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    Focal adhesion regulates osteogenic differentiation of mesenchymal stem cells and osteoblasts
    Yang Zhao, Qing Sun, Bo Huo
    Biomaterials Translational    2021, 2 (4): 312-322.   DOI: 10.12336/biomatertransl.2021.04.007
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    Focal adhesions are large macromolecular assemblies through which cells are connected with the extracellular matrix so that extracellular signals can be transmitted inside cells. Some studies have focused on the effect of cell shape on the differentiation of stem cells, but little attention has been paid to focal adhesion. In the present study, mesenchymal stem cells (MSCs) and osteoblast-like MC3T3-E1 cells were seeded onto micropatterned substrates on which circular adhesive islands with different spacing and area were created for focal adhesion. Results showed that the patterns of focal adhesion changed cell morphology but did not affect cell survival. For MSCs cultured for 3 days, patterns with small circles and large spacing promoted osteogenesis. For MSCs cultured for 7 days, patterns with large circles and spacing enhanced osteogenesis. For MC3T3-E1 cells, the patterns of focal adhesion had no effect on cell differentiation after 3 days of culture, but patterns with small circles and spacing improved osteogenic differentiation after 7 days. Moreover, the assembly of F-actin, phosphorylation of myosin, and nuclear translocation of yes-associated proteins (YAP) were consistent with the expression of differentiation markers, indicating that the pattern of focal adhesion may affect the osteogenesis of MSCs and osteoblasts through changes in cytoskeletal tension and nuclear localisation of YAP.

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    Preclinical evaluation of acute systemic toxicity of magnesium incorporated poly(lactic-co-glycolic acid) porous scaffolds by three-dimensional printing
    Jing Long, Bin Teng, Wei Zhang, Long Li, Ming Zhang, Yingqi Chen, Zhenyu Yao, Xiangbo Meng, Xinluan Wang, Ling Qin, Yuxiao Lai
    Biomaterials Translational    2021, 2 (3): 272-284.   DOI: 10.12336/biomatertransl.2021.03.009
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    Biodegradable polymer scaffolds combined with bioactive components which accelerate osteogenesis and angiogenesis have promise for use in clinical bone defect repair. The preclinical acute toxicity evaluation is an essential assay of implantable biomaterials to assess the biosafety for accelerating clinical translation. We have successfully developed magnesium (Mg) particles and beta-tricalcium phosphate (β-TCP) for incorporation into poly(lactic-co-glycolic acid) (PLGA) porous composite scaffolds (PTM) using low-temperature rapid prototyping three-dimensional-printing technology. The PTM scaffolds have been fully evaluated and found to exhibit excellent osteogenic capacity for bone defect repair. The preclinical evaluation of acute systemic toxicities is essential and important for development of porous scaffolds to facilitate their clinical translation. In this study, acute systemic toxicity of the PTM scaffolds was evaluated in mice by intraperitoneal injection of the extract solutions of the scaffolds. PTM composite scaffolds with different Mg and β-TCP content (denoted as PT5M, PT10M, and PT15M) were extracted with different tissue culture media, including normal saline, phosphate-buffered saline, and serum-free minimum essential medium, to create the extract solutions. The evaluation was carried out following the National Standard. The acute toxicity was fully evaluated through the collection of extensive data, including serum/organs ion concentration, fluorescence staining, and in vivo median lethal dose measurement. Mg in major organs (heart, liver, and lung), and Mg ion concentrations in serum of mice, after intraperitoneal injection of the extract solutions, were measured and showed that the extract solutions of PT15M caused significant elevation of serum Mg ion concentrations, which exceeded the safety threshold and led to the death of the mice. In contrast, the extract solutions of PT5M and PT10M scaffolds did not cause the death of the injected mice. The median lethal dose of Mg ions in vivo for mice was determined for the first time in this study to be 110.66 mg/kg, and the safety level of serum magnesium toxicity in mice is 5.4 mM, while the calcium serum safety level is determined as 3.4 mM. The study was approved by the Animal Care and Use Committee of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (approval No. SIAT-IRB-170401-YGS-LYX-A0346) on April 5, 2017. All these results showed that the Mg ion concentration of intraperitoneally-injected extract solutions was a determinant of mouse survival, and a high Mg ion concentration (more than 240 mM) was the pivotal factor contributing to the death of the mice, while changes in pH value showed a negligible effect. The comprehensive acute systemic toxicity evaluation for PTM porous composite scaffolds in this study provided a reference to guide the design and optimization of this composite scaffold and the results demonstrated the preclinical safety of the as-fabricated PTM scaffold with appropriate Mg content, strongly supporting the official registration process of the PTM scaffold as a medical device for clinical translation.

