Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation

Riabov, Vladimir; Salazar, Fabi�n; Htwe, Su Su; Gudima, Alexandru; Schmuttermaier, Christina; Barthes, Julien; Knopf-Marques, Helena; Kl�ter, Harald; Ghaemmaghami, Amir M.; Vrana, Nihal Engin; Kzhyshkowska, Julia

Abstract

The immediate tissue microenvironment of implanted biomedical devices and engineered tissues is highly influential on their long term fate and efficacy. The creation of a long-term anti-inflammatory microenvironment around implants and artificial tissues can facilitate their integration. Macrophages are highly plastic cells that define the tissue reactions on the implanted material. Local control of macrophage phenotype by long-term fixation of their healing activities and suppression of inflammatory reactions are required to improve implant acceptance. Herein, we describe the development of a cytokine cocktail (M2Ct) that induces stable M2-like macrophage phenotype with significantly decreased pro-inflammatory cytokine and increased anti-inflammatory cytokine secretion profile. The positive effect of the M2Ct was shown in an in vitro wound healing model; where M2Ct facilitated wound closure by human fibroblasts in co-culture conditions. Using a model for induction of inflammation by LPS we have shown that the M2Ct phenotype is stable for 12 days. However, in the absence of M2Ct in the medium macrophages underwent rapid pro-inflammatory re-programming upon IFNg stimulation. Therefore, loading and release of the cytokine cocktail from a self-standing, transferable gelatin/tyraminated hyaluronic acid based release system was developed to stabilize macrophage phenotype for in vivo applications in implantation and tissue engineering. The M2Ct cytokine cocktail retained its anti-inflammatory activity in controlled release conditions. Our data indicate that the direct application of a potent M2 inducing cytokine cocktail in a transferable release system can significantly improve the long term functionality of biomedical devices by decreasing pro-inflammatory cytokine secretion and increasing the rate of wound healing.

Citation

Riabov, V., Salazar, F., Htwe, S. S., Gudima, A., Schmuttermaier, C., Barthes, J., Knopf-Marques, H., Klüter, H., Ghaemmaghami, A. M., Vrana, N. E., & Kzhyshkowska, J. (2017). Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation. Acta Biomaterialia, 53, 389-398. https://doi.org/10.1016/j.actbio.2017.01.071

• Journal Article Type: Article
• Acceptance Date: Jan 26, 2017
• Online Publication Date: Feb 1, 2017
• Publication Date: Apr 15, 2017
• Deposit Date: Feb 23, 2017
• Publicly Available Date: Feb 23, 2017
• Journal: Acta Biomaterialia
• Print ISSN: 1742-7061
• Electronic ISSN: 1878-7568
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 53
• Pages: 389-398
• DOI: https://doi.org/10.1016/j.actbio.2017.01.071
• Keywords: Gelatin; Cytokine; Macrophage phenotype control; Controlled release; Wound healing
• Public URL: https://nottingham-repository.worktribe.com/output/837490
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S1742706117300806
• Additional Information: This article is maintained by: Elsevier; Article Title: Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation; Journal Title: Acta Biomaterialia; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.actbio.2017.01.071; Content Type: article; Copyright: © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
• Contract Date: Feb 23, 2017