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      International Journal of Nanomedicine (submit here)

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      Growth Factor and Its Polymer Scaffold-Based Delivery System for Cartilage Tissue Engineering

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          Abstract

          The development of biomaterials, stem cells and bioactive factors has led to cartilage tissue engineering becoming a promising tactic to repair cartilage defects. Various polymer three-dimensional scaffolds that provide an extracellular matrix (ECM) mimicking environment play an important role in promoting cartilage regeneration. In addition, numerous growth factors have been found in the regenerative process. However, it has been elucidated that the uncontrolled delivery of these factors cannot fully exert regenerative potential and can also elicit undesired side effects. Considering the complexity of the ECM, neither scaffolds nor growth factors can independently obtain successful outcomes in cartilage tissue engineering. Therefore, collectively, an appropriate combination of growth factors and scaffolds have great potential to promote cartilage repair effectively; this approach has become an area of considerable interest in recent investigations. Of late, an increasing trend was observed in cartilage tissue engineering towards this combination to develop a controlled delivery system that provides adequate physical support for neo-cartilage formation and also enables spatiotemporally delivery of growth factors to precisely and fully exert their chondrogenic potential. This review will discuss the role of polymer scaffolds and various growth factors involved in cartilage tissue engineering. Several growth factor delivery strategies based on the polymer scaffolds will also be discussed, with examples from recent studies highlighting the importance of spatiotemporal strategies for the controlled delivery of single or multiple growth factors in cartilage tissue engineering applications.

          Most cited references103

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          Basic Science of Articular Cartilage

          The most challenging aspects in treating articular cartilage injury include identifying the cellular and molecular mechanism(s) that lead to matrix changes and the differentiation and dedifferentiation behavior of chondrocytes, and understanding how they affect the structural integrity of the articular cartilage and tissue remodeling. Several treatment strategies have been proposed. A better understanding of the signaling pathways and growth and transcription factors for genes responsible for chondrogenesis is an important component in the development of new therapies to prevent cartilage degeneration or promote repair to replicate the physiologic and functional properties of the original cartilage.
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            BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation.

            Bone morphogenetic protein (BMP) signaling is required for endochondral bone formation. However, whether or not the effects of BMPs are mediated via canonical Smad pathways or through noncanonical pathways is unknown. In this study we have determined the role of receptor Smads 1, 5 and 8 in chondrogenesis. Deletion of individual Smads results in viable and fertile mice. Combined loss of Smads 1, 5 and 8, however, results in severe chondrodysplasia. Smad1/5(CKO) (cartilage-specific knockout) mutant mice are nearly identical to Smad1/5(CKO);Smad8(-/-) mutants, indicating that Smads 1 and 5 have overlapping functions and are more important than Smad8 in cartilage. The Smad1/5(CKO) phenotype is more severe than that of Smad4(CKO) mice, challenging the dogma, at least in chondrocytes, that Smad4 is required to mediate Smad signaling through BMP pathways. The chondrodysplasia in Smad1/5(CKO) mice is accompanied by imbalances in cross-talk between the BMP, FGF and Ihh/PTHrP pathways. We show that Ihh is a direct target of BMP pathways in chondrocytes, and that FGF exerts antagonistic effects on Ihh expression. Finally, we tested whether FGF exerts its antagonistic effects directly through Smad linker phosphorylation. The results support the alternative conclusion that the effects of FGFs on BMP signaling are indirect in vivo.
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              Enhanced MSC chondrogenesis following delivery of TGF-β3 from alginate microspheres within hyaluronic acid hydrogels in vitro and in vivo.

              Mesenchymal stem cells (MSCs) are being recognized as a viable cell source for cartilage repair and members of the transforming growth factor-beta (TGF-β) superfamily are a key mediator of MSC chondrogenesis. While TGF-β mediated MSC chondrogenesis is well established in in vitro pellet or hydrogel cultures, clinical translation will require effective delivery of TGF-βs in vivo. Here, we investigated the co-encapsulation of TGF-β3 containing alginate microspheres with human MSCs in hyaluronic acid (HA) hydrogels towards the development of implantable constructs for cartilage repair. TGF-β3 encapsulated in alginate microspheres with nanofilm coatings showed significantly reduced initial burst release compared to uncoated microspheres, with release times extending up to 6 days. HA hydrogel constructs seeded with MSCs and TGF-β3 containing microspheres developed comparable mechanical properties and cartilage matrix content compared to constructs supplemented with TGF-β3 continuously in culture media, whereas constructs with TGF-β3 directly encapsulated in the gels without microspheres had inferior properties. When implanted subcutaneously in nude mice, constructs containing TGF-β3 microspheres resulted in superior cartilage matrix formation when compared to groups without TGF-β3 or with TGF-β3 added directly to the gel. However, calcification was observed in implanted constructs after 8 weeks of subcutaneous implantation. To prevent this, the co-delivery of parathyroid hormone-related protein (PTHrP) with TGF-β3 in alginate microspheres was pursued, resulting in partially reduced calcification. This study demonstrates that the controlled local delivery of TGF-β3 is essential to neocartilage formation by MSCs and that further optimization is needed to avert the differentiation of chondrogenically induced MSCs towards a hypertrophic phenotype. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                IJN
                intjnano
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                14 August 2020
                2020
                : 15
                : 6097-6111
                Affiliations
                [1 ]Department of Orthopedics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, People’s Republic of China
                [2 ]School of Dentistry, University of Michigan , Ann Arbor, MI, 48109, USA
                [3 ]Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030, People’s Republic of China
                Author notes
                Correspondence: Xin Duan Tel +86-28-85422426 Email dxbaal@hotmail.com
                Zhou Xiang Tel +86-28-85422605 Email xiangzhou15@hotmail.com
                [*]

                These authors contributed equally to this work

                Article
                249829
                10.2147/IJN.S249829
                7434569
                32884266
                8f360042-85d1-4684-852c-e452d2450d68
                © 2020 Chen et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 14 February 2020
                : 02 July 2020
                Page count
                Figures: 4, Tables: 1, References: 112, Pages: 15
                Categories
                Review

                Molecular medicine
                polymer scaffold,growth factor,delivery,cartilage repair
                Molecular medicine
                polymer scaffold, growth factor, delivery, cartilage repair

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