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Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds
Journal article   Open access   Peer reviewed

Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds

Kara L Spiller, Sina Nassiri, Claire E Witherel, Rachel R Anfang, Johnathan Ng, Kenneth R Nakazawa, Tony Yu and Gordana Vunjak-Novakovic
Biomaterials, v 37
Jan 2015
DOI: https://doi.org/10.1016/j.biomaterials.2014.10.017
PMID: 25453950
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc4312192View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Animals Biomarkers - metabolism Bone and Bones - blood supply Cell Polarity - drug effects Cytokines - pharmacology Cytokines - secretion Drug Delivery Systems Female Flow Cytometry Gene Expression Regulation - drug effects Humans Immunohistochemistry Immunologic Factors - pharmacology Implants, Experimental Kinetics Macrophages - cytology Macrophages - drug effects Macrophages - secretion Mice, Inbred C57BL Neovascularization, Physiologic - drug effects Phenotype Subcutaneous Tissue - drug effects Time Factors Tissue Scaffolds - chemistry ESI Highly Cited Paper (Incites)
In normal tissue repair, macrophages exhibit a pro-inflammatory phenotype (M1) at early stages and a pro-healing phenotype (M2) at later stages. We have previously shown that M1 macrophages initiate angiogenesis while M2 macrophages promote vessel maturation. Therefore, we reasoned that scaffolds that promote sequential M1 and M2 polarization of infiltrating macrophages should result in enhanced angiogenesis and healing. To this end, we first analyzed the in vitro kinetics of macrophage phenotype switch using flow cytometry, gene expression, and cytokine secretion analysis. Then, we designed scaffolds for bone regeneration based on modifications of decellularized bone for a short release of interferon-gamma (IFNg) to promote the M1 phenotype, followed by a more sustained release of interleukin-4 (IL4) to promote the M2 phenotype. To achieve this sequential release profile, IFNg was physically adsorbed onto the scaffolds, while IL4 was attached via biotin-streptavidin binding. Interestingly, despite the strong interactions between biotin and streptavidin, release studies showed that biotinylated IL4 was released over 6 days. These scaffolds promoted sequential M1 and M2 polarization of primary human macrophages as measured by gene expression of ten M1 and M2 markers and secretion of four cytokines, although the overlapping phases of IFNg and IL4 release tempered polarization to some extent. Murine subcutaneous implantation model showed increased vascularization in scaffolds releasing IFNg compared to controls. This study demonstrates that scaffolds for tissue engineering can be designed to harness the angiogenic behavior of host macrophages towards scaffold vascularization.

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637 citations in Web of Science
638 citations in Scopus

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UN Sustainable Development Goals (SDGs)

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#3 Good Health and Well-Being

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Highly Cited Paper 
Collaboration types
Domestic collaboration
Web of Science research areas
Engineering, Biomedical
Materials Science, Biomaterials
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