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      Microporous polysaccharide multilayer coated BCP composite scaffolds with immobilised calcitriol promote osteoporotic bone regeneration both in vitro and in vivo

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          Abstract

          Incorporating a biomimetic coating and integrating osteoinductive biomolecules into basic bone substitutes are two common strategies to improve osteogenic capabilities in bone tissue engineering. Currently, the underlying mechanism of osteoporosis (OP)-related deficiency of osteogenesis remains unclear, and few treatments target at OP-related bone regeneration. Herein, we describe a self-assembling polyelectrolyte multilayered (PEM) film coating with local immobilisation of calcitriol (Cal) in biphasic calcium phosphate (BCP) scaffolds to promote osteoporotic bone regeneration by targeting the calcium sensing receptor (CaSR).

          Methods: The ovariectomy-induced functional changes in bone marrow mesenchymal stem cells (BMSCs), protective effects of Cal, and the potential mechanism were all verified. A PEM film composed of hyaluronic acid (HA) and chitosan (Chi) was prepared through layer-by-layer self-assembly. The morphology, growth behaviour, and drug retention capability of the composite scaffolds were characterised, and their biocompatibility and therapeutic efficacy for bone regeneration were systematically explored in vitro and in vivo.

          Results: The osteogenic differentiation, adhesion, and proliferation abilities of ovariectomised rat BMSCs (OVX-rBMSCs) decreased, in accordance with the deficiency of CaSR. Cal effectively activated osteogenesis in these OVX-rBMSCs by binding specifically to the active pocket of the CaSR structure, while the biomimetic PEM coating augmented OVX-rBMSCs proliferation and adhesion due to its porous surface structure. The PEM-coated scaffolds showed advantages in Cal loading and retention, especially at lower drug concentrations. HA/Chi PEM synergised with Cal to improve the proliferation, adhesion, and osteogenesis of OVX-rBMSCs and promote bone regeneration and BCP degradation in the critical-size calvarial bone defect model of OVX rats.

          Conclusion: A composite scaffold based on BCP, created by simply combining a biomimetic PEM coating and Cal immobilisation, could be clinically useful and has marked advantages as a targeted, off-the-shelf, cell-free treatment option for osteoporotic bone regeneration.

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          Most cited references60

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          Osteoporosis: now and the future.

          Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine.

            The goal of our study was to estimate the prevalence of osteoporosis and low bone mass based on bone mineral density (BMD) at the femoral neck and the lumbar spine in adults 50 years and older in the United States (US). We applied prevalence estimates of osteoporosis or low bone mass at the femoral neck or lumbar spine (adjusted by age, sex, and race/ethnicity to the 2010 Census) for the noninstitutionalized population aged 50 years and older from the National Health and Nutrition Examination Survey 2005-2010 to 2010 US Census population counts to determine the total number of older US residents with osteoporosis and low bone mass. There were more than 99 million adults aged 50 years and older in the US in 2010. Based on an overall 10.3% prevalence of osteoporosis, we estimated that in 2010, 10.2 million older adults had osteoporosis. The overall low bone mass prevalence was 43.9%, from which we estimated that 43.4 million older adults had low bone mass. We estimated that 7.7 million non-Hispanic white, 0.5 million non-Hispanic black, and 0.6 million Mexican American adults had osteoporosis, and another 33.8, 2.9, and 2.0 million had low bone mass, respectively. When combined, osteoporosis and low bone mass at the femoral neck or lumbar spine affected an estimated 53.6 million older US adults in 2010. Although most of the individuals with osteoporosis or low bone mass were non-Hispanic white women, a substantial number of men and women from other racial/ethnic groups also had osteoporotic BMD or low bone mass. © 2014 American Society for Bone and Mineral Research.
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              Application of chitosan-based polysaccharide biomaterials in cartilage tissue engineering: a review.

              Once damaged, articular cartilage has very little capacity for spontaneous healing because of the avascular nature of the tissue. Although many repair techniques have been proposed over the past four decades, none has sucessfully regenerated long-lasting hyaline cartilage tissue to replace damaged cartilage. Tissue engineering approaches, such as transplantation of isolated chondrocytes, have recently demonstrated tremendous clinical potential for regeneration of hyaline-like cartilage tissue and treatment of chondral lesions. As such a new approach emerges, new important questions arise. One of such questions is: what kinds of biomaterials can be used with chondrocytes to tissue-engineer articular cartilage? The success of chondrocyte transplantation and/or the quality of neocartilage formation strongly depend on the specific cell-carrier material. The present article reviews some of those biomaterials, which have been suggested to promote chondrogenesis and to have potentials for tissue engineering of articular cartilage. A new biomaterial, a chitosan-based polysaccharide hydrogel, is also introduced and discussed in terms of the biocompatibility with chondrocytes.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2019
                30 January 2019
                : 9
                : 4
                : 1125-1143
                Affiliations
                [1 ]Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
                [2 ]The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
                [3 ]Department of Orthopaedic Surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
                [4 ]Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), Vrije University Amsterdam and University of Amsterdam, Amsterdam, Nord-Holland, the Netherlands
                Qian Tang and Zhichao Hu contribute equally to this work
                Author notes
                ✉ Corresponding authors: Liyan Shen, Tel:+86-577-88002760 Email: shenliyan@ 123456wmu.edu.cn ; Changqing Zhang, Tel: +86-21-64369181 Email: zhangcq@ 123456sjtu.edu.cn ; Huazi Xu, Tel: +86-13616632111Email: spinexu@ 123456163.com

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov09p1125
                10.7150/thno.29566
                6401415
                30867820
                39351c66-4556-4d27-8558-79bfa6555462
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 29 August 2018
                : 14 January 2019
                Categories
                Research Paper

                Molecular medicine
                osteoporosis,critical-size bone defect,calcitriol,layer-by-layer assembly,polysaccharide

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