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  Subjects -> BIOLOGY (Total: 3308 journals)
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BIOLOGY (1576 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 29)
Achievements in the Life Sciences     Open Access   (Followers: 7)
ACS Pharmacology & Translational Science     Hybrid Journal   (Followers: 1)
ACS Synthetic Biology     Hybrid Journal   (Followers: 25)
Acta Biologica Colombiana     Open Access   (Followers: 7)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access   (Followers: 2)
Acta Biologica Turcica     Open Access  
Acta Biologica Venezuelica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 29)
Acta Biotheoretica     Hybrid Journal   (Followers: 4)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Fytotechnica et Zootechnica     Open Access   (Followers: 1)
Acta Limnologica Brasiliensia     Open Access   (Followers: 4)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales     Open Access   (Followers: 1)
Acta Neurobiologiae Experimentalis     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 11)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis     Open Access   (Followers: 1)
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 8)
Advanced Journal of Graduate Research     Open Access  
Advanced Nonlinear Studies     Hybrid Journal  
Advanced Studies in Biology     Open Access  
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Bioinformatics     Open Access   (Followers: 20)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biology     Open Access   (Followers: 12)
Advances in Cell Biology/ Medical Journal of Cell Biology     Open Access   (Followers: 30)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 17)
Advances in Enzyme Research     Open Access   (Followers: 11)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in High Energy Physics     Open Access   (Followers: 22)
Advances in Human Biology     Open Access   (Followers: 4)
Advances in Life Science and Technology     Open Access   (Followers: 18)
Advances in Life Sciences     Open Access   (Followers: 6)
Advances in Marine Biology     Full-text available via subscription   (Followers: 21)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 25)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 2)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Tropical Biodiversity and Environmental Sciences     Open Access   (Followers: 1)
Advances in Virus Research     Full-text available via subscription   (Followers: 6)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 8)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 2)
Ageing Research Reviews     Hybrid Journal   (Followers: 12)
Aging Cell     Open Access   (Followers: 25)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Hybrid Journal   (Followers: 18)
AJP Endocrinology and Metabolism     Hybrid Journal   (Followers: 24)
AJP Lung Cellular and Molecular Physiology     Hybrid Journal   (Followers: 3)
Al-Kauniyah : Jurnal Biologi     Open Access  
Alasbimn Journal     Open Access   (Followers: 2)
Alces : A Journal Devoted to the Biology and Management of Moose     Open Access  
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 9)
American Journal of Bioethics     Hybrid Journal   (Followers: 14)
American Journal of Human Biology     Hybrid Journal   (Followers: 16)
American Journal of Medical and Biological Research     Open Access   (Followers: 10)
American Journal of Plant Sciences     Open Access   (Followers: 20)
American Journal of Primatology     Hybrid Journal   (Followers: 17)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 80)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anadol University Journal of Science and Technology B : Theoritical Sciences     Open Access  
Anadolu University Journal of Science and Technology : C Life Sciences and Biotechnology     Open Access   (Followers: 2)
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 12)
Anatomical Science International     Hybrid Journal   (Followers: 3)
Animal Cells and Systems     Hybrid Journal   (Followers: 5)
Animal Models and Experimental Medicine     Open Access  
Annales de Limnologie - International Journal of Limnology     Hybrid Journal   (Followers: 1)
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3)
Annales Universitatis Mariae Curie-Sklodowska, sectio C – Biologia     Open Access   (Followers: 1)
Annals of Applied Biology     Hybrid Journal   (Followers: 7)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 19)
Annals of Human Biology     Hybrid Journal   (Followers: 5)
Annals of Science and Technology     Open Access  
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 14)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 25)
Annual Review of Cancer Biology     Full-text available via subscription   (Followers: 3)
Annual Review of Cell and Developmental Biology     Full-text available via subscription   (Followers: 39)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 25)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 13)
Anthropological Review     Open Access   (Followers: 24)
Antibiotics     Open Access   (Followers: 9)
Antioxidants     Open Access   (Followers: 5)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 9)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 4)
Apmis     Hybrid Journal   (Followers: 1)
APOPTOSIS     Hybrid Journal   (Followers: 9)
Applied Biology     Open Access   (Followers: 1)
Applied Bionics and Biomechanics     Open Access   (Followers: 7)
Applied Vegetation Science     Full-text available via subscription   (Followers: 10)
Aquaculture Environment Interactions     Open Access   (Followers: 4)
Aquaculture International     Hybrid Journal   (Followers: 26)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 7)
Aquatic Biology     Open Access   (Followers: 6)
Aquatic Ecology     Hybrid Journal   (Followers: 37)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 15)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 23)
Archaea     Open Access   (Followers: 3)
Archiv für Molluskenkunde: International Journal of Malacology     Full-text available via subscription   (Followers: 3)
Archives of Biological Sciences     Open Access  
Archives of Microbiology     Hybrid Journal   (Followers: 9)
Archives of Natural History     Hybrid Journal   (Followers: 8)
Archives of Oral Biology     Hybrid Journal   (Followers: 3)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 3)
Arquivos do Instituto Biológico     Open Access   (Followers: 1)
Arquivos do Museu Dinâmico Interdisciplinar     Open Access  
Arthropod Structure & Development     Hybrid Journal   (Followers: 2)
Arthropods     Open Access   (Followers: 1)
Artificial DNA: PNA & XNA     Hybrid Journal   (Followers: 3)
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Journal of Biodiversity     Open Access   (Followers: 5)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 4)
Asian Journal of Nematology     Open Access   (Followers: 4)
Asian Journal of Poultry Science     Open Access   (Followers: 4)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 4)
Avian Biology Research     Full-text available via subscription   (Followers: 5)
Avian Conservation and Ecology     Open Access   (Followers: 13)
Bacteriology Journal     Open Access   (Followers: 1)
Bacteriophage     Full-text available via subscription   (Followers: 3)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Plant Taxonomy     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Batman Üniversitesi Yaşam Bilimleri Dergisi     Open Access  
Berita Biologi     Open Access   (Followers: 1)
Between the Species     Open Access   (Followers: 1)
Bio Tribune Magazine     Hybrid Journal  
BIO Web of Conferences     Open Access  
BIO-Complexity     Open Access  
Bio-Grafía. Escritos sobre la Biología y su enseñanza     Open Access  
Bio-Lectura     Open Access  
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
BioCentury Innovations     Full-text available via subscription   (Followers: 1)
Biochemistry and Cell Biology     Hybrid Journal   (Followers: 16)
Biochimie     Hybrid Journal   (Followers: 6)
BioControl     Hybrid Journal   (Followers: 6)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 8)
Biodemography and Social Biology     Hybrid Journal  
BioDiscovery     Open Access   (Followers: 2)
Biodiversidade e Conservação Marinha : Revista CEPSUL     Open Access  
Biodiversitas : Journal of Biological Diversity     Open Access  
Biodiversity Data Journal     Open Access   (Followers: 4)
Biodiversity Informatics     Open Access   (Followers: 1)
Biodiversity Information Science and Standards     Open Access   (Followers: 2)
Biodiversity: Research and Conservation     Open Access   (Followers: 26)
Bioedukasi : Jurnal Pendidikan Biologi FKIP UM Metro     Open Access  
Bioeksperimen : Jurnal Penelitian Biologi     Open Access  
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 2)
Bioenergy Research     Hybrid Journal   (Followers: 3)
Bioengineering and Bioscience     Open Access   (Followers: 2)
BioEssays     Hybrid Journal   (Followers: 11)
Bioethics     Hybrid Journal   (Followers: 16)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 5)
Biofilms     Full-text available via subscription   (Followers: 1)
Biogeosciences (BG)     Open Access   (Followers: 11)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 3)
Bioinformatics     Hybrid Journal   (Followers: 378)
Bioinformatics and Biology Insights     Open Access   (Followers: 12)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 7)
Biointerphases     Open Access   (Followers: 1)
Biojournal of Science and Technology     Open Access  
BioLink : Jurnal Biologi Lingkungan, Industri, Kesehatan     Open Access   (Followers: 1)
Biologia     Hybrid Journal  
Biologia on-line : Revista de divulgació de la Facultat de Biologia     Open Access  
Biological Bulletin     Partially Free   (Followers: 6)
Biological Control     Hybrid Journal   (Followers: 8)
Biological Invasions     Hybrid Journal   (Followers: 24)

        1 2 3 4 5 6 7 8 | Last

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Acta Biomaterialia
Journal Prestige (SJR): 1.967
Citation Impact (citeScore): 7
Number of Followers: 29  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1742-7061
Published by Elsevier Homepage  [3181 journals]
  • A Multilayer Micromechanical Elastic Modulus Measuring Method in Ex Vivo
           Human Aneurysmal Abdominal Aortas
    • Abstract: Publication date: Available online 12 July 2019Source: Acta BiomaterialiaAuthor(s): Jorn P. Meekel, Giorgio Mattei, Victor S. Costache, Ron Balm, Jan D. Blankensteijn, Kak K. Yeung Abdominal aortic aneurysms (AAA) are common and potentially life-threatening aortic dilatations, due to the effect of hemodynamic changes on the aortic wall. Previous research has shown a potential pathophysiological role for increased macroscopic aneurysmal wall stiffness; however, not investigating micromechanical stiffness. We aimed to compile a new protocol to examine micromechanical live aortic stiffness (elastic moduli), correlated to histological findings with quantitative immunofluorescence (QIF). Live AAA biopsies (n=7) and non-dilated aortas (controls; n=3) were sectioned. Local elastic moduli of aortic intima, media and adventitia were analysed in the direction towards the lumen and vice versa with nanoindentation. Smooth muscle cells (SMC), collagen and fibroblasts were examined using QIF. Nanoindentation of AAA vs. controls demonstrated a 4-fold decrease in elastic moduli (p=0.022) for layers combined and a 26-fold decrease (p=0.017) for media-to-intima direction. QIF of AAA vs. controls revealed a 4-, 3- and 6-fold decrease of SMC, collagen and fibroblasts, respectively (p=0.036). Correlations were found between bidirectional intima and media measurements (ρ=0.661, p=0.038) and all QIF analyses (ρ=0.857-0.905, p=0.002-0.007). We present a novel protocol to analyse microscopic elastic moduli in live aortic tissues using nanoindentation. Hence, our preliminary findings of decreased elastic moduli and altered wall composition warrant further microscopic stiffness investigation to potentially clarify AAA pathophysiology and to explore potential treatment by wall strengthening.Statement of SignificanceAlthough extensive research on the pathophysiology of dilated abdominal aortas (aneurysms) has been performed, the exact underlying pathways are still largely unclear. Previously, the macroscopic stiffness of the pathologic and healthy aortic wall has been studied. This study however, for the first time, studied the microscopic stiffness changes in live tissue of dilated and non-dilated abdominal aortas. This new protocol provides a device to analyse the alterations on cellular level within their microenvironment, whereas previous studies studied the aorta as a whole. Outcomes of these measurements might help to better understand the underlying origin of the incidence and progression of aneurysms and other aortic diseases.Graphical abstractGraphical abstract for this article
       
  • Osteomimetic matrix components alter cell migration and drug response in a
           3D tumour-engineered osteosarcoma model
    • Abstract: Publication date: Available online 11 July 2019Source: Acta BiomaterialiaAuthor(s): M. Pavlou, M. Shah, P. Gikas, T. Briggs, S.J. Roberts, U. Cheema Osteosarcoma management continues to lack the appropriate prognostic tools to assign personalised treatment. This leaves non-responders to standard care vulnerable to recurring disease and pulmonary metastases. Developing 3D in vitro disease models to serve as a test bed for personalised treatment is a promising approach to address this issue. This study describes the generation of 3D osteosarcoma models termed “tumouroids”, which are geometrically compartmentalised to reproduce the bone cancer mass and its surrounding. Although the tumour microenvironment impacts osteosarcoma in many ways, this model was focused on interrogating the influence of a biomimetic matrix on tumour cell behaviour. The 3D matrix was supplemented with the bone-marrow proteins laminin, fibronectin and NuOss® bone granules. This led to increased invasion of osteosarcoma cell aggregates from within the bone-like matrix into the surrounding acellular bone-marrow-like ECM. The presence of bone granules also yielded an atypical molecular profile of osteosarcoma cells, suggesting malignant metabolic reprogramming. Changes include decreased MMP-9 (p
       