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    Role of hypoxia inducible factor 1α in cobalt nanoparticle induced cytotoxicity of human THP-1 macrophages
    Wendy Rachel Francis, Zhao Liu, Sian E Owens, Xiao Wang, Huaming Xue, Alex Lord, Venkateswarlu Kanamarlapudi, Zhidao Xia
    Biomaterials Translational    2021, 2 (2): 143-150.   DOI: 10.12336/biomatertransl.2021.02.004
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    Cobalt is one of the main components of metal hip prostheses and cobalt nanoparticles (CoNPs) produced from wear cause inflammation, bone lyses and cytotoxicity at high concentrations. Cobalt ions mimic hypoxia in the presence of normal oxygen levels, and activate hypoxic signalling by stabilising hypoxia inducible transcription factor 1α (HIF1α). This study aimed to assess in vitro the functional role of HIF1α in CoNP induced cellular cytotoxicity. HIF1α, lysosomal pH, tumour necrosis factor α and interleukin 1β expression were analysed in THP-1 macrophages treated with CoNP (0, 10 and 100 μg/mL). HIF1α knock out assays were performed using small interfering RNA to assess the role of HIF1α in CoNP-induced cytotoxicity. Increasing CoNP concentration increased lysosomal activity and acidity in THP-1 macrophages. Higher doses of CoNP significantly reduced cell viability, stimulated caspase 3 activity and apoptosis. Reducing HIF1α activity increased the pro-inflammatory activity of tumour necrosis factor α and interleukin 1β, but had no significant impact on cellular cytotoxicity. This suggests that whilst CoNP promotes cytotoxicity and cellular inflammation, the apoptotic mechanism is not dependent on HIF1α.

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    Transdermal delivery of interleukin-12 gene targeting dendritic cells enhances the anti-tumour effect of programmed cell death protein 1 monoclonal antibody
    Huoyan Hong, Xiaoyun Wang, Xinran Song, Gomaa El Fawal, Kaili Wang, Di Jiang, Yifei Pei, Zhe Wang, Hongsheng Wang
    Biomaterials Translational    2021, 2 (2): 151-164.   DOI: 10.12336/biomatertransl.2021.02.005
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    Recent studies have suggested that the anti-tumour effect of the programmed cell death protein 1 monoclonal antibody (aPD-1) depends on the expression of interleukin-12 (IL-12) by dendritic cells (DCs). Since DCs are abundant in skin tissues, transdermal delivery of IL-12 targeting DCs may significantly improve the anti-tumour effect of aPD-1. In this study, a novel mannosylated chitosan (MC)-modified ethosome (Eth-MC) was obtained through electrostatic adsorption. The Eth-MC loaded with plasmid containing the IL-12 gene (pIL-12@Eth-MC) stimulated DCs to express mature-related molecular markers such as CD86, CD80, and major histocompatibility complex-II in a targeted manner. The pIL-12@Eth-MC was then mixed with polyvinyl pyrrolidone solution to make microspheres using the electrospray technique, and sprayed onto the surface of electrospun silk fibroin-polyvinyl alcohol nanofibres to obtain a PVP-pIL-12@Eth-MC/silk fibroin-polyvinyl alcohol composite nanofibrous patch (termed a transcutaneous immunization (TCI) patch). The TCI patch showed a good performance on transdermal drug release. Animal experiments on melanoma-bearing mice showed that topical application of the TCI patches promoted the expression of IL-12 and inhibited the growth of tumour. Furthermore, combined application of the TCI patch and aPD-1 showed a stronger anti-tumour effect than aPD-1 monotherapy. The combination therapy significantly promoted the expression of IL-12, interferon-γ and tumour necrosis factor-α, the infiltration of CD4+ and CD8+ T cells into tumour tissues, and thus promoted the apoptosis of tumour cells. The present study provides a convenient and non-invasive strategy for improving the efficacy of immune checkpoint inhibitor therapy. This study was approved by the Institutional Animal Care and Use Committee at Donghua University (approval No. DHUEC-NSFC-2020-11) on March 31, 2020.

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    Surface topography and free energy regulate osteogenesis of stem cells: effects of shape-controlled gold nanoparticles
    Kamolrat Metavarayuth, Esteban Villarreal, Hui Wang, Qian Wang
    Biomaterials Translational    2021, 2 (2): 165-173.   DOI: 10.12336/biomatertransl.2021.02.006
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    The surface free energy of a biomaterial plays an important role in the early stages of cell-biomaterial interactions, profoundly influencing protein adsorption, interfacial water accessibility, and cell attachment on the biomaterial surface. Although multiple approaches have been developed to engineer the surface free energy of biomaterials, systematically tuning their surface free energy without altering other physicochemical properties remains challenging. In this study, we constructed an array of chemically-equivalent surfaces with comparable apparent roughness through assembly of gold nanoparticles adopting various geometrically-distinct shapes but all capped with the same surface ligand, (1-hexadecyl)trimethylammonium chloride, on cell culture substrates. We found that bone marrow stem cells exhibited distinct osteogenic differentiation behaviours when interacting with different types of substrates comprising shape-controlled gold nanoparticles. Our results reveal that bone marrow stem cells are capable of sensing differences in the nanoscale topographical features, which underscores the role of the surface free energy of nanostructured biomaterials in regulating cell responses. The study was approved by Institutional Animal Care and Use Committee, School of Medicine, University of South Carolina.

