Artificial extracellular matrices composed of collagen I and high-sulfated hyaluronan promote phenotypic and functional modulation of human pro-inflammatory M1 macrophages

Acta Biomater. 2013 Mar;9(3):5621-9. doi: 10.1016/j.actbio.2012.11.016. Epub 2012 Nov 17.


The sequential phases of biomaterial integration and wound healing require different macrophage functions mediated by distinct macrophage subsets. During the initial phase of healing, pro-inflammatory M1 macrophages (MΦ1) are required to clear the wound from microbes and debris; however, their unopposed, persistent activation often leads to disturbed integration of biomaterials and perturbed wound healing. Here we investigated whether pro-inflammatory macrophage functions are affected by immunomodulatory biomaterials based on artificial extracellular matrices (aECM). To address this issue, we tested the capacity of two-dimensional aECM consisting of collagen I and hyaluronan or sulfated derivatives of hyaluronan to affect functions of in vitro polarized human pro-inflammatory MΦ1. The aECM containing high-sulfated hyaluronan substantially decreased inflammatory macrophage functions, including pathogen uptake and release of the pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-12 due to impaired activation of nuclear factor "kappa-light-chain-enhancer" of activated B-cells. Moreover, these macrophages secreted immunregulatory IL-10 and showed reduced activity of the transcription factors signal transducer and activator of transcription 1 and interferon-regulating factor 5, both controlling macrophage polarization to MΦ1 subsets. Our data reveal that the collagen I matrix containing high-sulfated hyaluronan possesses immunomodulating properties and dampens inflammatory macrophage activities by impeding signaling pathways crucial for polarization of pro-inflammatory MΦ1. We therefore suggest this aECM as a promising coating for biomaterials to modulate inflammatory macrophage functions during the healing response and recommend its further testing as a three-dimensional construct and in in vivo models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation / drug effects
  • Collagen Type I / pharmacology*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / pharmacology*
  • Inflammation / pathology*
  • Inflammation Mediators / metabolism
  • Interferon Regulatory Factors / metabolism
  • Interleukin-10 / biosynthesis
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • NF-kappa B / metabolism
  • Phenotype
  • Rats
  • STAT1 Transcription Factor / metabolism


  • Biomarkers
  • Collagen Type I
  • IRF5 protein, human
  • Inflammation Mediators
  • Interferon Regulatory Factors
  • NF-kappa B
  • STAT1 Transcription Factor
  • Interleukin-10
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Hyaluronic Acid