  • Hyaluronan Hydrogels delivering BMP-6 for local targeting of malignant
           plasma cells and osteogenic differentiation of mesenchymal stromal cells
    • Abstract: Publication date: Available online 11 July 2019Source: Acta BiomaterialiaAuthor(s): Anna Luise Grab, Anja Seckinger, Patrick Horn, Dirk Hose, Elisabetta Ada Cavalcanti-Adam Multiple myeloma is a malignant disease characterized by accumulation of clonal plasma cells in the bone marrow. Uncoupling of bone formation and resorption by myeloma cells leads to osteolytic lesions. These are prone to fracture and represent a possible survival space for myeloma cells under treatment causing disease relapse. Here we report on a novel approach suitable for local treatment of multiple myeloma based on hyaluronic acid (HA) hydrogels mimicking the physical properties of the bone marrow. The HA hydrogels are complexed with heparin to achieve sustained presentation and controlled release of bone morphogenetic protein 6 (BMP-6). Others and we have shown that BMP-6 induces myeloma cell apoptosis and bone formation. Using quartz crystal microbalance and enzyme-linked immunosorbent assay, we measured an initial surface density of 400 ng BMP6/cm2, corresponding to two BMP-6 per heparin molecule, with 50% release within two weeks. HA-hydrogels presenting BMP-6 enhanced the phosphorylation of Smad1/5 while reducing the activity of BMP-6 antagonist sclerostin. These materials induced osteogenic differentiation of mesenchymal stromal cells and decreased the viability of myeloma cell lines and primary myeloma cells. BMP-6 functionalized HA-hydrogels represent a promising material for local treatment of myeloma-induced bone disease and residual myeloma cells within lesions to minimize disease relapse or fractures.Graphical abstractMultiple myeloma is a hematological cancer characterized by the accumulation of clonal plasma cells in the bone marrow and local suppression of bone formation, resulting in osteolytic lesions and fractures. Despite recent advances in systemic treatment of multiple myeloma, it is rare to achieve a targeted suppression of myeloma cells and healing of bone lesions. Here we present hydrogels which mimic the physico-chemical properties of the bone marrow, consisting of hyaluronic acid with crosslinked heparin for the controlled presentation of bioactive BMP-6. The hydrogels decrease the viability of myeloma cell lines and primary myeloma cells and induces osteogenic differentiation of mesenchymal stromal cells. The presentation of BMP-6 in the hyaluronan hydrogels enhances the phosphorylation of Smad1/5 while reducing the activity of the BMP-6 antagonist sclerostin. As such, BMP-6 functionalized hyaluronan hydrogels represent a promising material for the localized eradication of myeloma cells.Graphical abstract for this article
       
  • Additively manufactured functionally graded biodegradable porous iron
    • Abstract: Publication date: Available online 11 July 2019Source: Acta BiomaterialiaAuthor(s): Y. Li, H. Jahr, P. Pavanram, F.S.L Bobbert, U. Puggi, X-Y. Zhang, Pouran, M.A. Leeflang, H. Weinans, J. ZhouZadpoor Additively manufactured (AM) functionally graded porous metallic biomaterials offer unique opportunities to satisfy the contradictory design requirements of an ideal bone substitute. However, no functionally graded porous structures have ever been 3D-printed from biodegradable metals, even though biodegradability is crucial both for full tissue regeneration and for the prevention of implant-associated infections in the long term. Here, we present the first ever report on AM functionally graded biodegradable porous metallic biomaterials. We made use of a diamond unit cell for the topological design of four different types of porous structures including two functionally graded structures and two reference uniform structures. Specimens were then fabricated from pure iron powder using selective laser melting (SLM), followed by experimental and computational analyses of their permeability, dynamic biodegradation behavior, mechanical properties, and cytocompatibility. It was found that the topological design with functional gradients controlled the fluid flow, mass transport properties and biodegradation behavior of the AM porous iron specimens, as up to 4-fold variations in permeability and up to 3-fold variations in biodegradation rate were observed for the different experimental groups. After 4 weeks of in vitro biodegradation, the AM porous scaffolds lost 5-16% of their weight. This falls into the desired range of biodegradation rates for bone substitution and confirms our hypothesis that topological design could indeed accelerate the biodegradation of otherwise slowly degrading metals, like iron. Even after 4 weeks of biodegradation, the mechanical properties of the specimens (i.e., E = 0.5-2.1 GPa, σy = 8-48 MPa) remained within the range of the values reported for trabecular bone. Design-dependent cell viability did not differ from gold standard controls for up to 48 h. This study clearly shows the great potential of AM functionally graded porous iron as a bone substituting material. Moreover, we demonstrate that complex topological design permits the control of mechanical properties, degradation behavior of AM porous metallic biomaterials.Statement of SignificanceNo functionally graded porous structures have ever been 3D-printed from biodegradable metals, even though biodegradability is crucial both for full tissue regeneration and for the prevention of implant-associated infections in the long term. Here, we present the first report on 3D-printed functionally graded biodegradable porous metallic biomaterials. Our results suggest that topological design in general, and functional gradients in particular can be used as an important tool for adjusting the biodegradation behavior of AM porous metallic biomaterials. The biodegradation rate and mass transport properties of AM porous iron can be increased while maintaining the bone-mimicking mechanical properties of these biomaterials. The observations reported here underline the importance of proper topological design in the development of AM porous biodegradable metals.Graphical abstractGraphical abstract for this article
       
  • Resurrection of Antibiotics that Methicillin-Resistant Staphylococcus
           aureus Resists by Silver-Doped Bioactive Glass-Ceramic Micropartiscle
    • Abstract: Publication date: Available online 11 July 2019Source: Acta BiomaterialiaAuthor(s): Natalia Pajares-Chamorro, John Shook, Neal D. Hammer, Xanthippi Chatzistavrou This work describes a novel strategy to combat methicillin-resistant Staphylococcus aureus (MRSA) via the reactivation of inert antibiotics. This strategy exploits a multifunctional system consisting of bioactive glass-ceramic microparticles with antibacterial properties combined with various antibiotics to kill MRSA. Specifically, sol-gel derived silver-doped bioactive glass-ceramic microparticles (Ag-BG) combined with antibiotics that MRSA resists such as oxacillin or fosfomycin, significantly decreased the viability of MRSA. Ag-BG also potentiated the activity of vancomycin on static bacteria, which are typically resistant to this antibiotic. Notably, the synergistic activity is restricted to cell-envelope acting antibiotics as Ag-BG supplementation did not increase the efficacy of gentamicin. Bacteria viability assays and electron microscopy images demonstrate that Ag-BG synergizes to restore antibacterial activity to antibiotics that MRSA resists. The low cytotoxicity previously studied against oral bacteria, together with the known regenerative properties presented in previous studies, and the unique antibacterial properties observed in this work when they are combined with antibiotics, make this multifunctional system a promising approach for healing infected tissue.Statement of SignificanceThis study addresses a very significant issue in the field of antibiotic resistance presenting an innovative way to clear MRSA, by utilizing bioactive glass-ceramic microparticles in combination with antibiotics. Multifunctional glass-ceramic microparticles doped with silver ions (Ag-BG) have been previously observed to exhibit bioactive and antibacterial properties. In this study Ag-BG microparticles were observed to synergize with antibiotics restoring their sensitivity against MRSA. This research work presents a novel approach to resurrect ineffective antibiotics and render them effective against MRSA. Cytotoxicity to eukaryotic cells is not anticipated, as it has been previously observed that these microparticles can trigger hard and soft dental tissue regeneration, when they are utilized in certain concentrations. This study opens a new avenue in the treatment of multidrug resistance bacteria.Graphical abstractGraphical abstract for this article
       
  • Keratinocytes protect soft-tissue integration of dental implant materials
           against bacterial challenges in a 3D-tissue infection model
    • Abstract: Publication date: Available online 11 July 2019Source: Acta BiomaterialiaAuthor(s): Xiaoxiang Ren, Henny C. van der Mei, Yijin Ren, Henk J. Busscher The soft-tissue seal around dental implants protects the osseo-integrated screw against bacterial challenges. Surface properties of the implant material are crucial for implant survival against bacterial challenges, but there is no adequate in vitro model mimicking the soft-tissue seal around dental implants. Here, we set up a 3D-tissue model of the soft-tissue seal, in order to establish the roles of oral keratinocytes, gingival fibroblasts and materials surface properties in the protective seal. To this end, keratinocytes were grown on membrane filters in a transwell system, while fibroblasts were adhering to TiO2 surfaces underneath the membrane. In absence of keratinocytes on the membrane, fibroblasts growing on the TiO2 surface could not withstand challenges by commensal streptococci or pathogenic staphylococci. Keratinocytes growing on the membrane filters could withstand bacterial challenges, but tight junctions widened to allow invasion of bacteria to the underlying fibroblast layer in lower numbers than in absence of keratinocytes. The challenge of this bacterial invasion to the fibroblast layer on the TiO2 surface negatively affected tissue integration of the surface, demonstrating the protective barrier role of keratinocytes. Streptococci caused less damage to fibroblasts than staphylococci. Importantly, the protection offered by the soft-tissue seal appeared sensitive to surface properties of the implant material. Integration by fibroblasts of a hydrophobic silicone rubber surface was affected more upon bacterial challenges than integration of more hydrophilic hydroxyapatite or TiO2 surfaces. This differential response to different surface-chemistries makes the 3D-tissue infection model presented a useful tool in the development of new infection-resistant dental implant materials.Statement of SignificanceFailure rates of dental implants due to infection are surprisingly low, considering their functioning in the highly un-sterile oral cavity. This is attributed to the soft-tissue seal, protecting the osseo-integrated implant part against bacterial invasion. The seal consists of a layer of keratinocytes covering gingival fibroblasts, integrating the implant. Implant failure involves high patient discomfort and costs of replacing an infected implant, which necessitates development of improved, infection-resistant dental implant materials. New materials are often evaluated in mono-culture, examining bacterial adhesion or tissue interactions separately and neglecting the 3D-structure of the tissue seal. A 3D-tissue model allows to study new materials in a more relevant way, in which interactions between keratinocytes, gingival fibroblast, bacteria and materials surfaces are accounted for.Graphical abstractGraphical abstract for this article
       
  • Bio-instructive materials for musculoskeletal regeneration
    • Abstract: Publication date: Available online 11 July 2019Source: Acta BiomaterialiaAuthor(s): Tomas Gonzalez-Fernandez, Pawel Sikorski, J. Kent Leach The prevalence and cost of disorders affecting the musculoskeletal system are predicted to rise significantly in the coming years due to the aging global population and the increase of associated risk factors. Despite being the second largest cause of disability, the clinical options for therapeutic intervention remain limited. The clinical translation of cell-based therapies for the treatment of musculoskeletal disorders faces many challenges including maintenance of cell survival in the harsh in vivo environment and the lack of control over regulating cell phenotype upon implantation. In order to address these challenges, the development of bio-instructive materials to modulate cell behavior has taken center stage as a strategy to increase the therapeutic potential of various cell populations. However, the determination of the necessary cues for a specific application and how these signals should be presented from a biomaterial remains elusive. This review highlights recent biochemical and physical strategies used to engineer bio-instructive materials for the repair of musculoskeletal tissues. There is a particular emphasis on emerging efforts such as the engineering of immunomodulatory and antibacterial materials, as well as the incorporation of these strategies into biofabrication and organ-on-a-chip approaches.Statement of SignificanceDisorders affecting the musculoskeletal system affect individuals across the lifespan and have a profound effect on mobility and quality of life. While small defects in many tissues can heal successfully, larger defects are often unable to heal or instead heal with inferior quality fibrous tissue and require clinical intervention. Cell-based therapies are a promising option for clinical translation, yet challenges related to maintaining cell survival and instructing cell phenotype upon implantation have limited the success of this approach. Bio-instructive materials provide an exciting opportunity to modulate cell behavior and enhance the efficacy of cell-based approaches for musculoskeletal repair. However, the identification of critical instructive cues and how to present these stimuli is a focus of intense investigation. This review highlights recent biochemical and physical strategies used to engineer bio-instructive materials for the repair of musculoskeletal tissues, while also considering exciting progress in the engineering of immunomodulatory and antibacterial materials.Graphical abstractGraphical abstract for this article
       
