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      Journey into Bone Models: A Review

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          Abstract

          Bone is a complex tissue with a variety of functions, such as providing mechanical stability for locomotion, protection of the inner organs, mineral homeostasis and haematopoiesis. To fulfil these diverse roles in the human body, bone consists of a multitude of different cells and an extracellular matrix that is mechanically stable, yet flexible at the same time. Unlike most tissues, bone is under constant renewal facilitated by a coordinated interaction of bone-forming and bone-resorbing cells. It is thus challenging to recreate bone in its complexity in vitro and most current models rather focus on certain aspects of bone biology that are of relevance for the research question addressed. In addition, animal models are still regarded as the gold-standard in the context of bone biology and pathology, especially for the development of novel treatment strategies. However, species-specific differences impede the translation of findings from animal models to humans. The current review summarizes and discusses the latest developments in bone tissue engineering and organoid culture including suitable cell sources, extracellular matrices and microfluidic bioreactor systems. With available technology in mind, a best possible bone model will be hypothesized. Furthermore, the future need and application of such a complex model will be discussed.

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          Most cited references216

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          Hydrogels for tissue engineering.

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            Recent advances in bone tissue engineering scaffolds.

            Bone disorders are of significant concern due to increase in the median age of our population. Traditionally, bone grafts have been used to restore damaged bone. Synthetic biomaterials are now being used as bone graft substitutes. These biomaterials were initially selected for structural restoration based on their biomechanical properties. Later scaffolds were engineered to be bioactive or bioresorbable to enhance tissue growth. Now scaffolds are designed to induce bone formation and vascularization. These scaffolds are often porous, made of biodegradable materials that harbor different growth factors, drugs, genes, or stem cells. In this review, we highlight recent advances in bone scaffolds and discuss aspects that still need to be improved. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Three-dimensional bioprinting of thick vascularized tissues.

              The advancement of tissue and, ultimately, organ engineering requires the ability to pattern human tissues composed of cells, extracellular matrix, and vasculature with controlled microenvironments that can be sustained over prolonged time periods. To date, bioprinting methods have yielded thin tissues that only survive for short durations. To improve their physiological relevance, we report a method for bioprinting 3D cell-laden, vascularized tissues that exceed 1 cm in thickness and can be perfused on chip for long time periods (>6 wk). Specifically, we integrate parenchyma, stroma, and endothelium into a single thick tissue by coprinting multiple inks composed of human mesenchymal stem cells (hMSCs) and human neonatal dermal fibroblasts (hNDFs) within a customized extracellular matrix alongside embedded vasculature, which is subsequently lined with human umbilical vein endothelial cells (HUVECs). These thick vascularized tissues are actively perfused with growth factors to differentiate hMSCs toward an osteogenic lineage in situ. This longitudinal study of emergent biological phenomena in complex microenvironments represents a foundational step in human tissue generation.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                10 May 2018
                May 2018
                : 9
                : 5
                : 247
                Affiliations
                [1 ]German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R),10589 Berlin, Germany; julia.scheinpflug@ 123456bfr.bund.de (J.S.); franziskawschwarz@ 123456googlemail.com (F.S.); martin.textor@ 123456bfr.bund.de (M.T.)
                [2 ]Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany; moritz.pfeiffenberger@ 123456charite.de (M.P.); alexandra.damerau@ 123456charite.de (A.D.); annemarie.lang@ 123456charite.de (A.L.)
                [3 ]German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, 10117 Berlin, Germany
                Author notes
                [* ]Correspondence: frank.schulze@ 123456bfr.bund.de ; Tel.: +49-30-18412-3702
                [†]

                These authors contributed equally as first authors

                Author information
                https://orcid.org/0000-0003-1137-7148
                Article
                genes-09-00247
                10.3390/genes9050247
                5977187
                29748516
                704a4b49-5cf4-4f86-a529-b88e17e8d305
                © 2018 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
                : 21 March 2018
                : 03 May 2018
                Categories
                Review

                bone,in vitro models,biomaterials,bioreactors,organ-on-a-chip

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