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    Harvest of functional mesenchymal stem cells derived from in vivo osteo-organoids
    Shunshu Deng, Fuwei Zhu, Kai Dai, Jing Wang, Changsheng Liu
    Biomaterials Translational    2023, 4 (4): 270-279.   DOI: 10.12336/biomatertransl.2023.04.006
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    Bone marrow-derived mesenchymal stem cells (BM-MSCs) play a crucial role in stem cell therapy and are extensively used in regenerative medicine research. However, current methods for harvesting BM-MSCs present challenges, including a low yield of primary cells, long time of in vitro expansion, and diminished differentiation capability after passaging. Meanwhile mesenchymal stem cells (MSCs) recovered from cell banks also face issues like toxic effects of cryopreservation media. In this study, we provide a detailed protocol for the isolation and evaluation of MSCs derived from in vivo osteo-organoids, presenting an alternative to autologous MSCs. We used recombinant human bone morphogenetic protein 2-loaded gelatin sponge scaffolds to construct in vivo osteo-organoids, which were stable sources of MSCs with large quantity, high purity, and strong stemness. Compared with protocols using bone marrow, our protocol can obtain large numbers of high-purity MSCs in a shorter time (6 days vs. 12 days for obtaining passage 1 MSCs) while maintaining higher stemness. Notably, we found that the in vivo osteo-organoid-derived MSCs exhibited stronger anti-replicative senescence capacity during passage and amplification, compared to BM-MSCs. The use of osteo-organoid-derived MSCs addresses the conflict between the limitations of autologous cells and the risks associated with allogeneic sources in stem cell transplantation. Consequently, our protocol emerges as a superior alternative for both stem cell research and tissue engineering.

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    Fabrication of magnesium-doped porous polylactic acid microsphere for bone regeneration
    Ziwei Tao, Ziyang Yuan, Dong Zhou, Lang Qin, Lan Xiao, Shihao Zhang, Changsheng Liu, Jinzhong Zhao, Yulin Li
    Biomaterials Translational    2023, 4 (4): 280-290.   DOI: 10.12336/biomatertransl.2023.04.007
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    Biodegradable polymer microspheres that can be used as drug carriers are of great importance in biomedical applications, however, there are still challenges in controllable preparation of microsphere surface morphology and improvement of bioactivity. In this paper, firstly, poly(L-lactic acid) (PLLA) was synthesised by ring-opening polymerisation under anhydrous anaerobic conditions and further combined with the emulsion method, biodegradable PLLA microspheres (PM) with sizes ranging from 60–100 μm and with good sphericity were prepared. In addition, to further improve the surface morphology of PLLA microspheres and enhance their bioactivity, functionalised porous PLLA microspheres loaded with magnesium oxide (MgO)/magnesium carbonate (MgCO3) (PMg) were also prepared by the emulsion method. The results showed that the loading of MgO/MgCO3 resulted in the formation of a porous structure on the surface of the microspheres (PMg) and the dissolved Mg2+ could be released slowly during the degradation of microspheres. In vitro cellular experiments demonstrated the good biocompatibility of PM and PMg, while the released Mg2+ further enhanced the anti-inflammatory effect and osteogenic activity of PMg. Functionalised PMg not only show promise for controlled preparation of drug carriers, but also have translational potential for bone regeneration.

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    A comparative study of human and porcine–derived decellularised nerve matrices
    Rui Li, Shuai Qiu, Weihong Yang, Zilong Rao, Jiaxin Chen, Yuexiong Yang, Qingtang Zhu, Xiaolin Liu, Ying Bai, Daping Quan
    Biomaterials Translational    2023, 4 (3): 180-195.   DOI: 10.12336/biomatertransl.2023.03.006
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    Decellularised extracellular matrix (dECM) biomaterials originating from allogeneic and xenogeneic tissues have been broadly studied in the field of regenerative medicine and have already been used in clinical treatments. Allogeneic dECMs are considered more compatible, but they have the drawback of extremely limited human tissue sources. Their availability is also restricted by the health and age of the donors. To investigate the viability of xenogeneic tissues as a substitute for human tissues, we fabricated both porcine decellularised nerve matrix (pDNM) and human decellularised nerve matrix for a comprehensive comparison. Photomicrographs showed that both dECM scaffolds retained the ECM microstructures of native human nerve tissues. Proteomic analysis demonstrated that the protein compositions of both dECMs were also very similar to each other. Their functional ECM contents effectively promoted the proliferation, migration, and maturation of primary human Schwann cells in vitro. However, pDNM contained a few antigens that induced severe host immune responses in humanised mice. Interestingly, after removing the α–galactosidase antigen, the immune responses were highly alleviated and the pre–treated pDNM maintained a human decellularised nerve matrix–like pro–regenerative phenotype. Therefore, we believe that an α–galactosidase–free pDNM may serve as a viable substitute for human decellularised nerve matrix in future clinical applications.