  • Magnetic targeting combined with active targeting of dual-ligand iron
           oxide nanoprobes to promote penetration depth in tumors for effective
           magnetic resonance imaging and hyperthermia
    • Abstract: Publication date: Available online 11 July 2019Source: Acta BiomaterialiaAuthor(s): Ling Chen, Yang Wu, Haoan Wu, Jianzhong Li, Jun Xie, Fengchao Zang, Ming Ma, Ning Gu, Yu Zhang The combination of multi-targeting magnetic nanoprobes and multi-targeting strategies has potential to facilitate magnetic resonance imaging (MRI) and magnetic induction hyperthermia of the tumor. Although the thermo-agents based on magnetic iron oxide nanoparticles (MION) have been successfully used in the form of intratumoral injection in clinical cure of glioblastoma, the tumor-targeted thermotherapy by intravenous administration remains challenging. Herein, we constructed a c(RGDyK)- and D-glucosamine-grafted bispecific molecular nanoprobe (Fe3O4@RGD@GLU) with a magnetic iron oxide core of size 22.17 nm and a biocompatible shell of DSPE-PEG2000, which can specially target the tumor vessel and cancer cells. The selection of c(RGDyK) could make the nanoprobe enter the neovascularization endotheliocyte through αvβ3-mediated endocytosis, which drastically reduced the dependence on the enhanced permeability and retention (EPR) effect in tumor. This dual-ligand nanoprobe exhibited strong magnetic properties and favorable biocompatibility. In vitro studies confirmed the anti-phagocytosis ability against macrophages and the specific targeting capability of Fe3O4@RGD@GLU. Then, the imaging effect and anti-tumor efficacy were compared using different targeting strategies with untargeted nanoprobes, dual-targeted nanoprobes, and magnetic targeting combined with dual-targeted nanoprobes. Moreover, the combination strategy of magnetic targeting and active targeting promoted the penetration depth of nanoprobes in addition to the increased accumulation in tumor tissue. Thus, the dual-targeted magnetic nanoprobe together with the combined targeting strategy could be a promising method in tumor imaging and hyperthermia through in vivo delivery of theranostic agents.Statement of SignificanceMagnetic induction hyperthermia based on iron oxide nanoparticles has been used in clinic for adjuvant treatment of recurrent glioblastoma. Nonetheless, this application is limited to intratumoral injection, and tumor-targeted hyperthermia by intravenous injection remains challenging. In this study, we developed a multi-targeted strategy by combining magnetic targeting with active targeting of dual-ligand magnetic nanoprobes. This combination mode acquired optimum contrast imaging effect through MRI and tumor-suppressive effect through hyperthermia under an alternating current magnetic field. The design of the nanoprobe was suitable for targeting most tumor lesions, which enabled it to be an effective theranostic agent with extensive uses. This study showed significant enhancement of the penetration depth and accumulation of nanoprobes in the tumor tissue for efficient imaging and hyperthermia.Graphical abstractGraphical abstract for this article
       
  • Mineral Formation in the Primary Polyps of Pocilloporoid Corals
    • Abstract: Publication date: Available online 11 July 2019Source: Acta BiomaterialiaAuthor(s): Maayan Neder, Pierre Philippe Laissue, Anat Akiva, Derya Akkaynak, Marie Albéric, Oliver Spaeker, Yael Politi, Iddo Pinkas, Tali Mass In reef-building corals, larval settlement and its rapid calcification provides a unique opportunity to study the bio-calcium carbonate formation mechanism involving skeleton morphological changes. Here we investigate the mineral formation of primary polyps, just after settlement, in two taxa of the pocilloporoid corals: Stylophora pistillata (Esper, 1797) and Pocillopora acuta (Lamarck, 1816). We show that the initial mineral phase is nascent Mg-Calcite, with rod-like morphology in P. acuta, and dumbbell morphology in S. pistillata. These structures constitute the first layer of the basal plate which is comparable to Rapid Accretion Deposits (Centers of Calcification, CoC) in adult coral skeleton. We found also that the rod-like/dumbbell Mg-Calcite structures in subsequent growth step may merge into larger aggregates by deposition of aragonite needles. Our results suggest that a biologically controlled mineralization of initial skeletal deposits (CoC) occurs in three steps: first, vesicles filled with divalent ions are formed intracellularly. These vesicles are then transferred to the calcification site, forming nascent Mg-Calcite rod/pristine dumbbell structures. During the third step, aragonite crystals may develop between these structures forming spherulite-like aggregates.Statement of SignificanceCoral settlement and recruitment periods are highly sensitive to environmental conditions. Successful mineralization during these periods is vital and influences the coral’s chances of survival. Therefore, understanding the exact mechanism underlying carbonate precipitation is highly important. Here, we used in vivo microscopy, spectroscopy and molecular methods to provide new insights into mineral development. We show that the primary polyp’s mineral arsenal consists of two types of minerals: Mg-Calcite and aragonite. In addition, we provide new insights into the ion pathway by showing that divalent ions are concentrated in intracellular vesicles and are eventually deposited at the calcification site.Graphical abstractGraphical abstract for this article
       
  • Biomodulation of an Implant for Enhanced Bone-Implant Anchorage
    • Abstract: Publication date: Available online 10 July 2019Source: Acta BiomaterialiaAuthor(s): Deepak Bushan Raina, David Larsson, Erdem Aras Sezgin, Hanna Isaksson, Magnus Tägil, Lars Lidgren Aseptic loosening of implants is the major cause for revision surgery. By modulating the bone-implant interface, early bone-implant anchorage could be improved. Implant surface manipulation by the addition of osteopromotive molecules locally and systemically to promote implant integration has been described with limited success. This study describes a novel approach by making the implant capable of biologically modulating its surroundings. It was hypothesized that the early implant fixation would improve by filling the interior of the implant with a carrier providing spatio-temporal release of bone active drugs with known osteogenic effect. The implant consisted of a threaded polyether ether ketone (PEEK) hollow chamber with holes at the bottom. The implant was filled with a calcium sulphate (CaS)/hydroxyapatite (HA) carrier, delivering two bone active molecules; zoledronic acid (ZA) and bone morphogenic protein-2 (BMP-2). At first, a rat abdominal muscle pouch model indicated a sustained in-vivo release of both 125I-rhBMP-2 (57%) and 14C-ZA (22%) from the CaS/HA carrier over a period of 4-weeks. The biomodulated implant was then inserted in the proximal tibia in rats with the following experimental groups: G1) Empty implant, G2) Implant + CaS/HA, G3) Implant + CaS/HA+ ZA and G4) Implant + CaS/HA+ ZA + rhBMP-2. Significantly higher bone volume (BV) was seen around the implant in groups G3 (3.3±0.7 mm3) and G4 (3.1±0.7 mm3) compared to the control (1.3±0.4 mm3) using micro-computed tomography and qualitative histology. Group G3, also exhibited significantly higher pull-out force and absorbed energy when compared to the control group G1. These findings indicate that a low dose of ZA alone, released in a controlled manner from within a fenestrated implant is enough to improve implant anchorage without the need of adding rhBMP-2. This simple method of using a fenestrated implant containing a ceramic carrier releasing bone active molecules improved bone anchorage and could clinically reduce prosthetic failure.Statement of significanceAseptic loosening remains as a major cause for implant revisions and early reaction of surrounding bone to the prosthesis is important for longevity. A novel approach to enhance early bone-implant anchorage is presented.The implant is filled with a carrier providing controlled release of bone active molecules. In an animal model, a calcium sulphate (CaS)/hydroxyapatite (HA) carrier was used to provide a spatio-temporal release of bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA). Significantly better bone-implant integration was achieved using ZA alone, thereby eliminating the need for adding BMP-2. The developed method of implant biomodulation holds potential to prevent implant loosening and is an alternative to prosthetic coatings or systemic drug treatment. Importantly, all constituents are approved for clinical use.Graphical abstractGraphical abstract for this article
       
  • DNA Vaccination via RALA Nanoparticles in a Microneedle Delivery System
           Induces a Potent Immune Response against the Endogenous Prostate Cancer
           Stem Cell Antigen
    • Abstract: Publication date: Available online 9 July 2019Source: Acta BiomaterialiaAuthor(s): Grace Cole, Ahlam A. Ali, Emma McErlean, Eoghan J. Mulholland, Amy Short, Cian M. McCrudden, Joanne McCaffrey, Tracy Robson, Vicky L. Kett, Jonathan A. Coulter, Nicholas J. Dunne, Ryan F. Donnelly, Helen O. McCarthy Castrate resistant prostate cancer (CRPC) remains a major challenge for healthcare professionals. Immunotherapeutic approaches, including DNA vaccination, hold the potential to harness the host’s own immune system to mount a cell-mediated, anti-tumour response, capable of clearing disseminated tumour deposits. These anti-cancer vaccines represent a promising strategy for patients with advanced disease, however, to date DNA vaccines have demonstrated limited efficacy in clinical trials, owing to the lack of a suitable DNA delivery system. This study was designed to evaluate the efficacy of a two-tier delivery system incorporating cationic RALA/pDNA nanoparticles (NPs) into a dissolvable microneedle (MN) patch for the purposes of DNA vaccination against prostate cancer. Application of NP-loaded MN patches successfully resulted in endogenous production of the encoded prostate stem cell antigen (PSCA). Furthermore, immunisation with RALA/pPSCA loaded MNs elicited a tumour-specific immune response against TRAMP C-1 tumours ex vivo. Finally, vaccination with RALA/pPSCA loaded MNs demonstrated anti-tumour activity in both prophylactic and therapeutic prostate cancer models in vivo. This is further evidence that this two-tier MN delivery system is a robust platform for prostate cancer DNA vaccination.Statement of SignificanceThis article advances research regarding the development and utilisation of our unique microneedle (MN) DNA delivery system, which enables penetration through the stratum corneum and deposition within the highly immunogenic skin layers via a dissolvable MN matrix, and facilitates cellular uptake via complexation of pDNA cargo into nanoparticles (NPs) with the RALA delivery peptide. In the current study we report for the first time on using the NP-MN platform to immunise mice with encoded Prostate Stem Cell Antigen (mPSCA) for prostate cancer DNA vaccination. Application of the NP-MN system successfully resulted in local mPSCA expression within the treated ears of mice. Furthermore, immunisation of mice with the NP-MN system induced a tumour-specific cellular immune response, and inhibited the growth of TRAMP C-1 tumours in both prophylactic and therapeutic challenge models.These findings are significant as they represent the first use of the NP-MN system using the PSCA as a target for Prostate Cancer DNA Vaccination.Graphical abstractGraphical abstract for this article
       
