Tissue-engineered vascular graft remodeling in a growing lamb model: expression of matrix metalloproteinases

Cummings, Ian; George, Sarah J.; Kelm, Jens; Schmidt, Denise Rodrigues Costa; Emmert, Maximilian Y.; Weber, Benedikt; Zünd, Gregor; Hoerstrup, Simon P.

doi:10.1016/j.ejcts.2011.02.077

Cited by 39 publications

(33 citation statements)

References 26 publications

(46 reference statements)

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“…Prior post-mortem examination of TEVGs implanted in a murine model has demonstrated progressively higher MMP-2 expression over a 4-week time course following TEVG implantation, while MMP-9 expression peaked at 1 week after surgery and significantly decreased by 4 weeks. 6 The elevated expression of MMP-2 within a murine model of TEVG is consistent with the post-mortem findings of Cummings et al, 7 who observed elevated MMP-2 expression in a lamb model of TEVG implantation; however, MMP-9 expression also remained elevated for 80 weeks following implantation. These results suggest that MMPs may play a role in the remodeling of TEVGs and that this process may be prolonged for many months following implantation.…”

Section: Introductionsupporting

confidence: 86%

“…Two previous studies have quantified MMP activity within TEVGs implanted as IVC interposition grafts; however, these studies required histologic evaluation of explanted neotissue. 6,7 In the present study, we sought to evaluate the feasibility of noninvasive assessment of MMP activity in a clinically relevant large animal model of TEVG implantation. We observed elevated MMP activity within the region of TEVG implantation at 6 months following implantation using in vivo SPECT/CT imaging (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…6 Matrix metalloproteinases (MMPs) are enzymes that are thought to play important roles in tissue homeostasis and functional growth and may significantly contribute to ECM remodeling during neovessel formation. 6,7 Specifically, MMP-2 and -9 are basement membrane-degrading MMPs that can play critical roles in ECM remodeling. Prior post-mortem examination of TEVGs implanted in a murine model has demonstrated progressively higher MMP-2 expression over a 4-week time course following TEVG implantation, while MMP-9 expression peaked at 1 week after surgery and significantly decreased by 4 weeks.…”

Section: Introductionmentioning

confidence: 99%

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Targeted imaging of matrix metalloproteinase activity in the evaluation of remodeling tissue-engineered vascular grafts implanted in a growing lamb model

Stacy

Naito

Maxfield

et al. 2014

The Journal of Thoracic and Cardiovascular Surgery

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Objective(s) The clinical translation of tissue-engineered vascular grafts has been demonstrated in children. The remodeling of biodegradable, cell-seeded scaffolds to functional neovessels is partially attributed to matrix metalloproteinases. Noninvasive assessment of matrix metalloproteinase activity may 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 lambs (n=5) as inferior vena cava interposition grafts. At 2 and 6 months post-implantation, in vivo angiography assessed graft morphology. In vivo and ex vivo single photon emission tomography/X-ray computed tomography imaging was performed with a radiolabeled compound targeting matrix metalloproteinase activity at 6 months. Neotissue was examined at 6 months using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis. Results Seeded grafts demonstrated significant luminal and longitudinal growth from 2 to 6 months. In vivo imaging revealed subjectively higher matrix metalloproteinase activity in grafts vs. native tissue. Ex vivo imaging confirmed a quantitative increase in matrix metalloproteinase activity and demonstrated higher activity in unseeded vs. seeded grafts. Glycosaminoglycan content was increased in seeded grafts vs. unseeded grafts, without significant differences in collagen content. Conclusions Matrix metalloproteinase activity remains elevated in tissue-engineered grafts 6 months post-implantation and may indicate remodeling. Optimization of in vivo imaging to noninvasively evaluate matrix metalloproteinase activity may assist in serial assessment of vascular graft remodeling.