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    Three-dimensional biofabrication of nanosecond laser micromachined nanofibre meshes for tissue engineered scaffolds
    Ross H. McWilliam, Wenlong Chang, Zhao Liu, Jiayuan Wang, Fengxuan Han, Richard A. Black, Junxi Wu, Xichun Luo, Bin Li, Wenmiao Shu
    Biomaterials Translational    2023, 4 (2): 104-114.   DOI: 10.12336/biomatertransl.2023.02.005
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    There is a high demand for bespoke grafts to replace damaged or malformed bone and cartilage tissue. Three-dimensional (3D) printing offers a method of fabricating complex anatomical features of clinically relevant sizes. However, the construction of a scaffold to replicate the complex hierarchical structure of natural tissues remains challenging. This paper reports a novel biofabrication method that is capable of creating intricately designed structures of anatomically relevant dimensions. The beneficial properties of the electrospun fibre meshes can finally be realised in 3D rather than the current promising breakthroughs in two-dimensional (2D). The 3D model was created from commercially available computer-aided design software packages in order to slice the model down into many layers of slices, which were arrayed. These 2D slices with each layer of a defined pattern were laser cut, and then successfully assembled with varying thicknesses of 100 µm or 200 µm. It is demonstrated in this study that this new biofabrication technique can be used to reproduce very complex computer-aided design models into hierarchical constructs with micro and nano resolutions, where the clinically relevant sizes ranging from a simple cube of 20 mm dimension, to a more complex, 50 mm-tall human ears were created. In-vitro cell-contact studies were also carried out to investigate the biocompatibility of this hierarchal structure. The cell viability on a micromachined electrospun polylactic-co-glycolic acid fibre mesh slice, where a range of hole diameters from 200 µm to 500 µm were laser cut in an array where cell confluence values of at least 85% were found at three weeks. Cells were also seeded onto a simpler stacked construct, albeit made with micromachined poly fibre mesh, where cells can be found to migrate through the stack better with collagen as bioadhesives. This new method for biofabricating hierarchical constructs can be further developed for tissue repair applications such as maxillofacial bone injury or nose/ear cartilage replacement in the future.

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    Harnessing decellularised extracellular matrix microgels into modular bioinks for extrusion-based bioprinting with good printability and high post-printing cell viability
    Hanyu Chu, Kexin Zhang, Zilong Rao, Panpan Song, Zudong Lin, Jing Zhou, Liqun Yang, Daping Quan, Ying Bai
    Biomaterials Translational    2023, 4 (2): 115-127.   DOI: 10.12336/biomatertransl.2023.02.006
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    The printability of bioink and post-printing cell viability is crucial for extrusion-based bioprinting. A proper bioink not only provides mechanical support for structural fidelity, but also serves as suitable three-dimensional (3D) microenvironment for cell encapsulation and protection. In this study, a hydrogel-based composite bioink was developed consisting of gelatin methacryloyl (GelMA) as the continuous phase and decellularised extracellular matrix microgels (DMs) as the discrete phase. A flow-focusing microfluidic system was employed for the fabrication of cell-laden DMs in a high-throughput manner. After gentle mixing of the DMs and GelMA, both rheological characterisations and 3D printing tests showed that the resulting DM-GelMA hydrogel preserved the shear-thinning nature, mechanical properties, and good printability from GelMA. The integration of DMs not only provided an extracellular matrix-like microenvironment for cell encapsulation, but also considerable shear-resistance for high post-printing cell viability. The DM sizes and inner diameters of the 3D printer needles were correlated and optimised for nozzle-based extrusion. Furthermore, a proof-of-concept bioink composedg of RSC96 Schwann cells encapsulated DMs and human umbilical vein endothelial cell-laden GelMA was successfully bioprinted into 3D constructs, resulting in a modular co-culture system with distinct cells/materials distribution. Overall, the modular DM-GelMA bioink provides a springboard for future precision biofabrication and will serve in numerous biomedical applications such as tissue engineering and drug screening.