  • Endothelin-1 inhibits size dependent lymphatic clearance of PEG-based
           conjugates after intra-articular injection into the rat knee
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Thanh N. Doan, Fabrice C. Bernard, Jay M. McKinney, J. Brandon Dixon, Nick J. Willett Clearance of particles from the knee is an essential mechanism to maintain healthy joint homeostasis and critical to the delivery of drugs and therapeutics. One of the limitations in developing disease modifying drugs for joint diseases, such as osteoarthritis (OA), has been poor local retention of the drugs. Enhancing drug retention within the joint has been a target of biomaterial development, however, a fundamental understanding of joint clearance pathways has not been characterized. We applied near-infrared (NIR) imaging techniques to assess size-dependent in vivo clearance mechanisms of intra-articular injected, fluorescently-labelled polyethylene glycol (PEG-NIR) conjugates. The clearance of 2 kDa PEG-NIR (τ = 171 ± 11 min) was faster than 40 kDa PEG-NIR (τ = 243 ± 16 min). 40 kDa PEG-NIR signal was found in lumbar lymph node while 2 kDa PEG-NIR signal was not. Thus, these two conjugates may be cleared through different pathways, i.e. lymphatics for 40 kDa PEG-NIR and venous for 2 kDa PEG-NIR. Endothelin-1 (ET-1), a potent vasoconstrictor of vessels, is elevated in synovial fluid of OA patients but, its effects on joint clearance are unknown. Intra-articular injection of ET-1 dose-dependently inhibited the clearance of both 2 kDa and 40 kDa PEG-NIR. ET-1 caused a 1.63 ± 0.17-fold increase in peak fluorescence for 2 kDa PEG-NIR and a 1.85 ± 0.15-fold increase for 40 kDa PEG-NIR; and ET-1 doubled their clearance time constants. The effects of ET-1 were blocked by co-injection of ET receptor antagonists, bosentan or BQ-123. These findings provide fundamental insight into retention and clearance mechanisms that should be considered in the development and delivery of drugs and biomaterial carriers for joint diseases.Statement of SignificanceThis study demonstrates that in vivo knee clearance can be measured using NIR technology and that key factors, such as size of materials and biologics, can be investigated to define joint clearance mechanisms. Therapies targeting regulation of joint clearance may be an approach to treat joint diseases like osteoarthritis. Additionally, in vivo functional assessment of clearance may be used as diagnostics to monitor progression of joint diseases.Graphical abstractGraphical abstract for this article
       
  • Cartilage penetrating cationic peptide carriers for applications in drug
           delivery to avascular negatively charged tissues
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Armin Vedadghavami, Erica K. Wagner, Shikhar Mehta, Tengfei He, Chenzhen Zhang, Ambika G. Bajpayee Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148× showing that intra-tissue long-range charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues.Statement of SignificanceOsteoarthritis (OA) remains an untreatable disease partly due to short joint residence time of drugs and a lack of delivery methods that can effectively target the dense, avascular, highly negatively charged cartilage tissue. In this study, we designed cartilage penetrating and binding cationic peptide carriers (CPCs) that, due to their optimal charge provide adequate electrical driving force to rapidly transport OA drugs into cartilage and reach their cell and matrix targets in therapeutic doses before drugs exit the joint space. This way cartilage is converted from being a barrier to drug entry into a drug depot that can provide sustained drug release for several weeks. This study also investigates synergistic effects of short-range H-bond and hydrophobic interactions in combination with long-range electrostatic interactions on intra-cartilage solute transport. The work provides rules for rational design of cartilage penetrating charge-based carriers depending on the net charge of tissue (normal versus arthritic), macromolecule to be delivered and whether the application is in drug delivery or tissue imaging.Graphical abstractGraphical abstract for this article
       
  • Bioactive factors for cartilage repair and regeneration: Improving
           delivery, retention, and activity
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Jay M. Patel, Kamiel S. Saleh, Jason A. Burdick, Robert L. Mauck Articular cartilage is a remarkable tissue whose sophisticated composition and architecture allow it to withstand complex stresses within the joint. Once injured, cartilage lacks the capacity to self-repair, and injuries often progress to joint wide osteoarthritis (OA) resulting in debilitating pain and loss of mobility. Current palliative and surgical management provides short-term symptom relief, but almost always progresses to further deterioration in the long term. A number of bioactive factors, including drugs, corticosteroids, and growth factors, have been utilized in the clinic, in clinical trials, or in emerging research studies to alleviate the inflamed joint environment or to promote new cartilage tissue formation. However, these therapies remain limited in their duration and effectiveness. For this reason, current efforts are focused on improving the localization, retention, and activity of these bioactive factors. The purpose of this review is to highlight recent advances in drug delivery for the treatment of damaged or degenerated cartilage. First, we summarize material and modification techniques to improve the delivery of these factors to damaged tissue and enhance their retention and action within the joint environment. Second, we discuss recent studies using novel methods to promote new cartilage formation via biofactor delivery, that have potential for improving future long-term clinical outcomes. Lastly, we review the emerging field of orthobiologics, using delivered and endogenous cells as drug-delivering “factories” to preserve and restore joint health. Enhancing drug delivery systems can improve both restorative and regenerative treatments for damaged cartilage.Statement of significanceArticular cartilage is a remarkable and sophisticated tissue that tolerates complex stresses within the joint. When injured, cartilage cannot self-repair, and these injuries often progress to joint-wide osteoarthritis, causing patients debilitating pain and loss of mobility. Current palliative and surgical treatments only provide short-term symptomatic relief and are limited with regards to efficiency and efficacy. Bioactive factors, such as drugs and growth factors, can improve outcomes to either stabilize the degenerated environment or regenerate replacement tissue. This review highlights recent advances and novel techniques to enhance the delivery, localization, retention, and activity of these factors, providing an overview of the cartilage drug delivery field that can guide future research in restorative and regenerative treatments for damaged cartilage.Graphical abstractGraphical abstract for this article
       
  • Decorin-supplemented collagen hydrogels for the co-delivery of bone
           morphogenetic protein-2 and microvascular fragments to a composite
           bone-muscle injury model with impaired vascularization
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Marissa A. Ruehle, Mon-Tzu Alice Li, Albert Cheng, Laxminarayanan Krishnan, Nick J. Willett, Robert E. Guldberg Traumatic musculoskeletal injuries that result in bone defects or fractures often affect both bone and the surrounding soft tissue. Clinically, these types of multi-tissue injuries have increased rates of complications and long-term disability. Vascular integrity is a key clinical indicator of injury severity, and revascularization of the injury site is a critical early step of the bone healing process. Our lab has previously established a pre-clinical model of composite bone-muscle injury that exhibits impaired bone healing; however, the vascularization response in this model had not yet been investigated. Here, the early revascularization of a bone defect following composite injury is shown to be impaired, and subsequently the therapeutic potential of combined vascularization and osteoinduction was investigated to overcome the impaired regeneration in composite injuries. A decorin (DCN)-supplemented collagen hydrogel was developed as a biomaterial delivery vehicle for the co-delivery microvascular fragments (MVF), which are multicellular segments of mature vasculature, and bone morphogenetic protein-2 (BMP-2), a potent osteoinductive growth factor. We hypothesized that collagen + DCN would increase BMP-2 retention over collagen alone due to DCN’s ability to sequester TGF-ß growth factors. We further hypothesized that MVF would increase both early vascularization and subsequent BMP-2-mediated bone regeneration. Contrary to our hypothesis, BMP + MVF decreased the number of blood vessels relative to BMP alone and had no effect on bone healing. However, collagen + DCN was demonstrated to be a BMP-2 delivery vehicle capable of achieving bridging in the challenging composite defect model that is comparable to that achieved with a well-established alginate-based delivery system.Statement of SignificanceWe have previously established a model of musculoskeletal trauma that exhibits impaired bone healing. For the first time, this work shows that the early revascularization response is also significantly, albeit modestly, impaired. A decorin-supplemented collagen hydrogel was used for the first time in vivo as a delivery vehicle for both a cell-based vascular therapeutic, MVF, and an osteoinductive growth factor, BMP-2. While MVF did not improve vascular volume or bone healing, collagen + DCN is a BMP-2 delivery vehicle capable of achieving bridging in the challenging composite defect model. Based on its support of robust angiogenesis in vitro, collagen + DCN may be extended for future use with other vascular therapeutics such as pre-formed vascular networks.Graphical abstractGraphical abstract for this article
       
  • A computational study of the dual effect of intermittent and continuous
           administration of parathyroid hormone on bone remodeling
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Yu Zhao, Guigen Zhang Bone remodeling is a process known to be governed by constant interactions between osteoblast and osteoclast through complex pathway networks mediated by signaling factors. Experimental studies show that intermittent and continuous administration of PTH/PTHrP led to opposite outcomes in terms of bone mass. To investigate this dual effect of PTH/PTHrP, we develop a computational model based on a simplified signaling pathway network which includes relevant molecular effectors and cells. Multiple ordinary differential equations linking all considered components in the signaling pathway network through reaction kinetics are solved with dose values and patterns of injection from experiments as input. Modeling results show good agreement with experimental observations in that continuous injection of PTH/PTHrP generates catabolic effect on bone mass while intermittent injection yields anabolic effect. The signaling factors governing the interaction between osteoblast and osteoclast indeed play a key role in the dual effect of PTH/PTHrP. Furthermore, there appears to be an optimal interval for intermittent injection of PTH/PTHrP for yielding the most bone regeneration, and a synergistic outcome could be achieved by combining intermittent injection of PTH/PTHrP with application of a treatment (to mimic the filling of bone defects with polymeric scaffolds). This modeling work sheds valuable insights into the influence of temporal control of PTH/PTHrP on bone mass and presents a possible path toward bridging bioengineering approaches with clinical treatment strategies.Statement of SignificanceA computational model considering simplified signaling pathways containing crucial components of PTH, PTHrP, osteoblast precursor, osteoblast, osteoclast precursor, osteoclast, RANKL and IL-6 family cytokoines has been developed to study the dual effect of PTH/PTHrP on bone metabolism. The model takes the dose values and patterns of injection from experiments as input and yields predictions that convincingly match experimental measurements. This work highlights the importance of providing an optimal hormone treatment strategy for maintaining healthy bone metabolism. Moreover, the integrative approach of relying on experimental observations to find reasonable values for relevant modeling parameters has been proven to be powerful in advancing our understanding of biological interactions among cells and signaling factors.
       
  • Biodegradable polymerized simvastatin stimulates bone formation
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Nandakumar Venkatesan, A.D. Thilanga Liyanage, Jaime Castro-Núñez, Theodora Asafo-Adjei, Larry L. Cunningham, Thomas D. Dziubla, David A. Puleo Previous research from our labs demonstrated the synthesis of polymerized simvastatin by ring-opening polymerization and slow degradation with controlled release of simvastatin in vitro. The objective of the present study was to evaluate the degradation and intramembranous bone-forming potential of simvastatin-containing polyprodrugs in vivo using a rat calvarial onlay model. Poly(ethylene glycol)-block-poly(simvastatin) and poly(ethylene glycol)-block-poly(simvastatin)-ran-poly(glycolide) were compared with simvastatin conventionally encapsulated in poly(lactic-co-glycolic acid) (PLGA) and pure PLGA. The rate of degradation was higher for PLGA with and without simvastatin relative to the simvastatin polyprodrugs. Significant new bone growth at the circumference of poly(ethylene glycol)-block-poly(simvastatin) disks was observed beginning at 4 weeks, whereas severe bone resorption (4 weeks) and bone loss (8 weeks) were observed for PLGA loaded with simvastatin. No significant systemic effects were observed for serum total cholesterol and body weight. Increased expression of osteogenic (BMP-2, Runx2, and ALP), angiogenic (VEGF), and inflammatory cytokines (IL-6 and NF-ĸB) genes was seen with all polymers at the end of 8 weeks. Poly(ethylene glycol)-block-poly(simvastatin), with slow degradation and drug release, controlled inflammation, and significant osteogenic effect, is a candidate for use in bone regeneration applications.Statement of SignificanceTraditional drug delivery systems, e.g., drug encapsulated in poly(lactic-co-glycolic acid) (PLGA), are typically passive and have limited drug payload. As an alternative, we polymerized the drug simvastatin, which has multiple physiological effects, into macromolecules (“polysimvastatin”) via ring-opening polymerization. We previously demonstrated that the rate of degradation and drug (simvastatin) release can be adjusted by copolymerizing it with other monomers. The present results demonstrate significant new bone growth around polysimvastatin, whereas severe bone loss occurred for PLGA loaded with simvastatin. This degradable biomaterial with biofunctionality integrated into the polymeric backbone is a useful candidate for bone regeneration applications.Graphical abstractGraphical abstract for this article
       