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    Plant-produced recombinant SARS-CoV-2 receptor-binding domain; an economical, scalable biomaterial source for COVID-19 diagnosis
    Kaewta Rattanapisit, Gorawit Yusakul, Balamurugan Shanmugaraj, Kittinop Kittirotruji, Phassorn Suwatsrisakul, Eakachai Prompetchara, Suthira Taychakhoonavud, Waranyoo Phoolcharoen
    Biomaterials Translational    2021, 2 (1): 43-49.   DOI: 10.3877/cma.j.issn.2096-112X.2021.01.006
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    The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread rapidly causing a severe global health burden. The standard COVID-19 diagnosis relies heavily on molecular tests to detect viral RNA in patient samples; however, this method is costly, requires highly-equipped laboratories, multiple reagents, skilled laboratory technicians, and takes 3-6 hours to complete. To overcome these limitations, we developed a plant-based production platform for the SARS-CoV-2 receptor-binding domain as an economical source of detection reagents for a lateral-flow immunoassay strip (LFIA) which is suitable for detection of IgM/IgG antibodies in human samples. Further, we validated the plant-produced SARS-CoV-2 receptor-binding domain-based LFIA as a useful diagnostic tool for COVID-19. A total of 51 confirmed COVID-19 serum samples were tested using the LFIA, and the obtained results were consistent with those from polymerase chain reaction assays, while providing sensitivity and specificity of 94.1% and 98%, respectively. The developed LFIA is rapid, scalable, user-friendly, and relatively inexpensive with a simple test procedure, making it useful for the routine monitoring of COVID-19 in clinical settings. This study was approved on March 19, 2020 by the Ethics Committee of the Faculty of Medicine, Chulalongkorn University (COA No. 354/2020 and IRB No. 236/63).

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    Fate and transport of enveloped viruses in indoor built spaces - through understanding vaccinia virus and surface interactions
    Dahae Seong, Monchupa Kingsak, Yuan Lin, Qian Wang, Shamia Hoque
    Biomaterials Translational    2021, 2 (1): 50-60.   DOI: 10.3877/cma.j.issn.2096-112X.2021.01.007
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    The current coronavirus disease 2019 (COVID-19) pandemic has reinforced the necessity of understanding and establishing baseline information on the fate and transport mechanisms of viruses under indoor environmental conditions. Mechanisms governing virus interactions in built spaces have thus far been established based on our knowledge on the interaction of inorganic particles in indoor spaces and do not include characteristics specific to viruses. Studies have explored the biological and kinetic processes of microbes’ attachments on surfaces in other fields but not in the built environment. There is also extensive literature on the influence of indoor architecture on air flow, temperature profiles, and forces influencing aerosol transport. Bridging the gap between these fields will lead to the generation of novel frameworks, methodologies and know-how that can identify undiscovered pathways taken by viruses and other microbes in the built environment. Our study summarizes the assessment of the influence of surface properties on the adhesion kinetics of vaccinia virus on gold, silica, glass, and stainless-steel surfaces. We found that on gold the virus layer was more viscoelastic compared to stainless-steel. There was negligible removal of the layer from the stainless-steel surface compared to the others. The results further highlight the importance of converging different fields of research to assess the fate and transport of microbes in indoor built spaces.

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    Three-dimensional biofabrication of an aragonite-enriched self-hardening bone graft substitute and assessment of its osteogenicity in vitro and in vivo
    Yunsong Shi, Ruijun He, Xiangyu Deng, Zengwu Shao, Davide Deganello, Chunze Yan, Zhidao Xia
    Biomaterials Translational    2020, 1 (1): 69-81.   DOI: 10.3877/cma.j.issn.2096-112X.2020.01.007
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    A self-hardening three-dimensional (3D)-porous composite bone graft consisting of 65 wt% hydroxyapatite (HA) and 35 wt% aragonite was fabricated using a 3D-Bioplotter®. New tetracalcium phosphate and dicalcium phosphate anhydrous/aragonite/gelatine paste formulae were developed to overcome the phase separation of the liquid and solid components. The mechanical properties, porosity, height and width stability of the end products were optimised through a systematic analysis of the fabrication processing parameters including printing pressure, printing speed and distance between strands. The resulting 3D-printed bone graft was confirmed to be a mixture of HA and aragonite by X-ray diffraction, Fourier transform infrared spectroscopy and energy dispersive X-ray spectroscopy. The compression strength of HA/aragonite was between 0.56 and 2.49 MPa. Cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in vitro. The osteogenicity of HA/aragonite was evaluated in vitro by alkaline phosphatase assay using human umbilical cord matrix mesenchymal stem cells, and in vivo by juxtapositional implantation between the tibia and the anterior tibialis muscle in rats. The results showed that the scaffold was not toxic and supported osteogenic differentiation in vitro. HA/aragonite stimulated new bone formation that bridged host bone and intramuscular implants in vivo. We conclude that HA/aragonite is a biodegradable and conductive bone formation biomaterial that stimulates bone regeneration. Since this material is formed near 37°C, it will have great potential for incorporating bioactive molecules to suit personalised application; however, further study of its biodegradation and osteogenic capacity is warranted. The study was approved by the Animal Ethical Committee at Tongji Medical School, Huazhong University of Science and Technology (IACUC No. 738) on October 1, 2017.

