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      Multi-leveled Nanosilicate Implants Can Facilitate Near-Perfect Bone Healing

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          Abstract

          Several studies have shown that nanosilicate-reinforced scaffolds are suitable for bone regeneration. However, hydrogels are inherently too soft for load-bearing bone defects of critical sizes, and hard scaffolds typically do not provide a suitable three-dimensional (3D) microenvironment for cells to thrive, grow, and differentiate naturally. In this study, we bypass these long-standing challenges by fabricating a cell-free multi-level implant consisting of a porous and hard bone-like framework capable of providing load-bearing support and a softer native-like phase that has been reinforced with nanosilicates. The system was tested with rat bone marrow mesenchymal stem cells in vitro and as a cell-free system in a critical-sized rat bone defect. Overall, our combinatorial and multi-level implant design displayed remarkable osteoconductivity in vitro without differentiation factors, expressing significant levels of osteogenic markers compared to unmodified groups. Moreover, after 8 weeks of implantation, histological and immunohistochemical assays indicated that the cell-free scaffolds enhanced bone repair up to approximately 84% following a near-complete defect healing. Overall, our results suggest that the proposed nanosilicate bioceramic implant could herald a new age in the field of orthopedics.

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          Cell adhesion: the molecular basis of tissue architecture and morphogenesis.

          A variety of cell adhesion mechanisms underlie the way that cells are organized in tissues. Stable cell interactions are needed to maintain the structural integrity of tissues, and dynamic changes in cell adhesion participate in the morphogenesis of developing tissues. Stable interactions actually require active adhesion mechanisms that are very similar to those involved in tissue dynamics. Adhesion mechanisms are highly regulated during tissue morphogenesis and are intimately related to the processes of cell motility and cell migration. In particular, the cadherins and the integrins have been implicated in the control of cell movement. Cadherin mediated cell compaction and cellular rearrangements may be analogous to integrin-mediated cell spreading and motility on the ECM. Regulation of cell adhesion can occur at several levels, including affinity modulation, clustering, and coordinated interactions with the actin cytoskeleton. Structural studies have begun to provide a picture of how the binding properties of adhesion receptors themselves might be regulated. However, regulation of tissue morphogenesis requires complex interactions between the adhesion receptors, the cytoskeleton, and networks of signaling pathways. Signals generated locally by the adhesion receptors themselves are involved in the regulation of cell adhesion. These regulatory pathways are also influenced by extrinsic signals arising from the classic growth factor receptors. Furthermore, signals generated locally be adhesion junctions can interact with classic signal transduction pathways to help control cell growth and differentiation. This coupling between physical adhesion and developmental signaling provides a mechanism to tightly integrate physical aspects of tissue morphogenesis with cell growth and differentiation, a coordination that is essential to achieve the intricate patterns of cells in tissues.
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            Hydrogels as extracellular matrix mimics for 3D cell culture.

            Methods for culturing mammalian cells ex vivo are increasingly needed to study cell and tissue physiology and to grow replacement tissue for regenerative medicine. Two-dimensional culture has been the paradigm for typical in vitro cell culture; however, it has been demonstrated that cells behave more natively when cultured in three-dimensional environments. Permissive, synthetic hydrogels and promoting, natural hydrogels have become popular as three-dimensional cell culture platforms; yet, both of these systems possess limitations. In this perspective, we discuss the use of both synthetic and natural hydrogels as scaffolds for three-dimensional cell culture as well as synthetic hydrogels that incorporate sophisticated biochemical and mechanical cues as mimics of the native extracellular matrix. Ultimately, advances in synthetic-biologic hydrogel hybrids are needed to provide robust platforms for investigating cell physiology and fabricating tissue outside of the organism. (c) 2009 Wiley Periodicals, Inc.
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              Scaffolds for Bone Tissue Engineering: State of the art and new perspectives.