  • Development of osteopromotive poly (octamethylene citrate
           glycerophosphate) for enhanced bone regeneration
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Yun He, Qiyao Li, Chuying Ma, Denghui Xie, Limei Li, Yitao Zhao, Dingying Shan, Sarah K. Chomos, Cheng Dong, John W. Tierney, Lin Sun, Di Lu, Li Gui, Jian Yang The design and development of bioactive materials that are inherently conducive for osteointegration and bone regeneration with tunable mechanical properties and degradation remains a challenge. Herein, we report the development of a new class of citrate-based materials with glycerophosphate salts, β-glycerophosphate disodium (β-GP-Na) and glycerophosphate calcium (GP-Ca), incorporated through a simple and convenient one-pot condensation reaction, which might address the above challenge in the search of suitable orthopedic biomaterials. Tensile strength of the resultant poly (octamethylene citrate glycerophosphate), POC-βGP-Na and POC-GP-Ca, was as high as 28.2 ± 2.44  MPa and 22.76 ± 1.06  MPa, respectively. The initial modulus ranged from 5.28 ± 0.56  MPa to 256.44 ± 22.88  MPa. The mechanical properties and degradation rate of POC-GP could be controlled by varying the type of salts, and the feeding ratio of salts introduced. Particularly, POC-GP-Ca demonstrated better cytocompatibility and the corresponding composite POC-GP-Ca/hydroxyapatite (HA) also elicited improved osteogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro, as compared to POC-βGP-Na/HA and POC/HA. The superior in-vivo performance of POC-GP-Ca/HA microparticle scaffolds in promoting bone regeneration over POC-βGP-Na/HA and POC/HA was further confirmed in a rabbit femoral condyle defect model. Taken together, the tunability of mechanical properties and degradation rates, together with the osteopromotive nature of POC-GP polymers make these materials, especially POC-GP-Ca well suited for bone tissue engineering applications.Statement of SignificanceThe design and development of bioactive materials that are inherently conducive for osteointegration and bone regeneration with tunable mechanical properties and degradation remains a challenge. Herein, we report the development of a new class of citrate-based materials with glycerophosphate salts, β-glycerophosphate disodium (β-GPNa) and glycerophosphate calcium (GPCa), incorporated through a simple and convenient one-pot condensation reaction. The resultant POC-GP polymers showed significantly improved mechanical property and tunable degradation rate. Within the formulation investigated, POC-GPCa/HA composite further demonstrated better bioactivity in favoring osteogenic differentiation of hMSCs in vitro and promoted bone regeneration in rabbit femoral condyle defects. The development of POC-GP expands the repertoire of the well-recognized citrate-based biomaterials to meet the ever-increasing needs for functional biomaterials in tissue engineering and other biomedical applications.Graphical abstractGraphical abstract for this article
       
  • Porous PolyHIPE microspheres for protein delivery from an injectable bone
           graft
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Michael Whitely, Gabriel Rodriguez-Rivera, Christina Waldron, Sahar Mohiuddin, Stacy Cereceres, Nicholas Sears, Nicholas Ray, Elizabeth Cosgriff-Hernandez Delivery of osteoinductive factors such as bone morphogenetic protein 2 (BMP-2) has emerged as a prominent strategy to improve regeneration in bone grafting procedures. However, it remains challenging to identify a carrier that provides the requisite loading efficiency and release kinetics without compromising the mechanical properties of the bone graft. Previously, we reported on porous, polymerized high internal phase emulsion (polyHIPE) microspheres fabricated using controlled fluidics. Uniquely, this solvent-free method provides advantages over current microsphere fabrication strategies including in-line loading of growth factors to improve loading efficiency. In the current study, we utilized this platform to fabricate protein-loaded microspheres and investigated the effect of particle size (∼400 vs ∼800 μm) and pore size (∼15 vs 30 μm) on release profiles. Although there was no significant effect of these variables on the substantial burst release profile of the microspheres, the incorporation of the protein-loaded microspheres within the injectable polyHIPE resulted in a sustained release of protein from the bulk scaffold over a two-week period with minimal burst release. Bioactivity retention of encapsulated BMP-2 was confirmed first using a genetically-modified osteoblast reporter cell line. A functional assay with human mesenchymal stem cells established that the BMP-2 release from microspheres induced osteogenic differentiation. Finally, microsphere incorporation had minimal effect on the cure and compressive properties of an injectable polyHIPE bone graft. Overall, this work demonstrates that these microsphere-polyHIPE composites have strong potential to enhance bone regeneration through controlled release of BMP-2 and other growth factors.Statement of significanceThis manuscript describes a method for solvent-free fabrication of porous microspheres from high internal phase emulsions using a controlled fluids setup. The principles of emulsion templating and fluid dynamics provide exceptional control of particle size and pore architecture. In addition to the advantage of solvent-free fabrication, this method provides in-line loading of protein directly into the pores of the microspheres with high loading efficiencies. The incorporation of the protein-loaded microspheres within an injectable polyHIPE scaffold resulted in a sustained release of protein over a two-week period with minimal burst release. Retention of BMP-2 bioactivity and incorporation of microspheres with minimal effect on scaffold compressive properties highlights the potential of these new bone grafts.Graphical abstractGraphical abstract for this article
       
  • Biomaterial-assisted local and systemic delivery of bioactive agents for
           bone repair
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Yuze Zeng, Jiaul Hoque, Shyni Varghese Although bone tissues possess an intrinsic capacity for repair, there are cases where bone healing is either impaired or insufficient, such as fracture non-union, osteoporosis, osteomyelitis, and cancers. In these cases, treatments like surgical interventions are used, either alone or in combination with bioactive agents, to promote tissue repair and manage associated clinical complications. Improving the efficacy of bioactive agents often requires carriers, with biomaterials being a pivotal player. In this review, we discuss the role of biomaterials in realizing the local and systemic delivery of biomolecules to the bone tissue. The versatility of biomaterials enables design of carriers with the desired loading efficiency, release profile, and on-demand delivery. Besides local administration, systemic administration of drugs is necessary to combat diseases like osteoporosis, warranting bone-targeting drug delivery systems. Thus, chemical moieties with the affinity towards bone extracellular matrix components like apatite minerals have been widely utilized to create bone-targeting carriers with better biodistribution, which cannot be achieved by the drugs alone. Bone-targeting carriers combined with the desired drugs or bioactive agents have been extensively investigated to enhance bone healing while minimizing off-target effects. Herein, these advancements in the field have been systematically reviewed.Statement of significanceDrug delivery is imperative when surgical interventions are not sufficient to address various bone diseases/defects. Biomaterial-assisted delivery systems have been designed to provide drugs with the desired loading efficiency, sustained release, and on-demand delivery to enhance bone healing. By surveying recent advances in the field, this review outlines the design of biomaterials as carriers for the local and systemic delivery of bioactive agents to the bone tissue. Particularly, biomaterials that bear chemical moieties with affinity to bone are attractive, as they can present the desired bioactive agents to the bone tissue efficiently and thus enhance the drug efficacy for bone repair.Graphical abstractGraphical abstract for this article
       
  • Recent advances in musculoskeletal local drug delivery
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Shichao Zhang, Malcolm Xing, Bingyun Li Musculoskeletal disorders are a significant burden on the global economy and public health. Advanced drug delivery plays a key role in the musculoskeletal field and holds the promise of enhancing the repair of degenerated and injured musculoskeletal tissues. Ideally, drug delivery should have the ability to directly deliver therapeutic agents to the diseased/injured sites with a desirable drug level over a period of time. Here, we present a mini-review of the current state-of-the-art research associated with local drug delivery and its use for the treatment of musculoskeletal disorders. First, an overview of drug delivery strategies, with a focus on issues related to musculoskeletal pathology, potential therapeutic strategies, conventional and non-conventional drugs, and various delivery systems, is introduced. Then, we highlight recent advances in the emerging fields of musculoskeletal local drug delivery, involving therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., 3D printing and tissue engineering techniques), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery). The review concludes with future perspectives and associated challenges for developing local drug delivery for musculoskeletal applications.Statement of SignificanceThree important aspects are highlighted in this manuscript:1) The advanced musculoskeletal drug delivery is introduced from the aspects ranging from musculoskeletal disorders, potential therapeutic solutions, and various drug delivery systems.2) The recent advances in the emerging fields of musculoskeletal local drug delivery, involving therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., 3D printing and tissue engineering technique), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery), are highlighted.3) The challenges and perspectives of future research directions in the development of musculoskeletal local drug delivery are presented.Graphical abstractGraphical abstract for this article
       
  • Injectable biomaterials for delivery of interleukin-1 receptor antagonist:
           Toward improving its therapeutic effect
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Anna E.B. Clements, William L. Murphy Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring anti-inflammatory cytokine that inhibits IL-1 activity and has been proposed to treat a wide variety of systemic and local inflammatory pathologies for multiple decades. However, the short half-life and high concentration required to inhibit IL-1 activity has limited its use in clinical applications. Many strategies have been developed with the goal of improving the therapeutic efficacy of IL-1Ra for a variety of pathologies, including fusing IL-1Ra to protein/peptide/polymer partners, releasing IL-1Ra from injectable polymer or mineral particles, and release of IL-1Ra from injectable coacervates and gels. This literature review examines injectable biomaterials engineered to improve IL-1Ra delivery, both locally and systemically, to increase its efficacy and ease of use in clinic.Statement of SignificanceInterleukin-1 receptor antagonist (IL-1Ra) is a therapeutic protein with the potential to treat numerous inflammatory conditions and diseases. However, its short biological half-life and high therapeutic concentration may limit its utility in all but a few clinical scenarios. In this review, we present the biomaterial based delivery strategies which have been explored to deliver IL-1Ra to improve its efficacy and applicability to treat inflammation.Graphical abstractGraphical abstract for this article
       
  • Nanofiber-based transforming growth factor-β3 release induces
           fibrochondrogenic differentiation of stem cells
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Dovina Qu, Jennifer P. Zhu, Hannah R. Childs, Helen H. Lu Fibrocartilage is typically found in regions subject to complex, multi-axial loads and plays a critical role in musculoskeletal function. Mesenchymal stem cell (MSC)-mediated fibrocartilage regeneration may be guided by administration of appropriate chemical and/or physical cues, such as by culturing cells on polymer nanofibers in the presence of the chondrogenic growth factor TGF-β3. However, targeted delivery and maintenance of effective local factor concentrations remain challenges for implementation of growth factor-based regeneration strategies in clinical settings. Thus, the objective of this study was to develop and optimize the bioactivity of a biomimetic nanofiber scaffold system that enables localized delivery of TGF-β3. To this end, we fabricated TGF-β3-releasing nanofiber meshes that provide sustained growth factor delivery and demonstrated their potential for guiding synovium-derived stem cell (SDSC)-mediated fibrocartilage regeneration. TGF-β3 delivery enhanced cell proliferation and synthesis of relevant fibrocartilaginous matrix in a dose-dependent manner. By designing a scaffold that eliminates the need for exogenous or systemic growth factor administration and demonstrating that fibrochondrogenesis requires a lower growth factor dose compared to previously reported, this study represents a critical step towards developing a clinical solution for regeneration of fibrocartilaginous tissues.Statement of SignificanceFibrocartilage is a tissue that plays a critical role throughout the musculoskeletal system. However, due to its limited self-healing capacity, there is a significant unmet clinical need for more effective approaches for fibrocartilage regeneration. We have developed a nanofiber-based scaffold that provides both the biomimetic physical cues, as well as localized delivery of the chemical factors needed to guide stem cell-mediated fibrocartilage formation. Specifically, methods for fabricating TGF-β3-releasing nanofibers were optimized, and scaffold-mediated TGF-β3 delivery enhanced cell proliferation and synthesis of fibrocartilaginous matrix, demonstrating for the first time, the potential for nanofiber-based TGF-β3 delivery to guide stem cell-mediated fibrocartilage regeneration. This nanoscale delivery platform represents an exciting new strategy for fibrocartilage regeneration.Graphical abstractGraphical abstract for this article
       