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    Design and evaluation of a novel sub-scaffold dental implant system based on the osteoinduction of micro-nano bioactive glass
    Fujian Zhao, Zhen Yang, Lu Liu, Dafu Chen, Longquan Shao, Xiaofeng Chen
    Biomaterials Translational    2020, 1 (1): 82-88.   DOI: 10.3877/cma.j.issn.2096-112X.2020.01.008
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    Alveolar ridge atrophy brings great challenges for endosteal implantation due to the lack of adequate vertical bone mass to hold the implants. To overcome this limitation, we developed a novel dental implant design: sub-scaffold dental implant system (SDIS), which is composed of a metal implant and a micro-nano bioactive glass scaffold. This implant system can be directly implanted under mucous membranes without adding any biomolecules or destroying the alveolar ridge. To evaluate the performance of the novel implant system in vivo, SDISs were implanted into the sub-epicranial aponeurosis space of Sprague-Dawley rats. After 6 weeks, the SDIS and surrounding tissues were collected and analysed by micro-CT, scanning electron microscopy and histology. Our results showed that SDISs implanted into the sub-epicranial aponeurosis had integrated with the skull without any mobility and could stably support a denture. Moreover, this design achieved alveolar ridge augmentation, as active osteogenesis could be observed outside the cortical bone. Considering that the microenvironment of the sub-epicranial aponeurosis space is similar to that of the alveolar ridge, SDISs have great potential for clinical applications in the treatment of atrophic alveolar ridges. The study was approved by the Animal Care Committee of Guangdong Pharmaceutical University (approval No. 2017370).

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    Hyaluronic acid-based hydrogels with tobacco mosaic virus containing cell adhesive peptide induce bone repair in normal and osteoporotic rats
    Jishan Yuan, Panita Maturavongsadit, Zhihui Zhou, Bin Lv, Yuan Lin, Jia Yang, Jittima Amie Luckanagul
    Biomaterials Translational    2020, 1 (1): 89-98.   DOI: 10.3877/cma.j.issn.2096-112X.2020.01.009
    Abstract405)   HTML55)    PDF(pc) (3931KB)(464)       Save

    Tobacco mosaic virus (TMV) has been studied as a multi-functional agent for bone tissue engineering. An osteo-inductive effect of wild-type TMV has been reported, as it can significantly enhance the bone differentiation potential of bone marrow stromal cells both on a two-dimensional substrate and in a three-dimensional (3D) hydrogel system. A TMV mutant (TMV-RGD1) was created which featured the adhesion peptide arginyl-glycyl-aspartic acid (RGD), the most common peptide motif responsible for cell adhesion to the extracellular matrix, on the surface of the virus particle to enhance the bio-functionality of the scaffold material. We hypothesised that the incorporation of either wild-type TMV or TMV-RGD1 in the 3D hydrogel scaffold would induce bone healing in critical size defects of the cranial segmental bone. We have previously tested the virus-functionalised scaffolds, in vitro, with a hyaluronic acid-based system as an in-situ hydrogel platform for 3D cell encapsulation, culture, and differentiation. The results of these experiments suggested the potential of the virus-functionalised hydrogel to promote in vitro stem cell differentiation. The hydrogel-forming system we employed was shown to be safe and biocompatible in vivo. Here, we further explored the physiological responses regarding bone regeneration of a calvarial defect in both normal and osteoporotic ovariectomized rat models. Our results, based on histological analysis in both animal models, suggested that both wild-type TMV and TMV-RGD1 functionalised hydrogels could accelerate bone regeneration, without systemic toxicity, evaluated by blood counts. New bone formation was intensified by the incorporation of the RGD-mutant viral particles. This finding increased the potential for use of the rod-shaped plant virus as a platform for the addition of powerful biofunctionality for tissue engineering applications. This study was approved by the Ethics Committee on Animal Use of the Zhenjiang Affiliated First People’s Hospital affiliated to Jiangsu University.

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