Background
Modern hernia surgery is no longer imaginable without the application of mesh prosthesis leading to millions of biomaterial implantations each year worldwide. Implantation of alloplastic mesh material results in an inflammatory reaction to foreign bodies of a different nature that is surprisingly constant, characterized by a rapid accumulation of huge numbers of phagocytic cells, in particular blood monocytes and tissue-derived macrophages. This type of inflammation is known as foreign body reaction (FBR), which is characterized by a transcriptionally induced overexpression of the matrix metalloproteinases 2 (MMP-2).
MMP-2 (gelatinase A) plays an essential role in angiogenesis, inflammation, and fibrosis, and is necessary for a proper wound healing. Advanced investigations by Jansen et al. revealed that mesh implantation mediates enhanced MMP-2 gene transcription with concomitantly up-regulated MMP-2 protein synthesis and enzymatic activity, thus resulting in a chronic inflammatory reaction. Interestingly, a close correlation between MMP-2 expression and collagen formation and degradation is evident establishing a role for MMP-2 in critical events during wound repair. Affecting MMP-2 by modification of either the polymer itself or by coating of the mesh material is suggested to be a potential approach to reduce the chronic inflammatory reaction to alloplastic mesh materials, and thereby to reduce long-term complications like mesh shrinkage, migration, adhesion and in particular chronic pain. Furthermore, it is well known that the quality of perifilamentary scar formation which is characterized by the collagen type I/III ratio is of major impact to minimize the risk of complications or even to avoid the development of a recurrent hernia.
In a previously published study gentamicin coated polyvinylidenfluoride (PVDF) mesh material was detected to improve tissue integration due to an increased type I/III collagen ratio and a reduced MMP-2 protein expression. However, our model analysing MMP-2 gene expression in transgenic mice revealed distinct MMP-2 promoter activation dependent on the course of time and on the concentration of gentamicin. To further elucidate our proven beneficial effect of biomaterial supplementation on foreign body reaction and tissue integration an in-depth understanding of the gentamicin induced enhancement of MMP-2 is necessary. Therefore, gentamicin coated mesh materials with three different concentrations per unit of weight (μg/mg) were implanted in transgenic reporter mice harbouring a ß-galactosidase reporter gene (LacZ) driven by the regulatory sequences of the MMP-2 gene. To determine the significance of the response element-1 (RE-1) that extends from -1282/-1322, F8del mice were created that harbour MMP-2 regulatory sequence −1241/+423, thereby excluding the RE-1. The spatial and temporal transcriptional regulation of the MMP-2 gene was analyzed at the cellular level.