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    Mechanically conditioned cell sheets cultured on thermo-responsive surfaces promote bone regeneration
    Gen Wang, Zhangqin Yuan, Li Yu, Yingkang Yu, Pinghui Zhou, Genglei Chu, Huan Wang, Qianping Guo, Caihong Zhu, Fengxuan Han, Song Chen, Bin Li
    Biomaterials Translational    2023, 4 (1): 27-40.   DOI: 10.12336/biomatertransl.2023.01.005
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    Cell sheet–based scaffold–free technology holds promise for tissue engineering applications and has been extensively explored during the past decades. However, efficient harvest and handling of cell sheets remain challenging, including insufficient extracellular matrix content and poor mechanical strength. Mechanical loading has been widely used to enhance extracellular matrix production in a variety of cell types. However, currently, there are no effective ways to apply mechanical loading to cell sheets. In this study, we prepared thermo–responsive elastomer substrates by grafting poly(N–isopropyl acrylamide) (PNIPAAm) to poly(dimethylsiloxane) (PDMS) surfaces. The effect of PNIPAAm grafting yields on cell behaviours was investigated to optimize surfaces suitable for cell sheet culturing and harvesting. Subsequently, MC3T3–E1 cells were cultured on the PDMS–g–PNIPAAm substrates under mechanical stimulation by cyclically stretching the substrates. Upon maturation, the cell sheets were harvested by lowering the temperature. We found that the extracellular matrix content and thickness of cell sheet were markedly elevated upon appropriate mechanical conditioning. Reverse transcription quantitative polymerase chain reaction and Western blot analyses further confirmed that the expression of osteogenic–specific genes and major matrix components were up–regulated. After implantation into the critical–sized calvarial defects of mice, the mechanically conditioned cell sheets significantly promoted new bone formation. Findings from this study reveal that thermo–responsive elastomer, together with mechanical conditioning, can potentially be applied to prepare high–quality cell sheets for bone tissue engineering.

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    Systematic evaluation of three porcine-derived collagen membranes for guided bone regeneration
    Andrew Tai, Euphemie Landao-Bassonga, Ziming Chen, Minh Tran, Brent Allan, Rui Ruan, Dax Calder, Mithran Goonewardene, Hien Ngo, Ming Hao Zheng
    Biomaterials Translational    2023, 4 (1): 41-50.   DOI: 10.12336/biomatertransl.2023.01.006
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    Guided bone regeneration is one of the most common surgical treatment modalities performed when an additional alveolar bone is required to stabilize dental implants in partially and fully edentulous patients. The addition of a barrier membrane prevents non–osteogenic tissue invasion into the bone cavity, which is key to the success of guided bone regeneration. Barrier membranes can be broadly classified as non–resorbable or resorbable. In contrast to non–resorbable membranes, resorbable barrier membranes do not require a second surgical procedure for membrane removal. Commercially available resorbable barrier membranes are either synthetically manufactured or derived from xenogeneic collagen. Although collagen barrier membranes have become increasingly popular amongst clinicians, largely due to their superior handling qualities compared to other commercially available barrier membranes, there have been no studies to date that have compared commercially available porcine–derived collagen membranes with respect to surface topography, collagen fibril structure, physical barrier property, and immunogenic composition. This study evaluated three commercially available non–crosslinked porcine–derived collagen membranes (Striate+TM, Bio–Gide® and CreosTM Xenoprotect). Scanning electron microscopy revealed similar collagen fibril distribution on both the rough and smooth sides of the membranes as well as the similar diameters of collagen fibrils. However, D–periodicity of the fibrillar collagen is significantly different among the membranes, with Striate+TM membrane having the closest D–periodicity to native collagen I. This suggests that there is less deformation of collagen during manufacturing process. All collagen membranes showed superior barrier property evidenced by blocking 0.2–16.4 µm beads passing through the membranes. To examine the immunogenic agents in these membranes, we examined the membranes for the presence of DNA and alpha–gal by immunohistochemistry. No alpha–gal or DNA was detected in any membranes. However, using a more sensitive detection method (real–time polymerase chain reaction), a relatively strong DNA signal was detected in Bio–Gide® membrane, but not Striate+TM and CreosTM Xenoprotect membranes. Our study concluded that these membranes are similar but not identical, probably due to the different ages and sources of porcine tissues, as well as different manufacturing processes. We recommend further studies to understand the clinical implications of these findings.

