Abstract
Injured tendons are challenging in their regeneration; thus, tissue engineering represents a promising solution. This research tests the hypothesis that the response of amniotic epithelial stem cells (AECs) can be modulated by fiber diameter size of tendon biomimetic fleeces. Particularly, the effect of electrospun poly(lactide-co-glycolide) (PLGA) fleeces with highly aligned microfibers possessing two different diameter sizes (1.27 and 2.5 µm: ha1- and ha2-PLGA, respectively) was tested on the ability of AECs to differentiate towards the tenogenic lineage by analyzing tendon related markers (Collagen type I: COL1 protein and mRNA Scleraxis: SCX, Tenomodulin: TNMD and COL1 gene expressions) and to modulate their immunomodulatory properties by investigating the pro- (IL-6 and IL-12) and anti- (IL-4 and IL-10) inflammatory cytokines. It was observed that fiber alignment and not fiber size influenced cell morphology determining the morphological change of AECs from cuboidal to fusiform tenocyte-like shape. Instead, fleece mechanical properties, cell proliferation, tenogenic differentiation, and immunomodulation were regulated by changing the ha-PLGA microfiber diameter size. Specifically, higher DNA quantity and better penetration within the fleece were found on ha2-PLGA, while ha1-PLGA fleeces with small fiber diameter size had better mechanical features and were more effective on AECs trans-differentiation towards the tenogenic lineage by significantly translating more efficiently SCX into the downstream effector TNMD. Moreover, the fiber diameter of 1.27 µm induced higher expression of pro-regenerative, anti-inflammatory interleukins mRNA expression (IL-4 and IL-10) with favorable IL-12/IL-10 ratio with respect to the fiber diameter of 2.5 µm. The obtained results demonstrate that fiber diameter is a key factor to be considered when designing tendon biomimetic fleece for tissue repair and provide new insights into the importance of controlling matrix parameters in enhancing cell differentiation and immunomodulation either for the cells functionalized within or for the transplanted host tissue.
Highlights
Tendinopathies, common musculoskeletal pathologies, represent about 30% of tendon-related injuries [1,2,3]
After a series of optimization of the electrospinning process parameters, two PLGA fleeces with highly aligned fibers possessing two different diameter sizes have been chosen for further investigations in this study in which the fabrication conditions are reported in and + 10◦
Ha1-PLGA possessed a significantly higher percentage of fibers within these angles compared to ha2-PLGA ones (p < 0.05; Figure 1C), which can be attributed to the high polymer concentration resulted in more stable jets during the electrospinning process
Summary
Tendinopathies, common musculoskeletal pathologies, represent about 30% of tendon-related injuries [1,2,3]. Tendon injuries remain difficult to manage and often lead to the formation of scar tissue instead of the organized extracellular matrix (ECM) possessing inferior biochemical properties with altered functionality especially in terms of movement and strength. This can be devastating for the daily life of patients as it may dramatically impose a reduction in mobility associated with chronic pain [6] accompanied by increasing the chances of recurrences and tendon ruptures [1,7,8]. Innovative strategies that can regenerate tendons and improve their biomechanical properties are urgently sought
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