  • An in vitro and in vivo comparison of cartilage growth in
           chondrocyte-laden matrix metalloproteinase-sensitive poly(ethylene glycol)
           hydrogels with localized transforming growth factor β3
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Margaret C. Schneider, Stanley Chu, Mark A. Randolph, Stephanie J. Bryant While matrix-assisted autologous chondrocyte implantation has emerged as a promising therapy to treat focal chondral defects, matrices that support regeneration of hyaline cartilage remain challenging. The goal of this work was to investigate the potential of a matrix metalloproteinase (MMP)-sensitive poly(ethylene glycol) (PEG) hydrogel containing the tethered growth factor, transforming growth factor β3 (TGF-β3), and compare cartilage regeneration in vitro and in vivo. The in vitro environment comprised chemically-defined medium while the in vivo environment utilized the subcutaneous implant model in athymic mice. Porcine chondrocytes were isolated and expanded in 2D culture for 10 days prior to encapsulation. The presence of tethered TGF-β3 reduced cell spreading. Chondrocyte-laden hydrogels were analyzed for total sulfated glycosaminoglycan and collagen contents, MMP activity, and spatial deposition of aggrecan, decorin, biglycan, and collagens type II and I. The total amount of extracellular matrix (ECM) deposited in the hydrogel constructs was similar in vitro and in vivo. However, the in vitro environment was not able to support long-term culture up to 64 days of the engineered cartilage leading to the eventual breakdown of aggrecan. The in vivo environment, on the other hand, led to more elaborate ECM, which correlated with higher MMP activity, and an overall higher quality of engineered tissue that was rich in aggrecan, decorin, biglycan and collagen type II with minimal collagen type I. Overall, the MMP-sensitive PEG hydrogel containing tethered TGF-β3 is a promising matrix for hyaline cartilage regeneration in vivo.Statement of SignificanceRegenerating hyaline cartilage remains a significant clinical challenge. The resultant repair tissue is often fibrocartilage, which long-term cannot be sustained. The goal of this study was to investigate the potential of a synthetic hydrogel matrix containing peptide crosslinks that can be degraded by enzymes secreted by encapsulated cartilage cells (i.e., chondrocytes) and tethered growth factors, specifically TGF-β3, to provide localized chondrogenic cues to the cells. This hydrogel led to hyaline cartilage-like tissue growth in vitro and in vivo, with minimal formation of fibrocartilage. However, the tissue formed in vitro, could not be maintained long-term. In vivo this hydrogel shows great promise as a potential matrix for use in regenerating hyaline cartilage.Graphical abstractGraphical abstract for this article
       
  • The inclusion of zinc into mineralized collagen scaffolds for craniofacial
           bone repair applications
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Aleczandria S. Tiffany, Danielle L. Gray, Toby J. Woods, Kiran Subedi, Brendan A.C. Harley Implant osteoinduction and subsequent osteogenic activity are critical events that need improvement for regenerative healing of large craniofacial bone defects. Here we describe the augmentation of the mineral content of a class of mineralized collagen scaffolds under development for craniomaxillofacial bone regeneration via the inclusion of zinc ions to promote osteogenesis in vitro. Zinc is an essential trace element in skeletal tissue and bone, with soluble zinc being shown to promote osteogenic differentiation of porcine adipose derived stem cells. We report the development of a new class of zinc functionalized scaffolds fabricated by adding zinc sulfate to a mineralized collagen-glycosaminoglycan precursor suspension that was then freeze dried to form a porous biomaterial. We report analysis of zinc functionalized scaffolds via imaging (scanning electron microscopy), mechanical testing (compression), and compositional (X-ray diffraction, inductively coupled plasma mass spectrometry) analyses. Notably, zinc-functionalized scaffolds display morphological changes to the mineral phase and altered elastic modulus without substantially altering the composition of the brushite phase or removing the micro-scale pore morphology of the scaffold. These scaffolds also display zinc release kinetics on the order of days to weeks and promote successful growth and pro-osteogenic capacity of porcine adipose derived stem cells cultured within these zinc scaffolds. Taken together, we believe that zinc functionalized scaffolds provide a unique platform to explore strategies to improve in vivo osteogenesis in craniomaxillofacial bone injuries models.Statement of SignificanceCraniomaxillofacial bone defects that arise from traumatic, congenital, and post-oncologic origins cannot heal on their own and often require surgical intervention. We have developed a class of mineralized collagen scaffolds that promotes osteogenesis and bone regeneration. Here we describe the inclusion of zinc sulfate into the mineralized collagen scaffold to improve osteogenesis. Zinc functionalized scaffolds demonstrate altered crystallite microstructure but consistent Brushite chemistry, improved mechanics, and promote zinc transporter expression while supporting stem cell viability, osteogenic differentiation, and mineral biosynthesis.Graphical abstractGraphical abstract for this article
       
  • Self-mineralizing Ca-enriched methacrylated gellan gum beads for bone
           tissue engineering
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Sílvia Vieira, Alain da Silva Morais, Elina Garet, Joana Silva-Correia, Rui L. Reis, África González-Fernández, J. Miguel Oliveira In this study, methacrylated gellan-gum (GG-MA) heteropolysaccharide is proposed as a hydrogel for drug delivery and bone tissue engineering applications. Calcium-enriched beads obtained from the crosslinking of 1% (w/v) GG-MA solutions with 0.1 M CaCl2 were investigated, considering their intrinsic capacity to promote self-mineralization by ion binding and deposition. Indeed, when immersed in a physiological environment, the Ca-enriched beads promoted the development of a bone-like apatite layer, as confirmed by EDS and XRD chemical analysis. Additionally, the mild production process is compatible with drugs incorporation and release. After encapsulation, Dextran with different molecular weights as well as Dexamethasone 21-phosphate were efficiently released to the surrounding environment. The engineered system was also evaluated considering its biocompatibility, by means of qualitative determination of total complement activation, macrophage proliferation, cytokine release and in vitro cell culture. These experiments showed that the developed hydrogels may not stimulate a disproportionate pro-inflammatory reaction once transplanted. At last, when implanted subcutaneously in CD1 male mice up to 8 weeks, the beads were completely calcified, and no inflammatory reaction was observed. Summing up, these results show that calcium-enriched GG-MA hydrogel beads hold great potential as news tools for bone tissue regeneration and local drug delivery applications.Statement of SignificanceThis work describes a low-cost and straightforward strategy to prepare bioactive methacrylated gellan gum (GG-MA) hydrogels, which can be used as drug delivery systems. GG-MA is a highly anionic polymer, that can be crosslinked with divalent ions, as calcium. Taking advantage of this feature, it was possible to prepare Ca-enriched GG-MA hydrogel beads. These beads display a bioactive behavior, since they promote apatite deposition when placed in physiological conditions. Studies on the immune response suggest that the developed beads do not trigger severe immune responses. Importantly, the mild processing method render these beads compliant with drug delivery strategies, paving the way for the application of dual-functional materials on bone tissue engineering.Graphical abstractGraphical abstract for this article
       
  • Preventing S. aureus biofilm formation on titanium surfaces by the release
           of antimicrobial β-peptides from polyelectrolyte multilayers
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Angélica de L. Rodríguez López, Myung-Ryul Lee, Benjamín J. Ortiz, Benjamin D. Gastfriend, Riley Whitehead, David M. Lynn, Sean P. Palecek Staphylococcus aureus infections represent the major cause of titanium based-orthopaedic implant failure. Current treatments for S. aureus infections involve the systemic delivery of antibiotics and additional surgeries, increasing health-care costs and affecting patient’s quality of life. As a step toward the development of new strategies that can prevent these infections, we build upon previous work demonstrating that the colonization of catheters by the fungal pathogen Candida albicans can be prevented by coating them with thin polymer multilayers composed of chitosan (CH) and hyaluronic acid (HA) designed to release a β-amino acid-based peptidomimetic of antimicrobial peptides (AMPs). We demonstrate here that this β-peptide is also potent against S. aureus (MBPC = 4 μg/mL) and characterize its selectivity toward S. aureus biofilms. We demonstrate further that β-peptide-containing CH/HA thin-films can be fabricated on the surfaces of rough planar titanium substrates in ways that allow mammalian cell attachment and permit the long-term release of β-peptide. β-Peptide loading on CH/HA thin-films was then adjusted to achieve release of β-peptide quantities that selectively prevent S. aureus biofilms on titanium substrates in vitro for up to 24 days and remained antimicrobial after being challenged sequentially five times with S. aureus inocula, while causing no significant MC3T3-E1 preosteoblast cytotoxicity compared to uncoated and film-coated controls lacking β-peptide. We conclude that these β-peptide-containing films offer a novel and promising localized delivery approach for preventing orthopaedic implant infections. The facile fabrication and loading of β-peptide-containing films reported here provides opportunities for coating other medical devices prone to biofilm-associated infections.Statement of SignificanceTitanium (Ti) and its alloys are used widely in orthopaedic devices due to their mechanical strength and long-term biocompatibility. However, these devices are susceptible to bacterial colonization and the subsequent formation of biofilms. Here we report a chitosan and hyaluronic acid polyelectrolyte multilayer-based approach for the localized delivery of helical, cationic, globally amphiphilic β-peptide mimetics of antimicrobial peptides to inhibit S. aureus colonization and biofilm formation. Our results reveal that controlled release of this β-peptide can selectively kill S. aureus cells without exhibiting toxicity toward MC3T3-E1 preosteoblast cells. Further development of this polymer-based coating could result in new strategies for preventing orthopaedic implant-related infections, improving outcomes of these titanium implants.Graphical abstractGraphical abstract for this article
       
  • In vivo analysis of a first-in-class tri-alkyl norspermidine-biaryl
           antibiotic in an active release coating to reduce the risk of
           implant-related infection
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Dustin L. Williams, Richard T. Epperson, Nicholas N. Ashton, Nicholas B. Taylor, Brooke Kawaguchi, Raymond E. Olsen, Travis J. Haussener, Paul R. Sebahar, Gina Allyn, Ryan E. Looper Prosthetic joint infection (PJI) is a well-known and persisting problem. Active release coatings have promise to provide early protection to an implant by eradicating small colony biofilm contaminants or planktonic bacteria that can form biofilm. Traditional antibiotics can be limited as active release agents in that they have limited effect against biofilms and develop resistance at sub-lethal concentrations. A unique first-in-class compound (CZ-01127) was assessed as the active release agent in a silicone (Si)-based coating to prevent PJI in a sheep model of joint space infection. Titanium (Ti) plugs contained a porous coated Ti (PCTi) region and polymer-coated region. Plugs were implanted into a femoral condyle of sheep to assess the effect of the Si polymer on cancellous bone ingrowth, the effect of CZ-01127 on bone ingrowth, and the ability of CZ-01127 to prevent PJI. Microbiological results showed that CZ-01127 was able to eradicate bacteria in the local region of the implanted plugs. Data further showed that Si did not adversely affect bone ingrowth. However, bacteria that reached the joint space (synovium) were not fully eradicated. Outcomes suggested that the CZ-01127 coating provided local protection to the implant system in a challenging model, the design of which could be beneficial for testing future antimicrobial therapies for PJI.Statement of SignificancePeriprosthetic joint infection (PJI) is now commonplace, and constitutes an underlying problem that patients and physicians face. Active release antibiotic coatings have potential to prevent these infections. Traditional antibiotics are limited in their ability to eradicate bacteria that reside in biofilms, and are more susceptible to resistance development. This study addressed these limitations by testing the efficacy of a unique antimicrobial compound in a coating that was tested in a challenging sheep model of PJI. The unique coating was able to eradicate bacteria and prevent infection in the environment adjacent to the implant. Bacteria that escaped into the joint space still caused infection, yet benchmark data can be used to optimize the coating and translate it toward clinical use.Graphical abstractGraphical abstract for this article
       