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    Effect of radiation sterilisation on the structure and antibacterial properties of antimicrobial peptides
    Xiaodan Wang, Qinmei Li, Huawei Yang
    Biomaterials Translational    2023, 4 (1): 51-61.   DOI: 10.12336/biomatertransl.2023.01.007
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    Antimicrobial peptides (AMPs) have recently been exploited to fabricate anti–infective medical devices due to their biocompatibility and ability to combat multidrug–resistant bacteria. Modern medical devices should be thoroughly sterilised before use to avoid cross–infection and disease transmission, consequently it is essential to evaluate whether AMPs withstand the sterilisation process or not. In this study, the effect of radiation sterilisation on the structure and properties of AMPs was explored. Fourteen AMPs formed from different monomers with different topologies were synthesised by ring–opening polymerisation of N–carboxyanhydrides. The results of solubility testing showed that the star–shaped AMPs changed from water–soluble to water–insoluble after irradiation, while the solubility of linear AMPs remained unchanged. Matrix–assisted laser desorption/ionisation time of flight mass spectrometry showed that the molecular weight of the linear AMPs underwent minimal changes after irradiation. The results of minimum inhibitory concentration assay also illustrated that radiation sterilisation had little effect on the antibacterial properties of the linear AMPs. Therefore, radiation sterilisation may be a feasible method for the sterilisation of AMPs, which have promising commercial applications in medical devices.

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    Optimising soft tissue in-growth in vivo in additive layer manufactured osseointegrated transcutaneous implants
    Elena Giusto, Gordon Blunn, Roberta Ferro de Godoy, Chaozong Liu, Catherine Pendegrass
    Biomaterials Translational    2022, 3 (4): 243-249.   DOI: 10.12336/biomatertransl.2022.04.004
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    Osseointegrated transcutaneous implants could provide an alternative and improved means of attaching artificial limbs for amputees, however epithelial down growth, inflammation, and infections are common failure modalities associated with their use. To overcome these problems, a tight seal associated with the epidermal and dermal adhesion to the implant is crucial. This could be achieved with specific biomaterials (that mimic the surrounding tissue), or a tissue–specific design to enhance the proliferation and attachment of dermal fibroblasts and keratinocytes. The intraosseous transcutaneous amputation prosthesis is a new device with a pylon and a flange, which is specifically designed for optimising soft tissue attachment. Previously the flange has been fabricated using traditional machining techniques, however, the advent of additive layer manufacturing (ALM) has enabled 3–dimensional porous flanges with specific pore sizes to be used to optimise soft tissue integration and reduce failure of osseointegrated transcutaneous implants. The study aimed to investigate the effect of ALM–manufactured porous flanges on soft tissue ingrowth and attachment in an in vivo ovine model that replicates an osseointegrated percutaneous implant. At 12 and 24 weeks, epithelial downgrowth, dermal attachment and revascularisation into ALM–manufactured flanges with three different pore sizes were compared with machined controls where the pores were made using conventional drilling. The pore sizes of the ALM flanges were 700, 1000 and 1250 μm. We hypothesised that ALM porous flanges would reduce downgrowth, improve soft tissue integration and revascularisation compared with machined controls. The results supported our hypothesis with significantly greater soft tissue integration and revascularisation in ALM porous flanges compared with machined controls.

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    Osteogenic differentiation of encapsulated cells in dexamethasone–loaded phospholipid–induced silk fibroin hydrogels
    Chavee Laomeephol, Helena Ferreira, Sorada Kanokpanont, Jittima Amie Luckanagul, Nuno M Neves, Siriporn Damrongsakkul
    Biomaterials Translational    2022, 3 (3): 213-220.   DOI: 10.12336/biomatertransl.2022.03.005
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    The tissue engineering triad comprises the combination of cells, scaffolds and biological factors. Therefore, we prepared cell– and drug–loaded hydrogels using in situ silk fibroin (SF) hydrogels induced by dimyristoyl glycerophosphoglycerol (DMPG). DMPG is reported to induce rapid hydrogel formation by SF, facilitating cell encapsulation in the hydrogel matrix while maintaining high cell viability and proliferative capacity. In addition, DMPG can be used for liposome formulations in entrapping drug molecules. Dexamethasone (Dex) was loaded into the DMPG–induced SF hydrogels together with human osteoblast–like SaOS–2 cells, then the osteogenic differentiation of the entrapped cells was evaluated in vitro and compared to cells cultured under standard conditions. Calcium production by cells cultured in DMPG/Dex–SF hydrogels with Dex–depleted osteogenic medium was equivalent to that of cells cultured in conventional osteogenic medium containing Dex. The extended–release of the entrapped Dex by the hydrogels was able to provide a sufficient drug amount for osteogenic induction. The controlled release of Dex was also advantageous for cell viability even though its dose in the hydrogels was far higher than that in osteogenic medium. The results confirmed the possibility of using DMPG–induced SF hydrogels to enable dual cell and drug encapsulation to fulfil the practical applications of tissue–engineered constructs.