              This review is intended to give a state of the art description of scaffold-based strategies utilized in Bone Tissue Engineering. Numerous scaffolds have been tested in the orthopedic field with the aim of improving cell viability, attachment, proliferation and homing, osteogenic differentiation, vascularization, host integration and load bearing. The main traits that characterize a scaffold suitable for bone regeneration concerning its biological requirements, structural features, composition, and types of fabrication are described in detail. Attention is then focused on conventional and Rapid Prototyping scaffold manufacturing techniques. Conventional manufacturing approaches are subtractive methods where parts of the material are removed from an initial block to achieve the desired shape. Rapid Prototyping techniques, introduced to overcome standard techniques limitations, are additive fabrication processes that manufacture the final three-dimensional object via deposition of overlying layers. An important improvement is the possibility to create custom-made products by means of computer assisted technologies, starting from patient's medical images. As a conclusion, it is highlighted that, despite its encouraging results, the clinical approach of Bone Tissue Engineering has not taken place on a large scale yet, due to the need of more in depth studies, its high manufacturing costs and the difficulty to obtain regulatory approval. PUBMED search terms utilized to write this review were: "Bone Tissue Engineering", "regenerative medicine", "bioactive scaffolds", "biomimetic scaffolds", "3D printing", "3D bioprinting", "vascularization" and "dentistry".
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                Author and article information

                Journal
                ACS Appl Mater Interfaces
                ACS Appl Mater Interfaces
                am
                aamick
                ACS Applied Materials & Interfaces
                American Chemical Society
                1944-8244
                1944-8252
                19 April 2023
                03 May 2023
                : 15
                : 17
                : 21476-21495
                Affiliations
                []Department of Materials Science and Engineering, Faculty of Engineering & Technology, Tarbiat Modares University , P.O. Box 14115-143, Tehran 14115-143, Iran
                []NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU) , Vitoria-Gasteiz 01006, Spain
                [§ ]DTU Health Tech, Center for Intestinal Absorption and Transport of Biopharmaceuticals, Technical University of Denmark , Kongens Lyngby 2800, Denmark
                []Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , Vitoria-Gasteiz 01006, Spain
                []University Institute for Regenerative Medicine and Oral Implantology—UIRMI (UPV/EHU-Fundación Eduardo Anitua) , Vitoria-Gasteiz 01006, Spain
                [# ]Bioaraba, NanoBioCel Research Group , Vitoria-Gasteiz 01006, Spain
                []Department of Biomedical Engineering, College of Engineering, Texas A&M University , College Station, Texas TX 77843, United States
                []Department of Biomedical Engineering, Eindhoven University of Technology , Eindhoven 5612 AE, The Netherlands
                []Institute for Complex Molecular Systems, Eindhoven University of Technology , Eindhoven 5612 AE, The Netherlands
                []Department of Orthopedics, University Medical Center Utrecht, Utrecht University , Utrecht 3508 GA, The Netherlands
                Author notes
                Author information
                https://orcid.org/0000-0002-0773-300X
                https://orcid.org/0000-0002-4269-5889
                Article
                10.1021/acsami.3c01717
                10165608
                37073785
                d06640e0-a296-4ea6-a9da-67678ae60c13
                © 2023 The Authors. Published by American Chemical Society

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 06 February 2023
                : 03 April 2023
                Funding
                Funded by: European Commission, doi 10.13039/100010661;
                Award ID: 951747
                Funded by: Spanish Ministry of Economy, Industry, and Competitiveness, doi NA;
                Award ID: PID2019-106094RB-I00/AEI/10.13039/501100011033
                Funded by: Tarbiat Modares University, doi NA;
                Award ID: NA
                Funded by: Spanish Ministry of Economy, Industry, and Competitiveness, doi NA;
                Award ID: NA
                Funded by: Ministry of Science Research and Technology, doi 10.13039/501100008798;
                Award ID: NA
                Funded by: Det Frie Forskningsråd, doi 10.13039/501100004836;
                Award ID: 810500003B
                Funded by: Iran National Science Foundation, doi 10.13039/501100003968;
                Award ID: 97014136
                Funded by: Ministerio de Economía y Competitividad, doi 10.13039/501100003329;
                Award ID: PID2019-106094RB-I00/AEI/10.13039/501100011033
                Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek, doi 10.13039/501100003246;
                Award ID: R0004387
                Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek, doi 10.13039/501100003246;
                Award ID: OCENW.XS5.161
                Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek, doi 10.13039/501100003246;
                Award ID: 024.003.013
                Categories
                Research Article
                Custom metadata
                am3c01717
                am3c01717

                Materials technology
                bio glass,alginate,laponite,hydrogels,mesenchymal stem cells,nanomaterials,nanosilicate

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