Influence of MMP inhibitor GM6001 loading of fibre coated polypropylene meshes on wound healing: Implications for hernia repair

Abstract

Polypropylene meshes are standard for hernia repair. Matrix metalloproteinases play a central role in inflammation. To reduce the inflammatory response and improve remodelling with an associated reduction of hernia recurrence, we modified polypropylene meshes by nanofibre coating and saturation with the broad-spectrum matrix metalloproteinase inhibitor GM6001. The aim was to modulate the inflammatory reaction, increase collagen deposition and improve mesh biointegration. Polypropylene meshes were surface-modified with star-configured NCO-sP(EO -stat-PO) and covered with electrospun nanofibres (polypropylene-nano) and GM6001 (polypropylene-nano-GM). In a hernia model, defects were reconstructed with one of the meshes. Inflammation, neovascularization, bio-integration, proliferation and apoptosis were assessed histologically, collagen content and gelatinases biochemically. Mesh surface modification resulted in higher inflammatory response compared to polypropylene. Pro-inflammatory matrix metalloproteinase-9 paralleled findings while GM6001 reduced matrix metalloproteinase-9 significantly. Significantly increased matrix metalloproteinase-2 beneficial for remodelling was noted with polypropylene-nano-meshes. Increased vascular endothelial growth factor, neo-vascularization and collagen content were measured in polypropylene-nano-meshes compared to polypropylene. GM6001 significantly reduced myofibroblasts. This effect ended after d14 due to engineering limitations with release of maximal GM6001 loading. Nanofibre-coating of polypropylene-meshes confers better tissue vascularization to the cost of increased inflammation. This phenomenon can be only partially compensated by GM6001. Future research will enable higher GM6001 uptake in nano-coated meshes and may alter mesh biointegration in a more pronounced way.

Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia

“…GM6001 is known to be quickly degraded in vivo (half-life < 15 minutes; ref. 14 ; see also Material and Methods), which probably explains the difference between its effects in cell culture and a physiologic model system. The in vitro results do suggest that it may be possible to increase CAR T-cell efficacy by increasing MSLN antigen density using other strategies.…”

“…It is stable in vitro , but its half-life of in vivo is reported to be <15 minutes (ref. 14 ; and see details at https://www.emdmillipore.com/US/en/product/GM6001-MMP-Inhibitor,MM_NF-CC1010 ). Nomo-1 cells were treated with GM6001 (50 μmol/L) or DMSO control for 48 hours prior to evaluation of surface MSLN by flow cytometry; of soluble MSLN in the culture supernatant by ELISA; and of cell lysis activity by coculture with MSLN CAR T cells.…”

The Oak–Wood Extract Robuvit® Improves Recovery and Oxidative Stress after Hysterectomy: A Randomized, Double-blind, Placebo-Controlled Pilot Study

“…It has been discussed that MMP-9 inhibition modulates inflammatory reactions, resulting in faster neovascularization of connective tissues in an animal hernia model [55]. MMP inhibition with doxycycline was associated with improved hernia repair, concomitant reduction of MMP levels and increased collagen 1 deposition [56].…”

A Portable Electrospinner for Nanofiber Synthesis and Its Application for Cosmetic Treatment of Alopecia

“…Electrospinning is a cost-effective technique for synthesizing polymeric fibers with diameters ranging from a few nanometers to tens of microns. Nanofibers electrospun with conventional benchtop electrospinners have found application in textiles [1,2], energy harvesting and storage [3,4,5,6], tissue engineering [7,8,9,10], packaging of pharmaceuticals [11] and wound healing [12,13,14,15] among others [16,17,18,19,20]. Although these traditional electrospinners can produce copious quantities of nanofibers, their large size and stationary design limit their utility in many key applications such as point-of-need nanofiber deposition (e.g., direct application of nanofibers to wound dressings in the clinic) and consumer end-user scenarios.…”