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    Cellular responses to nanoscale substrate topography of TiO 2 nanotube arrays: cell morphology and adhesion
    Monchupa Kingsak, Panita Maturavongsadit, Hong Jiang, Qian Wang
    Biomaterials Translational    2022, 3 (3): 221-233.   DOI: 10.12336/biomatertransl.2022.03.006
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    Nanotopographical features can be beneficial in augmenting cell functions and increasing osteogenic potential. However, the relationships between surface topographies and biological responses are difficult to establish due to the difficulty in controlling the surface topographical features at a low–nanometre scale. Herein, we report the fabrication of well–defined controllable titanium dioxide (TiO2) nanotube arrays with a wide range of pore sizes, 30–175 nm in diameter, and use of the electrochemical anodization method to assess the effect of surface nanotopographies on cell morphology and adhesion. The results show that TiO2 nanotube arrays with pore sizes of 30 and 80 nm allowed for cell spreading of bone marrow–derived mesenchymal stem cells with increased cell area coverage. Additionally, cell adhesion was significantly enhanced by controlled nanotopographies of TiO2 nanotube arrays with 80 nm pore size. Our results demonstrate that surface modification at the nano–scale level with size tunability under controlled chemical/physical properties and culture conditions can greatly impact cell responses. These findings point to a new direction of material design for bone–tissue engineering in orthopaedic applications.

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    Three-dimensional-printed titanium prostheses with bone trabeculae enable mechanical-biological reconstruction after resection of bone tumours
    Feifei Pu, Wei Wu, Doudou Jing, Yihan Yu, Yizhong Peng, Jianxiang Liu, Qiang Wu, Baichuan Wang, Zhicai Zhang, Zengwu Shao
    Biomaterials Translational    2022, 3 (2): 134-141.   DOI: 10.12336/biomatertransl.2022.02.005
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    Reconstruction after resection has always been an urgent problem in the treatment of bone tumours. There are many methods that can be used to reconstruct bone defects; however, there are also many complications, and it is difficult to develop a safe and effective reconstruction plan for the treatment of bone tumours. With the rapid development of digital orthopaedics, three-dimensional printing technology can solve this problem. The three-dimensional printing of personalised prostheses has many advantages. It can be used to print complex structures that are difficult to fabricate using traditional processes and overcome the problems of stress shielding and low biological activity of conventional prostheses. In this study, 12 patients with bone tumours were selected as research subjects, and based on individualised reverse-engineering design technology, a three-dimensional model of each prosthesis was designed and installed using medical image data. Ti6Al4V was used as the raw material to prepare the prostheses, which were used to repair bone defects after surgical resection. The operation time was 266.43 ± 21.08 minutes (range 180–390 minutes), and intraoperative blood loss was 857.26 ± 84.28 mL (range 800–2500 mL). One patient had delayed wound healing after surgery, but all patients survived without local tumour recurrence, and no tumour metastasis was found. No aseptic loosening or structural fracture of the prosthesis, and no non-mechanical prosthesis failure caused by infection, tumour recurrence, or progression was observed. The Musculo-Skeletal Tumour Society (MSTS) score of limb function was 22.53 ± 2.09 (range 16–26), and ten of the 12 patients scored ≥ 20 and were able to function normally. The results showed that three-dimensional printed prostheses with an individualised design can achieve satisfactory short-term clinical efficacy in the reconstruction of large bone defects after bone tumour resection.

