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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

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


Authors

Vladimir Riabov

Fabi�n Salazar

Su Su Htwe

Alexandru Gudima

Christina Schmuttermaier

Julien Barthes

Helena Knopf-Marques

Harald Kl�ter

Nihal Engin Vrana

Julia Kzhyshkowska



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.

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.