Abstract
We developed a (three-dimensional) 3D scaffold, we named HY-FIB, incorporating a force-transmission band of braided hyaluronate embedded in a cell localizing fibrin hydrogel and poly-lactic-co-glycolic acid (PLGA) nanocarriers as transient components for growth factor controlled delivery. The tenogenic supporting capacity of HY-FIB on human-Bone Marrow Mesenchymal Stem Cells (hBM-MSCs) was explored under static conditions and under bioreactor-induced cyclic strain conditions. HY-FIB elasticity enabled to deliver a mean shear stress of 0.09 Pa for 4 h/day. Tendon and cytokine marker expression by hBM-MSCs were studied. Results: hBM-MSCs embedded in HY-FIB and subjected to mechanical stimulation, resulted in a typical tenogenic phenotype, as indicated by type 1 Collagen fiber immunofluorescence. RT-qPCR showed an increase of type 1 Collagen, scleraxis, and decorin gene expression (3-fold, 1600-fold, and 3-fold, respectively, at day 11) in dynamic conditions. Cells also showed pro-inflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokine gene expressions, with a significant increase of anti-inflammatory cytokines in dynamic conditions (IL-10 and TGF-β1 300-fold and 4-fold, respectively, at day 11). Mechanical signaling, conveyed by HY-FIB to hBM-MSCs, promoted tenogenic gene markers expression and a pro-repair cytokine balance. The results provide strong evidence in support of the HY-FIB system and its interaction with cells and its potential for use as a predictive in vitro model.
Highlights
Tissue engineering strategies for tendon healing and regeneration are designed to improve existing therapies or provide new treatment possibilities
The active form of hGDF-5 loaded into poly-lactic-co-glycolic acid (PLGA)-NCs for controlled delivery within HY-FIB environment was investigated in a previous study [53]
We investigated the effect of the HY-FIB 3D environment on hBM-MSCs tenogenic and cytokine marker gene expression in both static and dynamic, mechanical, input scenarios
Summary
Tissue engineering strategies for tendon healing and regeneration are designed to improve existing therapies or provide new treatment possibilities. Cells 2020, 9, 1268 of stem cells in tendon regeneration In this sense, 3D scaffold design and fabrication coupled to specific bioreactor arrangements could develop highly predictive 3D in vitro culture and differentiation systems to explore cell behaviors in response to defined external biochemical and mechanical stimuli [1]. Grier et al described an aligned collagen-glycosaminoglycan scaffold able to enhance tenogenic differentiation of MSCs via cyclic tensile strain within a bioreactor, in the absence of growth factor supplementation [36]. We describe the use of the same scaffold (named HY-FIB here) to investigate the effect of the 3D environment on hBM-MSCs for 11 days with or without mechanical stimulation and in the absence of any specific biochemical differentiation signal. The results provide strong evidence that HY-FIB environment plus mechanical signaling, promoted tenogenic markers expression, collagen production and better pro-repair cytokine balance by hBM-MSCs
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