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    On the mechanical aspect of additive manufactured polyether-ether-ketone scaffold for repair of large bone defects
    Seyed Ataollah Naghavi, Changning Sun, Mahbubeh Hejazi, Maryam Tamaddon, Jibao Zheng, Leilei Wang, Chenrui Zhang, Swastina Nath Varma, Dichen Li, Mehran Moazen, Ling Wang, Chaozong Liu
    Biomaterials Translational    2022, 3 (2): 142-151.   DOI: 10.12336/biomatertransl.2022.02.006
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    Polyether-ether-ketone (PEEK) is widely used in producing prosthesis and have gained great attention for repair of large bone defect in recent years with the development of additive manufacturing. This is due to its excellent biocompatibility, good heat and chemical stability and similar mechanical properties which mimics natural bone. In this study, three replicates of rectilinear scaffolds were designed for compression, tension, three-point bending and torsion test with unit cell size of 0.8 mm, a pore size of 0.4 mm, strut thickness of 0.4 mm and nominal porosity of 50%. Stress-strain graphs were developed from experimental and finite element analysis models. Experimental Young’s modulus and yield strength of the scaffolds were measured from the slop of the stress-strain graph to be 395 and 19.50 MPa respectively for compression, 427 and 6.96 MPa respectively for tension, 257 and 25.30 MPa respectively for three-point bending and 231 and 12.83 MPa respectively for torsion test. The finite element model was found to be in good agreement with the experimental results. Ductile fracture of the struct subjected to tensile strain was the main failure mode of the PEEK scaffold, which stems from the low crystallinity of additive manufacturing PEEK. The mechanical properties of porous PEEK are close to those of cancellous bone and thus are expected to be used in additive manufacturing PEEK bone implants in the future, but the lower yield strength poses a design challenge.

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    Graphene-incorporated hyaluronic acid-based hydrogel as a controlled Senexin A delivery system
    Panita Maturavongsadit, Weiwei Wu, Jingyu Fan, Igor B. Roninson, Taixing Cui, Qian Wang
    Biomaterials Translational    2022, 3 (2): 152-161.   DOI: 10.12336/biomatertransl.2022.02.007
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    Perivascular delivery of therapeutic agents against established aetiologies for occlusive vascular remodelling has great therapeutic potential for vein graft failure. However, none of the perivascular drug delivery systems tested experimentally have been translated into clinical practice. In this study, we established a novel strategy to locally and sustainably deliver the cyclin-dependent kinase 8/19 inhibitor Senexin A (SenA), an emerging drug candidate to treat occlusive vascular disease, using graphene oxide-hybridised hyaluronic acid-based hydrogels. We demonstrated an approach to accommodate SenA in hyaluronic acid-based hydrogels through utilising graphene oxide nanosheets allowing for non-covalent interaction with SenA. The resulting hydrogels produced sustained delivery of SenA over 21 days with tunable release kinetics. In vitro assays also demonstrated that the hydrogels were biocompatible. This novel graphene oxide-incorporated hyaluronic acid hydrogel offers an optimistic outlook as a perivascular drug delivery system for treating occlusive vascular diseases, such as vein graft failure.

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    Antifouling and antimicrobial cobaltocenium-containing metallopolymer double-network hydrogels
    Hui Li, Peng Yang, JiHyeon Hwang, Parasmani Pageni, Alan W. Decho, Chuanbing Tang
    Biomaterials Translational    2022, 3 (2): 162-171.   DOI: 10.12336/biomatertransl.2022.02.008
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    Compared with single-network hydrogels, double-network hydrogels offer higher mechanical strength and toughness. Integrating useful functions into double-network hydrogels can expand the portfolios of the hydrogels. We report the preparation of double-network metallopolymer hydrogels with remarkable hydration, antifouling, and antimicrobial properties. These cationic hydrogels are composed of a first network of cationic cobaltocenium polyelectrolytes and a second network of polyacrylamide, all prepared via radical polymerization. Antibiotics were further installed into the hydrogels via ion-complexation with metal cations. These hydrogels exhibited significantly enhanced hydration, compared with polyacrylamide-based hydrogels, while featuring robust mechanical strength. Cationic metallopolymer hydrogels exhibited strong antifouling against oppositely charged proteins. These antibiotic-loaded hydrogels demonstrated a synergistic effect on the inhibition of bacterial growth and antifouling of bacteria, as a result of the unique ion complexation of cobaltocenium cations.

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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
    Abstract582)   HTML42)    PDF(pc) (1813KB)(593)       Save

    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
    Abstract578)   HTML52)    PDF(pc) (1268KB)(876)       Save

    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
    Abstract601)   HTML60)    PDF(pc) (3931KB)(1033)       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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