title: Targeted imaging of matrix metalloproteinase activity in the evaluation of remodeling tissue-engineered vascular grafts implanted in a growing lamb model.
abstract: OBJECTIVE
  The clinical translation of tissue-engineered vascular grafts has been demonstrated in children. The remodeling of biodegradable, cell-seeded scaffolds to functional neovessels has been partially attributed to matrix metalloproteinases. Noninvasive assessment of matrix metalloproteinase activity can indicate graft remodeling and elucidate the progression of neovessel formation. Therefore, matrix metalloproteinase activity was evaluated in grafts implanted in lambs using in vivo and ex vivo hybrid imaging. Graft growth and remodeling was quantified using in vivo x-ray computed tomography angiography.
  
  
  METHODS
  Cell-seeded and unseeded scaffolds were implanted in 5 lambs as inferior vena cava interposition grafts. At 2 and 6 months after implantation, in vivo angiography was used to assess graft morphology. In vivo and ex vivo single photon emission tomography/computed tomography imaging was performed with a radiolabeled compound targeting matrix metalloproteinase activity at 6 months. The neotissue was examined at 6 months using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis.
  
  
  RESULTS
  The seeded grafts demonstrated significant luminal and longitudinal growth from 2 to 6 months. In vivo imaging revealed subjectively greater matrix metalloproteinase activity in grafts versus native tissue. Ex vivo imaging confirmed a quantitative increase in matrix metalloproteinase activity and demonstrated greater activity in unseeded versus seeded grafts. The glycosaminoglycan content was increased in seeded grafts versus unseeded grafts, without significant differences in collagen content.
  
  
  CONCLUSIONS
  Matrix metalloproteinase activity remained elevated in tissue-engineered grafts 6 months after implantation and could indicate remodeling. Optimization of in vivo imaging to noninvasively evaluate matrix metalloproteinase activity could assist in the serial assessment of vascular graft remodeling.
authors: Yale University School of Medicine, New Haven, Conn.
authors: Mitchel R
authors: MR
authors: Stacy
authors: University of California, San Francisco, Benioff Children's Hospital, San Francisco, Calif.
authors: Yuji
authors: Y
authors: Naito
authors: Yale University School of Medicine, New Haven, Conn.
authors: Mark W
authors: MW
authors: Maxfield
authors: Nationwide Children's Hospital, Columbus, Ohio.
authors: Hirotsugu
authors: H
authors: Kurobe
authors: Nationwide Children's Hospital, Columbus, Ohio.
authors: Shuhei
authors: S
authors: Tara
authors: Yale University School of Medicine, New Haven, Conn.
authors: Chung
authors: C
authors: Chan
authors: Yale University School of Medicine, New Haven, Conn.
authors: Kevin A
authors: KA
authors: Rocco
authors: Nationwide Children's Hospital, Columbus, Ohio.
authors: Toshiharu
authors: T
authors: Shinoka
authors: Yale University School of Medicine, New Haven, Conn.
authors: Albert J
authors: AJ
authors: Sinusas
authors: Nationwide Children's Hospital, Columbus, Ohio. Electronic address: christopher.breuer@nationwidechildrens.org.
authors: Christopher K
authors: CK
authors: Breuer
mesh_terms: D000367:Age Factors; D000818:Animals; D001705:Bioprosthesis; D001807:Blood Vessel Prosthesis; D019917:Blood Vessel Prosthesis Implantation / Q000295:instrumentation*; D001854:Bone Marrow Cells / Q000201:enzymology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005240:Feasibility Studies; D006025:Glycosaminoglycans / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D023421:Models, Animal; D061330:Multidetector Computed Tomography; D010690:Phlebography / Q000379:methods; D011474:Prosthesis Design; D012756:Sheep; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D015899:Tomography, Emission-Computed, Single-Photon; D015854:Up-Regulation; D066253:Vascular Remodeling; D014682:Vena Cava, Inferior / Q000000981:diagnostic imaging / Q000201:enzymology / Q000601:surgery*
chemical_list: D006025:Glycosaminoglycans; D003094:Collagen; D020782:Matrix Metalloproteinases