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      Immobilization of BMP-2 and VEGF within Multilayered Polydopamine-Coated Scaffolds and the Resulting Osteogenic and Angiogenic Synergy of Co-Cultured Human Mesenchymal Stem Cells and Human Endothelial Progenitor Cells

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          Abstract

          We have previously reported the fabrication of a polycaprolactone and hydroxyapatite composite scaffold incorporating growth factors to be used for bone regeneration. Two growth factors were incorporated employing a multilayered coating based on polydopamine (PDA). In particular, Bone morphogenetic protein-2 (BMP-2) was bound onto the inner PDA layer while vascular endothelial growth factor (VEGF) was immobilized onto the outer one. Herein, the in vitro release of both growth factors is evaluated. A fastest VEGF delivery followed by a slow and more sustained release of BMP-2 was demonstrated, thus fitting the needs for bone tissue engineering applications. Due to the relevance of the crosstalk between bone-promoting and vessel-forming cells during bone healing, the functionalized scaffolds are further assessed on a co-culture setup of human mesenchymal stem cells and human endothelial progenitor cells. Osteogenic and angiogenic gene expression analysis indicates a synergistic effect between the growth factor-loaded scaffolds and the co-culture conditions. Taken together, these results indicate that the developed scaffolds hold great potential as an efficient platform for bone-tissue applications.

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          Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair.

          Osteoblast-derived VEGF is important for bone development and postnatal bone homeostasis. Previous studies have demonstrated that VEGF affects bone repair and regeneration; however, the cellular mechanisms by which it works are not fully understood. In this study, we investigated the functions of osteoblast-derived VEGF in healing of a bone defect. The results indicate that osteoblast-derived VEGF plays critical roles at several stages in the repair process. Using transgenic mice with osteoblast-specific deletion of Vegfa, we demonstrated that VEGF promoted macrophage recruitment and angiogenic responses in the inflammation phase, and optimal levels of VEGF were required for coupling of angiogenesis and osteogenesis in areas where repair occurs by intramembranous ossification. VEGF likely functions as a paracrine factor in this process because deletion of Vegfr2 in osteoblastic lineage cells enhanced osteoblastic maturation and mineralization. Furthermore, osteoblast- and hypertrophic chondrocyte-derived VEGF stimulated recruitment of blood vessels and osteoclasts and promoted cartilage resorption at the repair site during the periosteal endochondral ossification stage. Finally, osteoblast-derived VEGF stimulated osteoclast formation in the final remodeling phase of the repair process. These findings provide a basis for clinical strategies to improve bone regeneration and treat defects in bone healing.
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            Fabrication of Scaffolds for Bone-Tissue Regeneration

            The present article describes the state of the art in the rapidly developing field of bone tissue engineering, where many disciplines, such as material science, mechanical engineering, clinical medicine and genetics, are interconnected. The main objective is to restore and improve the function of bone tissue by scaffolds, providing a suitable environment for tissue regeneration and repair. Strategies and materials used in oral regenerative therapies correspond to techniques generally used in bone tissue engineering. Researchers are focusing on developing and improving new materials to imitate the native biological neighborhood as authentically as possible. The most promising is a combination of cells and matrices (scaffolds) that can be fabricated from different kinds of materials. This review summarizes currently available materials and manufacturing technologies of scaffolds for bone-tissue regeneration.
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              Bone tissue engineering via growth factor delivery: from scaffolds to complex matrices

              Abstract In recent years, bone tissue engineering has emerged as a promising solution to the limitations of current gold standard treatment options for bone related-disorders such as bone grafts. Bone tissue engineering provides a scaffold design that mimics the extracellular matrix, providing an architecture that guides the natural bone regeneration process. During this period, a new generation of bone tissue engineering scaffolds has been designed and characterized that explores the incorporation of signaling molecules in order to enhance cell recruitment and ingress into the scaffold, as well as osteogenic differentiation and angiogenesis, each of which is crucial to successful bone regeneration. Here, we outline and critically analyze key characteristics of successful bone tissue engineering scaffolds. We also explore candidate materials used to fabricate these scaffolds. Different growth factors involved in the highly coordinated process of bone repair are discussed, and the key requirements of a growth factor delivery system are described. Finally, we concentrate on an analysis of scaffold-based growth factor delivery strategies found in the recent literature. In particular, the incorporation of two-phase systems consisting of growth factor-loaded nanoparticles embedded into scaffolds shows great promise, both by providing sustained release over a therapeutically relevant timeframe and the potential to sequentially deliver multiple growth factors.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                03 September 2020
                September 2020
                : 21
                : 17
                : 6418
                Affiliations
                [1 ]Department of Health Technology, Centre for Nanomedicine and Theranostics, DTU Health Tech, Technical University of Denmark, Produktionstorvet, Building 423, 2800 Kgs. Lyngby, Denmark; mgodoy@ 123456uic.es
                [2 ]Materials Science Institute of Barcelona (ICMAB-CSIC), Campus de la UAB s/n, 08193 Bellaterra, Spain; nuria.portoles.gil@ 123456gmail.com (N.P.-G.); amlopez@ 123456icmab.es (A.M.L.-P.); conchi@ 123456icmab.es (C.D.)
                Author notes
                [* ]Correspondence: leri@ 123456dtu.dk ; Tel.: +45-45258155
                Author information
                https://orcid.org/0000-0002-7232-3998
                https://orcid.org/0000-0002-2580-4641
                https://orcid.org/0000-0002-3777-3205
                https://orcid.org/0000-0002-6976-8283
                https://orcid.org/0000-0001-8177-4806
                Article
                ijms-21-06418
                10.3390/ijms21176418
                7503899
                32899269
                1847c817-631d-4585-88fa-d1adb57359f8
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 August 2020
                : 31 August 2020
                Categories
                Article

                Molecular biology
                angiogenesis,bone tissue engineering,co-delivery,growth factors,multilayers,osteogenesis,polydopamine,scaffolds

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