Tissue-engineered Vascular Grafts Demonstrate Evidence of Growth and Development When Implanted in a Juvenile Animal Model

Brennan, Matthew P.; Dardik, Alan; Hibino, Narutoshi; Roh, Jason D.; Nelson, Gregory N.; Papademitris, Xenophon; Shinoka, Toshiharu; Breuer, Christopher K.

doi:10.1097/sla.0b013e318184dcbd

Cited by 139 publications

(103 citation statements)

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“…Additionally, our chimeric hBMC-SCID/bg mouse model enabled us to validate our immunohistochemical findings further with species-specific quantitative RT-PCR (Fig. 2I), a method that could not be used in prior studies, which employed autologous BMC sources (4,9,10).…”

Section: Discussionmentioning

confidence: 98%

“…Ongoing clinical studies evaluating BMC-seeded grafts as venous conduits for congenital heart surgery report excellent safety profiles and 100% patency rates at 1-3 years of follow-up (6-8). Additionally, these grafts demonstrate growth potential, suggesting they may be more effective for the pediatric patient population than currently available vascular grafts (8,9).Although the functional efficacy and clinical utility of TEVGs are promising, little is known about how these BMC-seeded polyester tubes transform into living blood vessels in host recipients. It has been proposed that stem cells within the seeded BMC population differentiate into the endothelial cells (ECs) and smooth muscle cells (SMCs) of the developing neovessel, ultimately replacing the degrading polyester tube (10).…”

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Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling

Roh

Sawh-Martinez

Brennan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs) are the earliest tissue-engineered vascular grafts (TEVGs) to be used clinically. These TEVGs transform into living blood vessels in vivo, with an endothelial cell (EC) lining invested by smooth muscle cells (SMCs); however, the process by which this occurs is unclear. To test if the seeded BMCs differentiate into the mature vascular cells of the neovessel, we implanted an immunodeficient mouse recipient with human BMC (hBMC)-seeded scaffolds. As in humans, TEVGs implanted in a mouse host as venous interposition grafts gradually transformed into living blood vessels over a 6-month time course. Seeded hBMCs, however, were no longer detectable within a few days of implantation. Instead, scaffolds were initially repopulated by mouse monocytes and subsequently repopulated by mouse SMCs and ECs. Seeded BMCs secreted significant amounts of monocyte chemoattractant protein-1 and increased early monocyte recruitment. These findings suggest TEVGs transform into functional neovessels via an inflammatory process of vascular remodeling.bone marrow | monocyte chemoattractant protein-1 | tissue engineering | neovascularization C ongenital heart disease is a leading cause of infant mortality, often requiring early surgical intervention to correct fatal cardiovascular malformations. Prosthetic vascular grafts are widely used in these reconstructive operations, but revisions are often necessary because of their inability to grow or effectively remodel within a growing child (1-3). A strategy to address this issue is the use of living tissue-engineered vascular grafts (TEVGs). Constructed from biodegradable polyester tubes seeded with autologous bone marrow mononuclear cells (BMCs), these grafts undergo extensive remodeling in animal recipients and appear to transform into living blood vessels, similar in morphology and function to the native veins into which they are interposed (4, 5). Ongoing clinical studies evaluating BMC-seeded grafts as venous conduits for congenital heart surgery report excellent safety profiles and 100% patency rates at 1-3 years of follow-up (6-8). Additionally, these grafts demonstrate growth potential, suggesting they may be more effective for the pediatric patient population than currently available vascular grafts (8,9).Although the functional efficacy and clinical utility of TEVGs are promising, little is known about how these BMC-seeded polyester tubes transform into living blood vessels in host recipients. It has been proposed that stem cells within the seeded BMC population differentiate into the endothelial cells (ECs) and smooth muscle cells (SMCs) of the developing neovessel, ultimately replacing the degrading polyester tube (10). This hypothesis, however, has not been directly examined.We recently developed a method for constructing small-diameter biodegradable synthetic scaffolds suitable for use as vascular grafts in mice (11). These tubular scaffolds are composed of the same materials and design used in clinical TEVGs...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

