title: MMP levels in the response to degradable implants in the presence of a hydroxamate-based matrix metalloproteinase sequestering biomaterial in vivo.
abstract: The inflammatory response to an implanted tissue engineered construct alters the remodeling that occurs and this can diminish the intended therapeutic effect. It was hypothesized that the use of a hydroxamate-based matrix metalloproteinase (MMP) sequestering biomaterial (MI) in the form of approximately 200 microm microspheres would lower the amount and activity of MMP in vivo in response to a subcutaneous, degradable implant (gelatin or Integra disc). MMP degrade extracellular matrix, facilitating inflammatory cell migration and local remodeling of the implant environment. Gelatin or Integra discs were implanted subcutaneously in the backs of CD1 mice together with 30 mg of MI microspheres or with 30 mg of similarly sized control poly(methyl methacrylate) (PMMA) microspheres in a paired study. To sample the implant space, weakly adsorbed protein or attached cells were recovered from explanted discs by soaking the discs in PBS overnight at 4 degrees C. Unexpectedly, MMP-2, -8, -9, and TIMP-1 levels were surprisingly similar in this recovered fluid for the two treatments. Also, there were significantly more (and at day 4 an order of magnitude more) leukocytes recovered from the gelatin discs coimplanted with the MI microspheres than with the PMMA control. It is suggested that the MI microspheres disturbed the natural MMP control pathway leading to high-leukocyte numbers, especially at early times. These results highlight the challenge associated with controlling the fate of tissue engineered constructs in vivo.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Omar F
authors.initials: OF
authors.lastname: Khan
authors.forename: Jacques
authors.initials: J
authors.lastname: Jean-Francois
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sefton
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D002465:Cell Movement; D006877:Hydroxamic Acids / Q000737:chemistry; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020784:Matrix Metalloproteinase 8 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008863:Microspheres; D019904:Polymethyl Methacrylate / Q000737:chemistry; D013696:Temperature; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis
chemical_list: D001672:Biocompatible Materials; D006877:Hydroxamic Acids; D019715:Tissue Inhibitor of Metalloproteinase-1; D019904:Polymethyl Methacrylate; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9