Controlling the Multiscale Network Structure of Fibers To Stimulate Wound Matrix Rebuilding by Fibroblast Differentiation

The extracellular matrix (ECM) plays the role of a double-edged sword for controlling the differentiation of fibroblasts toward contractile myofibroblasts in the wound healing process. However, the exact structure-function relationship between ECM morphology and fibroblast behaviors still remains unclear. To better understand this relationship, herein, we designed and prepared a series of biocompatible polycaprolactone (PCL)-based fibers with different fiber diameters (nano vs micro) and different alignments (random vs aligned) using a simple electrospinning process, with a particular attention to the morphological effect of PCL fiber scaffolds on guiding fibroblast behaviors. Microfibers with the larger fiber diameters induce less cell spreading, adhesion, differentiation, and migration because of their lower surface tension. In contrast, nanofibers will retain fibroblast cells with typical spindle shapes and promote the expression of focal adhesion proteins through the integrin pathway. Furthermore, nanofibers upregulate the expression of alpha-smooth muscle actin (alpha-SMA), transforming growth factor, and vimentin filaments, indicating that the size change of the PCL fiber matrix from micrometers to nanometers indeed alters fibroblast differentiation to activate more alpha-SMA-expressed contractile myofibroblasts. Such a fiber size-dependent fibroblast behavior is largely attributed to the enhanced surface tension from the dressing matrix, which helps to promote the conversion of fibroblasts to myofibroblasts via either tissue regeneration or fibrosis. Therefore, this work further indicated that the rearrangement of collagen from nano-tropocollagen to micro-collagen bundles during the wound healing process can reverse fibroblasts to myofibroblasts from motivated to demise. This finding allows us to achieve the structural-based design of a new fibrous matrix for promoting wound healing and tissue regeneration.