The relationship between collagen scaffold cross-linking agents and neutrophils in the foreign body reaction

Biomaterials. 2010 Dec;31(35):9192-201. doi: 10.1016/j.biomaterials.2010.08.049. Epub 2010 Sep 9.


In order to get more insight into the role of neutrophils on the micro-environment and consequently on macrophages in the foreign body reaction in mice, we investigated the fate of the two differently cross-linked dermal sheep collagen disks (glutaraldehyde = GDSC, hexamethylenediisocyanate = HDSC) in mice implanted in one anatomical location, namely subcutaneously. In GDSC massive infiltration of neutrophils is seen at day 2 and day 21, whereas in HDSC only minor infiltration is seen at day 2. The presence of neutrophils coincided with high levels of IFN-γ, a cytokine that activates macrophages. Major differences were seen in degradation rate of the two disks: GDSC was almost completely degraded after 28 days, whereas HDSC remained intact. Degradation of GDSC occurred through collagenolytic activity and phagocytosis by macrophages. Phagocytosis was observed at day 2 and day 21. IL-13 was only observed in HDSC, and this resulted in the presence of giant cells in HDSC. These giant cells produced IL-10, that promoted TIMP-1 expression and that inhibits collagenolytic and phagocytic activity. We conclude that the function of macrophages in mice is largely influenced by differences in micro-environment induced by GDSC and HDSC and that the presence/absence of neutrophils play a major role in the shaping of this micro-environment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Collagen / chemistry*
  • Cross-Linking Reagents / chemistry
  • Cross-Linking Reagents / pharmacology*
  • Foreign-Body Reaction / chemically induced*
  • Foreign-Body Reaction / immunology
  • Foreign-Body Reaction / metabolism*
  • Giant Cells / metabolism
  • Glutaral / chemistry
  • Glutaral / pharmacology
  • Immunohistochemistry
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-13 / metabolism
  • Isocyanates / chemistry
  • Isocyanates / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophil Infiltration / drug effects
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Phagocytosis / drug effects
  • Sheep
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism


  • Cross-Linking Reagents
  • Interleukin-13
  • Isocyanates
  • Tissue Inhibitor of Metalloproteinase-1
  • Interleukin-10
  • Interferon-gamma
  • Collagen
  • Glutaral