  • In vitro testing of a first-in-class tri-alkylnorspermidine-biaryl
           antibiotic in an anti-biofilm silicone coating
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Nicholas N. Ashton, Gina Allyn, Scott T. Porter, Travis J. Haussener, Paul R. Sebahar, Ryan E. Looper, Dustin L. Williams Biofilm-related infection is among the worst complication to prosthetic joint replacement procedures; once established on the implant surface, biofilms show strong recalcitrance to clinical antibiotic therapy, frequently requiring costly revision procedures and prolonged systemic antibiotics for their removal. A well-designed active release coating might assist host immunity in clearing bacterial contaminants within the narrow perioperative window and ultimately prevent microbial colonization of the joint prosthesis. A first-in-class compound (CZ-01127) was tested as the active release agent in a silicone (Si) coating using an in vitro dynamic flow model of surgical site contamination and compared with analogous coatings containing clinical gold-standard antibiotics vancomycin and gentamicin; the CZ-01127 coating outperformed both vancomycin and gentamicin coatings and was the only to decrease the methicillin-resistant Staphylococcus aureus (MRSA) inocula below detectable limits for the first 3 days. The antimicrobial activity of CZ-01127, and for comparison vancomycin and gentamicin, were characterized against both planktonic and biofilm MRSA using the minimum inhibitory concentration (MIC) assay, serial passages, and serial dilution tests against established biofilms grown with a CBR 90 CDC biofilm reactor. Despite a similar MIC (1 µg/ml) and behavior in a 25-day serial passage analysis, CZ-01127 displayed much greater bactericidal activity against established biofilms and was the only to decrease biofilm colony forming units (CFUs) below detectable limits at the highest concentration tested (500 µg/ml). Coating release profiles were characterized using ATR-FTIR and displayed burst release kinetics within the decisive period of the perioperative window suggesting the silicon carrier is broadly useful for screening antibiotic compound for local delivery applications.Statement of SignificanceWith an aging population, an increasing number of people are undergoing total joint replacement procedures in which diseased joint tissues are replaced with permanent metallic implants. Some of these procedures are burdened by costly and debilitating infections. A promising approach to prevent infections is the use of an antimicrobial coating on the surface of the implant which releases antibiotics into the surgical site to prevent infection. In this study, we tested a new antibiotic compound formulated in a silicone coating. Data showed that this compound was more effective at killing pathogenic methicillin resistant Staphylococcus aureus (MRSA) bacteria than two clinical gold-standard antibiotics—vancomycin and gentamicin—and could be a promising agent for antimicrobial coating technologies.Graphical abstractGraphical abstract for this article
       
  • Ultrasound-triggered antibiotic release from PEEK clips to prevent spinal
           fusion infection: Initial evaluations
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Lauren J. Delaney, Daniel MacDonald, Jay Leung, Keith Fitzgerald, Alex M. Sevit, John R. Eisenbrey, Neil Patel, Flemming Forsberg, Christopher K. Kepler, Taolin Fang, Steven M. Kurtz, Noreen J. Hickok Despite aggressive peri-operative antibiotic treatments, up to 10% of patients undergoing instrumented spinal surgery develop an infection. Like most implant-associated infections, spinal infections persist through colonization and biofilm formation on spinal instrumentation, which can include metal screws and rods for fixation and an intervertebral cage commonly comprised of polyether ether ketone (PEEK). We have designed a PEEK antibiotic reservoir that would clip to the metal fixation rod and that would achieve slow antibiotic release over several days, followed by a bolus release of antibiotics triggered by ultrasound (US) rupture of a reservoir membrane. We have found using human physiological fluid (synovial fluid), that higher levels (100–500 μg) of vancomycin are required to achieve a marked reduction in adherent bacteria vs. that seen in the common bacterial medium, trypticase soy broth. To achieve these levels of release, we applied a polylactic acid coating to a porous PEEK puck, which exhibited both slow and US-triggered release. This design was further refined to a one-hole or two-hole cylindrical PEEK reservoir that can clip onto a spinal rod for clinical use. Short-term release of high levels of antibiotic (340 ± 168 μg), followed by US-triggered release was measured (7420 ± 2992 μg at 48 h). These levels are sufficient to prevent adhesion of Staphylococcus aureus to implant materials. This study demonstrates the feasibility of an US-mediated antibiotic delivery device, which could be a potent weapon against spinal surgical site infection.Statement of SignificanceSpinal surgical sites are prone to bacterial colonization, due to presence of instrumentation, long surgical times, and the surgical creation of a dead space (≥5 cm3) that is filled with wound exudate. Accordingly, it is critical that new approaches are developed to prevent bacterial colonization of spinal implants, especially as neither bulk release systems nor controlled release systems are available for the spine. This new device uses non-invasive ultrasound (US) to trigger bulk release of supra-therapeutic doses of antibiotics from materials commonly used in existing surgical implants. Thus, our new delivery system satisfies this critical need to eradicate surviving bacteria, prevent resistance, and markedly lower spinal infection rates.Graphical abstractGraphical abstract for this article
       
  • Implantable antimicrobial biomaterials for local drug delivery in bone
           infection models
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Jeremy D. Caplin, Andrés J. García Increased use of implantable biomedical devices demonstrates their potential in treating a wide variety of ailments and disorders in bone trauma and orthopaedic, reconstructive, and craniofacial applications. However, the number of cases involving implant failure or malfunction due to bacterial infection have also increased in recent years. Implanted devices can facilitate the growth of bacteria as these micro-organisms have the potential to adhere to the implant and grow and develop to form biofilms. In an effort to better understand and mitigate these occurrences, biomaterials containing antimicrobial agents that can be released or presented within the local microenvironment have become an important area of research. In this review, we discuss critical factors that regulate antimicrobial therapy to sites of bone infection, such as key biomolecular considerations and platforms for delivery, as well as current in vivo models and current advances in the field.Statement of SignificanceThis review outlines the important factors that are taken into consideration for the development of biomaterials for local delivery of therapeutics to the site of bone infections. An overview of important criteria for development of this model (such as type of bone defect, antimicrobial therapeutic, and delivery vehicle) are provided, along with current research that utilizes these considerations. Additionally, this review highlights recent clinical trials that have utilized antimicrobial therapeutics for treatment of osteomyelitis.Graphical abstractGraphical abstract for this article
       
  • Special issue on Drug Delivery for Musculoskeletal Applications
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Johnna Temenoff, Robert Hastings
       
  • Intra-articular targeting of nanomaterials for the treatment of
           osteoarthritis
    • Abstract: Publication date: 15 July 2019Source: Acta Biomaterialia, Volume 93Author(s): Shannon Brown, Shreedevi Kumar, Blanka Sharma Osteoarthritis is a prevalent and debilitating disease that involves pathological contributions from numerous joint tissues and cells. The joint is a challenging arena for drug delivery, since the joint has poor bioavailability for systemically administered drugs and experiences rapid clearance of therapeutics after intra-articular injection. Moreover, each tissue within the joint presents unique barriers to drug localization. In this review, the various applications of nanotechnology to overcome these drug delivery limitations are investigated. Nanomaterials have reliably shown improvements to retention profiles of drugs within the joint space relative to injected free drugs. Additionally, nanomaterials have been modified through active and passive targeting strategies to facilitate interactions with and localization within specific joint tissues such as cartilage and synovium. Last, the limitations of drawing cross-study comparisons, the implications of synovial fluid, and the potential importance of multi-modal therapeutic strategies are discussed. As emerging, cell-specific disease modifying osteoarthritis drugs continue to be developed, the need for targeted nanomaterial delivery will likely become critical for effective clinical translation of therapeutics for osteoarthritis.Statement of SignificanceImproving drug delivery to the joint is a pressing clinical need. Over 27 million Americans live with osteoarthritis, and this figure is continuously expanding. Numerous drugs have been investigated but have failed in clinical trials, likely related to poor bioavailability to target cells. This article comprehensively reviews the advances in nano-scale delivery vehicles designed to overcome the delivery barriers in the joint. This is the first review to analyze active and passive targeting strategies systematically for different target sites while also delineating between tissue homing and whole joint retention. By bringing together the lessons learned across numerous nano-scale platforms, researchers may be able to hone future nanomaterial designs, allowing emerging therapeutics to perform with clinically relevant efficacy and disease modifying potential.Graphical abstractGraphical abstract for this article
       
  • Effects of Gamma Radiation Sterilization on the Structural and Biological
           Properties of Decellularized Corneal Xenografts
    • Abstract: Publication date: Available online 5 July 2019Source: Acta BiomaterialiaAuthor(s): Mohammad Mirazul Islam, Roholah Sharifi, Shamina Mamodaly, Rakibul Islam, Daniel Nahra, Dina B. Abusamra, Pui Chuen Hui, Yashar Adibnia, Mehdi Goulamaly, Eleftherios I. Paschalis, Andrea Cruzat, Jing Kong, Per H. Nilsson, Pablo Argüeso, Tom Eirik Mollnes, James Chodosh, Claes H. Dohlman, Miguel Gonzalez-Andrades To address the shortcomings associated with corneal transplants, substantial efforts have been focused on developing new modalities such as xenotransplantion. Xenogeneic corneas are anatomically and biomechanically similar to the human cornea, yet their applications require prior decellularization to remove the antigenic components to avoid rejection. In the context of bringing decellularized corneas into clinical use, sterilization is a crucial step that determines the success of the transplantation. Well-standardized sterilization methods, such as gamma irradiation (GI), have been applied to decellularized porcine corneas (DPC) to avoid graft-associated infections in human recipients. However, little is known about the effect of GI on decellularized corneal xenografts. Here, we evaluated the radiation effect on the ultrastructure, optical, mechanical and biological properties of DPC. Transmission electron microscopy revealed that gamma irradiated decellularized porcine cornea (G-DPC) preserved its structural integrity. Moreover, the radiation did not reduce the optical properties of the tissue. Neither DPC nor G-DPC led to further activation of complement system compared to native porcine cornea when exposed to plasma. Although, DPC were mechanically comparable to the native tissue, GI increased the mechanical strength, tissue hydrophobicity and resistance to enzymatic degradation. Despite these changes, human corneal epithelial, stromal, endothelial and hybrid neuroblastoma cells grew and differentiated on DPC and G-DPC. Thus, GI may achieve effective tissue sterilization without affecting critical properties that are essential for corneal transplant survival.Graphical abstractGraphical abstract for this article
       
  • Co-immobilization of CD133 antibodies, vascular endothelial growth
           factors, and REDV peptides promotes capture, proliferation, and
           differentiation of endothelial progenitor cells
    • Abstract: Publication date: Available online 5 July 2019Source: Acta BiomaterialiaAuthor(s): Yiyuan Duan, Shan Yu, Peifang Xu, Xuemei Wang, Xue Feng, Zhengwei Mao, Changyou Gao Capture of endothelial progenitor cells (EPCs) in situ has been considered as a promising strategy for the rapid endothelialization and long-term patency of artificial blood vessels and implant devices. In this study, a CD133+ EPC capture surface was fabricated by grafting CD133 antibody (a more specific EPC surface marker than CD34) and Arg-Glu-Asp-Val (REDV) peptides on the methacrylate-grafted hyaluronic acid (MA-HA) and heparin-hybridized (MA-HA&Heparin) resisting layer. Vascular endothelial growth factor (VEGF) was further conjugated to the immobilized heparin. This engineered surface showed good hemocompatibility and significantly higher ability of capturing CD133+ EPCs from human peripheral blood mononuclear cells (PBMCs) and obviously upregulated the expression of endothelial cell (EC) marker genes of EPCs such as VEGF receptor 2 (VEGFR2), CD31, VE-cadherin, and von Willebrand factor (vWF), facilitating the differentiation of EPCs into ECs. The dramatically enhanced EPC proliferation on this surface was dependent on the integrin-VEGFR synergistic signaling, as ERK1/2 phosphorylation was only significantly enhanced on the REDV and VEGF co-immobilized surface. This study highlights a new surface coating strategy for blood-contact materials based on the specific EPC capturing and rapid endothelialization.Graphical abstractGraphical abstract for this article
       
  • Guiding mesenchymal stem cell differentiation using mesoporous silica
           nanoparticle-based films
    • Abstract: Publication date: Available online 5 July 2019Source: Acta BiomaterialiaAuthor(s): Lea Andrée, David Barata, Pichaporn Sutthavas, Pamela Habibovic, Sabine van Rijt The development of smart interfaces that can guide tissue formation is of great importance in the field of regenerative medicine. Nanoparticles represent an interesting class of materials that can be used to enhance regenerative treatments by enabling close control over surface properties and directing cellular responses. Moreover, nanoparticles can be used to provide temporally controlled delivery of (multiple) biochemical compounds. Here, we exploited the cargo loading and surface functionalization properties of mesoporous silica nanoparticles (MSNs) to design films that can guide human mesenchymal stem cell (hMSC) differentiation towards the osteogenic lineage. We developed biocompatible MSN-based films that support stem cell adhesion and proliferation and demonstrated that these MSN films simultaneously allowed efficient local delivery of biomolecules without effecting film integrity. Films loaded with the osteogenesis-stimulating drug dexamethasone (Dex) were able to induce osteogenic differentiation of hMSCs in vitro. Dex delivery from the films led to increased alkaline phosphatase levels and matrix mineralization compared to directly supplementing Dex to the medium. Furthermore, we demonstrated that Dex release kinetics can be modulated using surface modifications with supported lipid bilayers. Together, these data demonstrate that MSN films represent an interesting approach to create biomaterial interfaces with controllable biomolecule release and surface properties to improve the bioactivity of biomaterials.Graphical abstractGraphical abstract for this article
       
