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The inflammatory response following implantation of a biomaterialis one of the major regulatory aspects of the overall regenerative process. The progressof inflammation determines whether functional tissue is restored or if nonfunctionalfibrotic tissue is formed. This delicate balance is directed by the activity ofdifferent cells. Among these, macrophages and their different phenotypes, theinflammatory M1 to anti-inflammatory M2, are considered key players in the process.Recent approaches exploit macrophage’s regenerative potential in tissue engineering.Here, we propose a collagen scaffold functionalized with chondroitin sulfate (CSCL), aglycosaminoglycan known to be able to tune inflammation. We studied CSCL effects onbone-marrow-derived macrophages in physiological, and lipopolysaccharides-inflamed,conditions in vitro. Our data demonstrate that CSCL is able to modulate macrophagephenotype by inhibiting the LPS/CD44/NF-kB cascade. As a consequence, an upregulation ofanti-inflammatory markers (TGF-β, Arg, MRC1, and IL-10) was found concomitantly with adecrease in the expression of pro-inflammatory markers (iNOS, TNF-α, IL-1β, IL-12β). Wethen implanted CSCL subcutaneously in a rat model to test whether the same molecularmechanism could be maintained in an in vivo environment. In vivo data confirmed the invitro studies. A significant reduction in the number of infiltrating cells around andwithin the implants was observed at 72 h, with a significant downregulation ofpro-inflammatory genes expression. The present work provides indications regarding theimmunomodulatory potential of molecules used for the development of biomimetic materialsand suggests their use to direct macrophage immune modulation for tissuerepair

Biomimetic collagenous scaffold to tune inflammation by targeting macrophages