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Section: Introductionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeted imaging of matrix metalloproteinase activity in the evaluation of remodeling tissue-engineered vascular grafts implanted in a growing lamb model

Stacy

Naito

Maxfield

et al. 2014

The Journal of Thoracic and Cardiovascular Surgery

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“…For pre-clinical evaluation, tissue engineered constructs and their remodeling are typically tested in healthy animals [28–30]. However, there are great expectations that TE and regenerative medicine research will offer solutions for patients affected by the cardiovascular complications of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Mitigation of diabetes-related complications in implanted collagen and elastin scaffolds using matrix-binding polyphenol

et al. 2013

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There is a major need for scaffold-based tissue engineered vascular grafts and heart valves with long-term patency and durability to be used in diabetic cardiovascular patients. We hypothesized that diabetes, by virtue of glycoxidation reactions, can directly crosslink implanted scaffolds, drastically altering their properties. In order to investigate the fate of tissue engineered scaffolds in diabetic conditions, we prepared valvular collagen scaffolds and arterial elastin scaffolds by decellularization and implanted them subdermally in diabetic rats. Both types of scaffolds exhibited significant levels of advanced glycation end products (AGEs), chemical crosslinking and stiffening - alterations which are not favorable for cardiovascular tissue engineering. Pre-implantation treatment of collagen and elastin scaffolds with penta-galloyl glucose (PGG), an antioxidant and matrix-binding polyphenol, chemically stabilized the scaffolds, reduced their enzymatic degradation, and protected them from diabetes-related complications by reduction of scaffold-bound AGE levels. PGG-treated scaffolds resisted diabetes-induced crosslinking and stiffening, were protected from calcification, and exhibited controlled remodeling in vivo, thereby supporting future use of diabetes-resistant scaffolds for cardiovascular tissue engineering in patients with diabetes.

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“…Rigorous long-term safety and efficacy assessment in vivo must be completed to evaluate time-dependent durability of bioengineered vascular grafts because in vitro studies alone or short-term in vivo experiments do not capture time-dependent degeneration of the implanted material. Despite this need, very few studies have critically assessed long-term (defined as ≥3 months for small animals,[5] ≥12 months for large animals[10] and humans[11]) safety and efficacy of bioengineered vascular grafts in vivo . Although common evaluative end-points predominantly focus on graft stenosis due to neointimal hyperplasia or intravascular thrombosis, intra-graft calcification is often overlooked despite its importance in vascular tissues such as biological heart valves,[12, 13] smooth muscle biology,[14] and arterial mineralization in patients with vascular disease, diabetes, and chronic kidney failure (patients likely to be recipients of vascular grafts).…”

Section: Introductionmentioning

confidence: 99%

Vascular scaffolds with enhanced antioxidant activity inhibit graft calcification

et al. 2017

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There is a need for off-the-shelf, small-diameter vascular grafts that are safe and exhibit high long-term patency. Decellularized tissues can potentially be used as vascular grafts; however, thrombogenic and unpredictable remodeling properties such as intimal hyperplasia and calcification are concerns that hinder their clinical use. The objective of this study was to investigate the long-term function and remodeling of extracellular matrix (ECM)-based vascular grafts composited with antioxidant poly(1, 8-octamethylenecitrate-co-cysteine) (POCC) with or without immobilized heparin. Rat aortas were decellularized to create the following vascular grafts: 1) ECM hybridized with POCC (Poly-ECM), 2) Poly-ECM subsequently functionalized with heparin (Poly-ECM-Hep), and 3) non-modified vascular ECM. Grafts were evaluated as interposition grafts in the abdominal aorta of adult rats at three months. All grafts displayed antioxidant activity, were patent, and exhibited minimal intramural cell infiltration with varying degrees of calcification. Areas of calcification co-localized with osteochondrogenic differentiation of vascular smooth muscle cells, lipid peroxidation, oxidized DNA damage, and cell apoptosis, suggesting an important role for oxidative stress in the calcification of grafts. The extent of calcification within grafts was inversely proportional to their antioxidant activity: Poly-ECM-Hep>ECM>Poly-ECM. The incorporation of antioxidants into vascular grafts may be a viable strategy to inhibit degenerative changes.

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Tissue-engineered vascular graft remodeling in a growing lamb model: expression of matrix metalloproteinases

Cited by 39 publications

References 26 publications

Targeted imaging of matrix metalloproteinase activity in the evaluation of remodeling tissue-engineered vascular grafts implanted in a growing lamb model

Targeted imaging of matrix metalloproteinase activity in the evaluation of remodeling tissue-engineered vascular grafts implanted in a growing lamb model

Mitigation of diabetes-related complications in implanted collagen and elastin scaffolds using matrix-binding polyphenol

Vascular scaffolds with enhanced antioxidant activity inhibit graft calcification

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