair and restore structural integrity and function to the damaged site. In extreme cases, such as severe burns, this repair process is disrupted and can result in fibrotic scar formation, characterised by the abnormal deposition of highly dysfunctional tissue [3]. In such cases, skin autografts are required, but this treatment option is often limited due to unavailability of healthy donor tissue
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