Magnetic responsive materials modulate the inflammatory profile of IL-1β conditioned tendon cells

Abstract

Tendinopathies represent half of all musculoskeletal injuries worldwide. Inflammatory events contribute to both tendon healing and to tendinopathy conditions but the cellular triggers leading to one or the other are unknown. In previous studies, we showed that magnetic field actuation modulates human tendon cells (hTDCs) behavior in pro-inflammatory environments, and that magnetic responsive membranes could positively influence inflammation responses in a rat ectopic model. Herein, we propose to investigate the potential synergistic action of the magnetic responsive membranes, made of a polymer blend of starch with polycaprolactone incorporating magnetic nanoparticles (magSPCL), and the actuation of pulsed electromagnetic field (PEMF): 5 Hz, 4mT of intensity and 50% of duty cycle, in IL-1 β-treated-hTDCs, and in the immunomodulatory response of macrophages. It was found that the expression of pro-inflammatory (TNF α, IL-6, IL-8, COX-2) and ECM remodeling (MMP-1,-2,-3) markers tend to decrease in cells cultured onto magSPCL membranes under PEMF, while the expression of TIMP-1 and anti-inflammatory genes (IL-4, IL-10) increases. Also, CD16 ++ and CD206 + macrophages were only found on magSPCL membranes with PEMF application. Magnetic responsive membranes show a modulatory effect on the inflammatory profile of hTDCs favoring anti-inflammatory cues which is also supported by the anti-inflammatory/repair markers expressed in macrophages. These results suggest that magnetic responsive magSPCL membranes can contribute for inflammation resolution acting on both resident cell populations and inflammatory cells, and thus significantly contribute to tendon regenerative strategies. Statement of significance Magnetically-assisted strategies have received great attention in recent years to remotely trigger and guide cell responses. Inflammation plays a key role in tendon healing but persistent pro-inflammatory molecules can contribute to tendon disorders, and therefore provide a therapeutic target for advanced treatments. We have previously reported that magnetic fields modulate the response of human tendon cells (hT-DCs) conditioned to pro-inflammatory environments (IL-1 β-treated-hTDCs), and that magnetic responsive membranes positively influence immune responses. In the present work, we combined pulsed electromagnetic field (PEMF) and magnetic responsive membranes to guide the inflammatory profile of IL-1 βtreated-hTDCs and of macrophages. The results showed that the synergistic action of PEMF and magnetic membranes supports the applicability of magnetically actuated systems to regulate inflammatory events and stimulate tendon regeneration.

Human tendon-derived cell sheets created by magnetic force-based tissue engineering hold tenogenic and immunomodulatory potential

“…3A). The maintenance of SCX expression levels has been also observed in our previous works [27]. Overall, IL-1β treatment combined with PEMF stimulation leads to an increment in tendon gene expression up to the levels of non-IL-1β magCSs (Control group).…”

“…As expected, the expression of MMP-1, MMP-2 and MMP-3 increased with IL-1β treatment in comparison to control group (MMP-1, p<0.01; MMP-2, MMP-3 p<0.0001) and to magCSs exposed to PEMF (MMP-1, p<0.05; MMP-2, MMP-3, p<0.0001) (Fig. 4Ai) [17,27]. Interestingly MMP-1 and MMP-3 levels in IL-1β-magCSs stimulated with PEMF are higher than in control group (MMP-1, p<0.01; MMP-3, P<0.0001).…”

“…The impact of IL-1β supplementation and PEMF exposure was evaluated on the tendon markers expressed by magCSs to assess their influence on the maintenance of tenogenic profile. With an exception for SCX, the relative expression of MKX, TNMD, and DCN were significantly affected by the IL-1β treatment [19,27,28] (Fig. 3).…”

Amniotic Epithelial Stem Cells Counteract Acidic Degradation By-Products of Electrospun PLGA Scaffold by Improving Their Immunomodulatory Profile In Vitro

“…Different polymers including poly( -caprolactone) (PCL), poly(lactic acid) (PLA), and poly(lactide-co-glycolide) (PLGA) are FDA-approved polymers that have been widely applied for biomedical and in particular tendon applications [1,2,[4][5][6][7][8][9][10][11][12][13][14]. Although PLA and PCL are two biocompatible polymers, they are characterized by high hydrophobic properties that decreased cell adhesion due to the lack of cell recognition sites on their surfaces [9,15,16].…”

Interplay of Forces and the Immune Response for Functional Tendon Regeneration

“…The effects of biomaterials on macrophage polarization in tendon repair have been summarized; that is, biomaterials with ECM coatings, hydrophilic surfaces, and nanometer sizes can induce macrophage activation (Lin et al, 2018), whereas in recent years, other properties of biomaterials have also been shown to regulate macrophages. Magnetic materials, for example, have been shown to induce macrophage to M2 transition (Vinhas et al, 2020). The fiber arrangement of biomaterials also influences the polarization of macrophages to promote tendon repair (Schoenenberger et al, 2020).…”