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      Fast degrading elastomer enables rapid remodeling of a cell-free synthetic graft into a neo-artery

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      1 , 2 , 1 , 1 , 3 , 4
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          Abstract

          Host remodeling is important for the success of medical implants including vascular substitutes. Synthetic and tissue-engineered grafts have yet to show clinical effectiveness in arteries smaller than 5 mm. We designed cell-free biodegradable elastomeric grafts that degrade rapidly to yield neo-arteries nearly free of foreign materials 3 months after interposition grafting in rat abdominal aorta. This design focuses on enabling rapid host remodeling. Three months post-implantation, the neo-arteries resemble native arteries in the following aspects: regular, strong and synchronous pulsation, a confluent endothelium and contractile smooth muscle layers, co-expression of elastin, collagen and glycosaminoglycan, and tough and compliant mechanical properties. Therefore, future study employing large animal models more representative of human vascular regeneration is warranted before clinical translation. This cell-free approach represents a philosophical shift from the prevailing focus on cells in vascular tissue engineering, and may impact regenerative medicine in general.

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          Most cited references31

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          Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component.

          Recently, macrophages have been characterized as having an M1 or M2 phenotype based on receptor expression, cytokine and effector molecule production, and function. The effects of macrophage phenotype upon tissue remodeling following the implantation of a biomaterial are largely unknown. The objectives of this study were to determine the effects of a cellular component within an implanted extracellular matrix (ECM) scaffold upon macrophage phenotype, and to determine the relationship between macrophage phenotype and tissue remodeling. Partial-thickness defects in the abdominal wall musculature of Sprague-Dawley rats were repaired with autologous body wall tissue, acellular allogeneic rat body wall ECM, xenogeneic pig urinary bladder tissue, or acellular xenogeneic pig urinary bladder ECM. At 3, 7, 14, and 28 days the host tissue response was characterized using histologic, immunohistochemical, and RT-PCR methods. The acellular test articles were shown to elicit a predominantly M2 type response and resulted in constructive remodeling, while those containing a cellular component, even an autologous cellular component, elicited a predominantly M1 type response and resulted in deposition of dense connective tissue and/or scarring. We conclude that the presence of cellular material within an ECM scaffold modulates the phenotype of the macrophages participating in the host response following implantation, and that the phenotype of the macrophages participating in the host response appears to be related to tissue remodeling outcome.
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            Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study.

            A common approach for tissue regeneration is cell delivery, for example by direct transplantation of stem or progenitor cells. An alternative, by recruitment of endogenous cells, needs experimental evidence. We tested the hypothesis that the articular surface of the synovial joint can regenerate with a biological cue spatially embedded in an anatomically correct bioscaffold. In this proof of concept study, the surface morphology of a rabbit proximal humeral joint was captured with laser scanning and reconstructed by computer-aided design. We fabricated an anatomically correct bioscaffold using a composite of poly-epsilon-caprolactone and hydroxyapatite. The entire articular surface of unilateral proximal humeral condyles of skeletally mature rabbits was surgically excised and replaced with bioscaffolds spatially infused with transforming growth factor beta3 (TGFbeta3)-adsorbed or TGFbeta3-free collagen hydrogel. Locomotion and weightbearing were assessed 1-2, 3-4, and 5-8 weeks after surgery. At 4 months, regenerated cartilage samples were retrieved from in vivo and assessed for surface fissure, thickness, density, chondrocyte numbers, collagen type II and aggrecan, and mechanical properties. Ten rabbits received TGFbeta3-infused bioscaffolds, ten received TGFbeta3-free bioscaffolds, and three rabbits underwent humeral-head excision without bioscaffold replacement. All animals in the TGFbeta3-delivery group fully resumed weightbearing and locomotion 3-4 weeks after surgery, more consistently than those in the TGFbeta3-free group. Defect-only rabbits limped at all times. 4 months after surgery, TGFbeta3-infused bioscaffolds were fully covered with hyaline cartilage in the articular surface. TGFbeta3-free bioscaffolds had only isolated cartilage formation, and no cartilage formation occurred in defect-only rabbits. TGFbeta3 delivery yielded uniformly distributed chondrocytes in a matrix with collagen type II and aggrecan and had significantly greater thickness (p=0.044) and density (p<0.0001) than did cartilage formed without TGFbeta3. Compressive and shear properties of TGFbeta3-mediated articular cartilage did not differ from those of native articular cartilage, and were significantly greater than those of cartilage formed without TGFbeta3. Regenerated cartilage was avascular and integrated with regenerated subchondral bone that had well defined blood vessels. TGFbeta3 delivery recruited roughly 130% more cells in the regenerated articular cartilage than did spontaneous cell migration without TGFbeta3. Our findings suggest that the entire articular surface of the synovial joint can regenerate without cell transplantation. Regeneration of complex tissues is probable by homing of endogenous cells, as exemplified by stratified avascular cartilage and vascularised bone. Whether cell homing acts as an adjunctive or alternative approach of cell delivery for regeneration of tissues with different organisational complexity warrants further investigation. New York State Stem Cell Science; US National Institutes of Health. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Macrophage diversity and polarization in atherosclerosis: a question of balance.

              Diversity and plasticity are hallmarks of mononuclear phagocytes, which are reflected in plaque formation and evolution. Different monocyte subsets, which differentially contribute to plaque infiltration and to atherosclerosis complications, have been identified. Similarly, depending on different environmental signals plaque-associated macrophages can express polarized pro- and antiatherogenic programs by influencing lipid metabolism, inflammatory responses, and plaque stability. Thus, a "macrophage balance" plays a major role in the pathogenesis of atherosclerotic plaques and affects evolution and complications of atherosclerosis.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                6 December 2011
                July 2012
                01 January 2013
                : 18
                : 7
                : 1148-1153
                Affiliations
                [1 ]Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
                [2 ]Department of Maxillofacial Surgery, Qindu Hospital, Fourth Military Medical University, Xian, China
                [3 ]Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
                [4 ]McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
                Author notes
                Correspondence should be addressed to Y.W. ( yaw20@ 123456pitt.edu )
                Article
                NIHMS342399
                10.1038/nm.2821
                3438366
                22729285
                dafa5830-c3c9-49ff-81fe-b8c7e5bbed1d

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