Non-cross-linked porcine-based collagen I-III membranes do not require high vascularization rates for their integration within the implantation bed: a paradigm shift

Acta Biomater. 2012 Aug;8(8):3061-72. doi: 10.1016/j.actbio.2012.04.041. Epub 2012 May 3.


There are conflicting reports concerning the tissue reaction of small animals to porcine-based, non-cross-linked collagen I-III membranes/matrices for use in guided tissue/bone regeneration. The fast degradation of these membranes/matrices combined with transmembrane vascularization within 4 weeks has been observed in rats compared with the slow vascularization and continuous integration observed in mice. The aim of the present study was to analyze the tissue reaction to a porcine-based non-cross-linked collagen I-III membrane in mice. Using a subcutaneous implantation model, the membrane was implanted subcutaneously in mice for up to 60 days. The extent of scaffold vascularization, tissue integration and scaffold thickness were assessed using general and specialized histological methods, together with a unique histomorphometrical analysis technique. A dense Bombyx mori-derived silk fibroin membrane was used as a positive control, whilst a polytetrafluoroethylene (PTFE) membrane served as a negative control. Within the observation period, the collagen membrane induced a mononuclear cellular tissue response, including anti-inflammatory macrophages and the absence of multinucleated giant cells within its implantation bed. Transmembrane scaffold vascularization was not observed, whereas a mild scaffold vascularization was generated through microvessels located at both scaffold surfaces. However, the silk fibroin induced a mononuclear and multinucleated cell-based tissue response, in which pro-inflammatory macrophages and multinucleated giant cells were associated with an increasing transmembrane scaffold vascularization and a breakdown of the membrane within the experimental period. The PTFE membrane remained as a stable barrier throughout the study, and visible cellular degradation was not observed. However, multinucleated giant cells were located on both interfaces. The present study demonstrated that the tested non-cross-linked collagen membrane remained as a stable barrier membrane throughout the study period. The membrane integrated into the subcutaneous connective tissue and exhibited only a mild peripheral vascularization without experiencing breakdown. The silk fibroin, in contrast, induced granulation tissue formation, which resulted in its high vascularization and the breakdown of the material over time. The presence of multinucleated giant cells at both interfaces of the PFTE membrane is a sign of its slow cellular biodegradation and might lead to adhesions between the membrane and its surrounding tissue. This hypothesis could explain the observed clinical complications associated with the retrieval of these materials after guided tissue regeneration.

MeSH terms

  • Animals
  • Collagen Type I / pharmacology*
  • Collagen Type III / pharmacology*
  • Cross-Linking Reagents / pharmacology*
  • Female
  • Fibroins / ultrastructure
  • Immunohistochemistry
  • Membranes / drug effects
  • Membranes, Artificial
  • Mice
  • Microscopy, Electron, Scanning
  • Neovascularization, Physiologic / drug effects*
  • Polytetrafluoroethylene / pharmacology
  • Prosthesis Implantation*
  • Rats
  • Sus scrofa
  • Tissue Scaffolds


  • Collagen Type I
  • Collagen Type III
  • Cross-Linking Reagents
  • Membranes, Artificial
  • Polytetrafluoroethylene
  • Fibroins