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confidence: 99%

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Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling

Roh

Sawh-Martinez

Brennan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…By seeding the construct with autologous cells, such as progenitor and/or mononuclear cells, using a cell carrier matrix, host-cells can be attracted to the implant site via chemo-attractive paracrine pathways. These attracted immune cells then support a distinct remodeling process, resulting in enhanced extracellular matrix and collagen formation [11].…”

Section: Strategies In Tissue Engineering: In Vivo or Ex Vivo?mentioning

confidence: 99%

Tissue engineering on matrix: future of autologous tissue replacement

et al. 2011

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“…After the initial inflammatory phase incited by TEVG implantation, an endothelial lining forms along the graft lumen, and SMCs migrate from the adjacent vessel to populate the graft [20], forming what will eventually become the neointimal and neomedial layers of the vessel, respectively [6,15,21]. Interestingly, our results did not demonstrate any differences in the area fraction of α-SMA + SMCs in 2-week specimens, but did identify decreased SMC proliferation in the PGDF-KO group.…”

Section: Myeloid Cell Pdgf-b and Tevg Neotissue Development Research Armentioning

confidence: 99%

The Role of Myeloid Cell-Derived PDGF-B in Neotissue Formation in a Tissue-Engineered Vascular Graft

et al. 2017

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Aim: Inflammatory myeloid lineage cells mediate neotissue formation in tissueengineered vascular grafts, but the molecular mechanism is not completely understood. We examined the role of vasculogenic PDGF-B in tissue-engineered vascular graft neotissue development. Materials & methods: Myeloid cell-specific PDGF-B knockout mice (PDGF-KO) were generated using bone marrow transplantation, and scaffolds were implanted as inferior vena cava interposition grafts in either PDGF-KO or wildtype mice. Results: After 2 weeks, grafts from PDGF-KO mice had more remaining scaffold polymer and less intimal neotissue development. Increased macrophage apoptosis, decreased smooth muscle cell proliferation and decreased collagen content was also observed. Conclusion: Myeloid cell-derived PDGF contributes to vascular neotissue formation by regulating macrophage apoptosis, smooth muscle cell proliferation and extracellular matrix deposition. Progress in tissue engineering continues to promise a solution to the lack of tissue available for reconstructive and replacement surgery. Our lab has worked over the past several years developing a tissue-engineered vascular graft (TEVG) for use in congenital heart and vascular surgery. Traditionally used prosthetic materials in the form of Dacron ® or Gore-Tex ® pose significant risk for thromboembolic and infectious complications and also lack growth capacity, making them less ideal for use in the pediatric population. Our ability to create a TEVG with growth capacity [1,2] has therefore been an important advancement in the field, but graft stenosis continues to be a major limitation to widespread clinical application. We have therefore concentrated our efforts on understanding the underlying processes of TEVG neotissue formation and stenosis development.We developed a murine model of TEVG stenosis [3] and found that seeding the grafts with bone marrow-derived mononuclear cells prior to implantation increases graft patency [4] in a dose responsive manner [5], but the seeded cells disappear shortly after implantation [6,7]. We thus hypothesized that a paracrine mechanism, rather than proliferation of seeded cells, was responsible for the remodeling of the TEVG and then demonstrated that host endothelial and smooth muscle cells from the adjacent vessel migrate to form the TEVG neotissue.Host monocytes and macrophages were identified as key mediators of graft remodeling. They infiltrate the graft in large numbers shortly after implantation, and excessive infiltration leads to graft stenosis [8].

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Tissue-engineered Vascular Grafts Demonstrate Evidence of Growth and Development When Implanted in a Juvenile Animal Model

Abstract: INTRODUCTION-The development of a living, autologous vascular graft with the ability to grow holds great promise for advancing the field of pediatric cardiothoracic surgery.

Cited by 139 publications

References 25 publications

Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling

Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling

Tissue engineering on matrix: future of autologous tissue replacement

The Role of Myeloid Cell-Derived PDGF-B in Neotissue Formation in a Tissue-Engineered Vascular Graft

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