Heparinization of beta tricalcium phosphate: osteo-immunomodulatory effects

"This is the pre-peer reviewed version of the following article: A. Diez-Escudero, M. Espanol, M. Bonany, X. Lu, C. Persson, M.-P. Ginebra, Adv. Healthcare Mater. 2018, 7, 1700867, which has been published in final form at https://doi.org/10.1002/adhm.201700867. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."Immune cells play a vital role in regulating bone dynamics. This has boosted the interest in developing biomaterials that can modulate both the immune and skeletal systems. In this study, calcium phosphates discs (i.e., beta-tricalcium phosphate, ß-TCP) are functionalized with heparin to investigate the effects on immune and stem cell responses. The results show that the functionalized surfaces downregulate the release of hydrogen peroxide and proinflammatory cytokines (tumor necrosis factor alpha and interleukin 1 beta) from human monocytes and neutrophils, compared to nonfunctionalized discs. The macrophages show both elongated and round shapes on the two ceramic substrates, but the morphology of cells on heparinized ß-TCP tends toward a higher elongation after 72 h. The heparinized substrates support rat mesenchymal stem cell (MSC) adhesion and proliferation, and anticipate the differentiation toward the osteoblastic lineage as compared to ß-TCP and control. The coupling between the inflammatory response and osteogenesis is assessed by culturing MSCs with the macrophage supernatants. The downregulation of inflammation in contact with the heparinized substrates induces higher expression of bone-related markers by MSCsPeer ReviewedPostprint (author's final draft