Stiffness- and Bioactive Factor-Mediated Protection of Self-Assembled Cartilage against Macrophage Challenge in a Novel Co-Culture System

Author:

Donahue Ryan P.1ORCID,Link Jarrett M.1ORCID,Meli Vijaykumar S.12,Hu Jerry C.1,Liu Wendy F.1234,Athanasiou Kyriacos A.1ORCID

Affiliation:

1. Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA

2. The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA, USA

3. Department of Chemical and Biomolecular Engineering, University of California, Irvine, Irvine, CA, USA

4. Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA

Abstract

Objective: Tissue-engineered cartilage implants must withstand the potential inflammatory and joint loading environment for successful long-term repair of defects. The work’s objectives were to develop a novel, direct cartilage-macrophage co-culture system and to characterize interactions between self-assembled neocartilage and differentially stimulated macrophages. Design: In study 1, it was hypothesized that the proinflammatory response of macrophages would intensify with increasing construct stiffness; it was expected that the neocartilage would display a decrease in mechanical properties after co-culture. In study 2, it was hypothesized that bioactive factors would protect neocartilage properties during macrophage co-culture. Also, it was hypothesized that interleukin 10 (IL-10)-stimulated macrophages would improve neocartilage mechanical properties compared to lipopolysaccharide (LPS)-stimulated macrophages. Results: As hypothesized, stiffer neocartilage elicited a heightened proinflammatory macrophage response, increasing tumor necrosis factor alpha (TNF-α) secretion by 5.47 times when LPS-stimulated compared to construct-only controls. Interestingly, this response did not adversely affect construct properties for the stiffest neocartilage but did correspond to a significant decrease in aggregate modulus for soft and medium stiffness constructs. In addition, bioactive factor-treated constructs were protected from macrophage challenge compared to chondrogenic medium-treated constructs, but IL-10 did not improve neocartilage properties, although stiff constructs appeared to bolster the anti-inflammatory nature of IL-10-stimulated macrophages. However, co-culture of bioactive factor-treated constructs with LPS-treated macrophages reduced TNF-α secretion by over 4 times compared to macrophage-only controls. Conclusions: In conclusion, neocartilage stiffness can mediate macrophage behavior, but stiffness and bioactive factors prevent macrophage-induced degradation. Ultimately, this co-culture system could be utilized for additional studies to develop the burgeoning field of cartilage mechano-immunology.

Publisher

SAGE Publications

Subject

Physical Therapy, Sports Therapy and Rehabilitation,Biomedical Engineering,Immunology and Allergy

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