  • Cell-free synthesis of connexin 43-integrated exosome-mimetic
           nanoparticles for siRNA delivery
    • Abstract: Publication date: Available online 5 July 2019Source: Acta BiomaterialiaAuthor(s): Mei Lu, Xiaoyun Zhao, Haonan Xing, Hui Liu, Lang Lang, Tianzhi Yang, Zhe Xun, Dongkai Wang, Pingtian Ding Exosomes are naturally secreted nanovesicles that have emerged as a promising therapeutic nanodelivery platform, due to their specific composition and biological properties. However, challenges like considerable complexity, low isolation yield, drug payload, and potential safety concerns substantially reduce their pharmaceutical acceptability. Given that the nano-bio-interface is a crucial factor for nanocarrier behavior and function, modification of synthetic nanoparticles with the intrinsic hallmarks of exosomes’ membrane to create exosome mimetics could allow for siRNA delivery in a safer and more efficient manner. Herein, connexin 43 (Cx43)-embedded, exosome-mimicking lipid bilayers coated chitosan nanoparticles (Cx43/L/CS NPs) were constructed by using cell-free (CF) synthesis systems with plasmids encoding Cx43 in the presence of lipid-coated CS NPs (L/CS NPs). The integration of de novo synthesized Cx43 into the lipid bilayers of L/CS NPs occurred cotranslationally during one-pot reaction and, more importantly, the integrated Cx43 was functionally active in transport. In addition to considerably lower cytotoxicity (< four-fold) than cationic Lipo 2000, the obtained Cx43/L/CS-siRNA NPs showed feasible cellular uptake and silencing efficacy that was significantly higher than free siRNA and CS-siRNA NPs. By using a gap junction (GJ) inhibitor, 18β-glycyrrhetinic acid, we demonstrated that Cx43 facilitated the delivery of siRNA into Cx43-expressing U87 MG cells. Additionally, the cellular entry of Cx43/L/CS-siRNA NPs may rely on different endocytic mechanisms, depending on the types of recipient cells. However, Cx43/L/CS-siRNA NPs still exhibited far from adequate delivery efficiency compared with transfection reagent Lipo 2000. Taken together, our study provides a brand new strategy to construct Cx43-functionalized, exosome-mimetic nanoparticles, which may further encourage the establishment of more biomimetic nanocarriers with higher biocompatibility and delivery efficiency.Graphical abstractGraphical abstract for this article
       
  • Nanotopography on titanium promotes osteogenesis via autophagy-mediated
           signaling between YAP and β-catenin
    • Abstract: Publication date: Available online 5 July 2019Source: Acta BiomaterialiaAuthor(s): Lingjie Li, Sheng Yang, Ling Xu, Yuzhou Li, Yiru Fu, He Zhang, Jinlin Song Nanostructured titanium implants are recognized for inducing osteogenesis, but the cell signal transductions related to topography are not fully understood. Implant topography is associated with the functionality of osteogenic transcription factors directed by β-catenin in the nucleus, and autophagic flux in the cytoplasm; YAP (Yes-associated protein) is implicated in the destruction of β-catenin in the cytoplasm and is susceptible to autophagic flux. This study investigated whether surface topography of the titanium implant modulates autophagy-lysosome degradation of cytoplasmic YAP. Titanium surfaces were modified with smooth, micro, or nanotopographies. Compared with the smooth and micro surfaces, nanotopography was associated with higher β-catenin nuclear translocation, osteogenic differentiation, and autophagy, and less cytoplasmic YAP. Blockade of the autophagy-lysosome pathway resulted in YAP retention in MC3T3-E1 cells. Cytoplasmic YAP restricted β-catenin nuclear translocation. In the nano surface group, β-catenin accumulation in the nucleus and expression of osteogenesis genes was improved. However, in the absence of cell-cell (confluent) contact, manipulation of YAP and β-catenin localization associated with topography-induced autophagy was lost. In summary, the osteogenesis observed in response to titanium implants with nanotopography involves a signaling link between YAP and β-catenin.Graphical abstractGraphical abstract for this article
       
  • Concanavalin A-targeted mesoporous silica nanoparticles for infection
           treatment
    • Abstract: Publication date: Available online 3 July 2019Source: Acta BiomaterialiaAuthor(s): Marina Martínez-Carmona, Isabel Izquierdo-Barba, Montserrat Colilla, María Vallet-Regí The ability of bacteria to form biofilms hinders any conventional treatment for chronic infections and has serious socio-economic implications. For this purpose, a nanocarrier capable of overcoming the barrier of the mucopolysaccharide matrix of the biofilm and releasing its loaded-antibiotic within this matrix would be desirable. Herein, we developed a new nanosystem based on levofloxacin (LEVO)-loaded mesoporous silica nanoparticles (MSNs) decorated with the lectin concanavalin A (ConA). The presence of ConA promotes the internalization of this nanosystem into the biofilm matrix, which increases the antimicrobial efficacy of the antibiotic hosted within the mesopores. This nanodevice is envisioned as a promising alternative to conventional treatments for infection by improving the antimicrobial efficacy and reducing side effects.Statement of SignificanceThe present study is focused on finding an adequate therapeutic solution for the treatment of bone infection using nanocarriers that are capable of overcoming the biofilm barrier by increasing the therapeutic efficacy of the loaded antibiotic. For this purpose, we present a nanoantibiotic that increases the effectiveness of levofloxacin to destroy the biofilm formed by the model bacterium E. coli.. This work opens new lines of research in the treatment of chronic infections based on nanomedicines.Graphical abstractGraphical abstract for this article
       
  • 3-D Printed Ti-6Al-4V Scaffolds for Supporting Osteoblast and Restricting
           Bacterial Functions Without Using Drugs: Predictive Equations and
           Experiments
    • Abstract: Publication date: Available online 3 July 2019Source: Acta BiomaterialiaAuthor(s): Nicole J. Bassous, Christopher L. Jones, Thomas J. Webster Conditions resulting from musculoskeletal deficiencies (MSDs) are wide-ranging and retain the likelihood for restricting motion or producing pain, especially in the lower back, neck, and upper limbs. Engineered scaffold devices are being produced to replace antiquated modalities that suffer from structural and mechanical deficiencies in the treatment of MSDs. Here, as-fabricated Ti-6Al-4V-based HiveTM interbody fusion scaffolds, commercialized by HD Lifesciences LLC, were assayed for their osteogenicity and antibacterial potential using a series of characterization and in vitro tests, as well as by quantitative analyses. A topographical assessment of the HiveTM meshes indicated that the elementally pure substrates are microscopically porous and rough, in addition to displaying structural heterogeneity. Roughness estimations and static contact angle measurements recommended the use of the as-fabricated Ti-6Al-4V substrates for supporting cellular attachment, especially, due to the improved surface roughness and wettability values of these scaffolds relative to the unembellished Ti-6Al-4V surfaces. Quantitative correlations relating the surface properties of roughness and energy were applied to predict cellular behaviors. Cell growth suppositions were experimentally corroborated. Critical in vitro data indicated the competencies of HiveTM scaffolds for promoting the adhesion and proliferation of human fetal osteoblasts (hFOBs); accumulating substantial calcium buildups from metabolizing hFOBs; and restricting the attachment of bacterial biofilms. The model system that investigated the pre-adsorption of casein proteins along HiveTM test substrates additionally furthered the notion that bacterial attachment may be restricted, with short-scale adhesion dynamics serving as the theoretical basis for this hypothesis.Statement of SignificanceSintered Ti-6Al-4V spinal fusion devices (HiveTM) manufactured and marketed by HD Lifesciences LLC were assessed for their biocompatibility and antibacterial performance. A mixed methods approach was employed, whereby quantitative measures were used to predict the ability for HiveTM substrates to adsorb specialized proteins and to restrict bacterial surface colonization. In vitro tests that evaluated bone cell and bacterial adhesion, calcium deposition, and protein adsorption supported quantitative predictions. The data herein presented demonstrate the following: (1) surface energy is an important predictor of implant-cell interactions, (2) strong correlations exist between surface energy and surface roughness, (3) mathematical models can be used to improve implant devices, and (4) porous, rough, 3D-printed materials perform well in terms of biocompatibility and antimicrobial efficacy.Graphical abstractGraphical abstract for this article
       
  • In Vivo Characterization of the Deformation of the Human Optic Nerve Head
           Using Optical Coherence Tomography and Digital Volume Correlation
    • Abstract: Publication date: Available online 3 July 2019Source: Acta BiomaterialiaAuthor(s): Dan E. Midgett, Harry A. Quigley, Thao. D. Nguyen We developed a method to measure the 3-dimensional (3D) strain field in the optic nerve head (ONH) in vivo between two intraocular pressures (IOP). Radial optical coherence tomography (OCT) scans were taken of the ONH of 5 eyes from 5 glaucoma patients before and after IOP-lowering surgery and from 5 eyes from 3 glaucoma suspect patients before and after raising IOP by wearing tight-fitting swimming goggles. Scans taken at higher and lower IOP were compared using a custom digital volume correlation (DVC) algorithm to calculate strains in the anterior lamina cribrosa (ALC), retina, and choroid. Changes in anterior lamina depth (ALD) relative to Bruch’s membrane were also analyzed. Average displacement error was estimated to be subpixel and strain errors were smaller than 0.37%. Suturelysis decreased IOP by 9 - 20 mmHg and decreased compressive anterior-posterior strain Ezz in the ALC by 0.76% (p=0.002,n=5). Goggle-wearing increased IOP by 3-4 mmHg and produced compressive Ezz in the ALC (-0.32%,p=0.001,n=5). Greater IOP decrease was associated with greater ALD change (p=0.047,n=10) and greater strains in the ALC (Ezz:p=0.002,n=10). A deepening of ALD was associated with lower IOP and greater ALC strains (p⩽0.045,n=10). A DVC-based method to measure strains from OCT images caused by IOP changes as small as 2.3 mmHg provides preliminary evidence that ALD is shallower and ALC strains are less compressive at higher IOP and that ALD change is associated with ALC strains.Statement of SignificanceGlaucoma causes vision loss through progressive damage of the retinal ganglion axons at the lamina cribrosa, a connective tissue structure in the optic nerve head that supports the axons as they pass through the eye wall. It is hypothesized that strains caused by intraocular pressure (IOP) may initiate this damage, but few studies have measured the strain response to pressure of the optic nerve head in patients. We present a method to measure the 3D displacement and strain field in the optic nerve head caused by IOP alteration in glaucoma patients using clinically available images. We used this method to measure strain within the optic nerve head from IOP changes caused by glaucoma surgery and wearing tight-fitting swimming goggles.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Functional quantum dot-siRNA nanoplexes to regulate
           chondrogenic differentiation of mesenchymal stem cells” [Acta Biomater.
           46 (2016) 165–176]
    • Abstract: Publication date: Available online 2 July 2019Source: Acta BiomaterialiaAuthor(s): Yang Wu, Bo Zhou, Fuben Xu, Xiaoyong Wang, Gang Liu, Li Zheng, Jinmin Zhao, Xingdong Zhang
       
  • Plasma deposited poly-oxazoline nanotextured surfaces dictate
           osteoimmunomodulation towards ameliorative osteogenesis
    • Abstract: Publication date: Available online 2 July 2019Source: Acta BiomaterialiaAuthor(s): Zetao Chen, Rahul Madathiparambil Visalakshan, Jia Guo, Fei Wei, Linjun Zhang, Lingling Chen, Zhengmei Lin, Krasimir Vasilev, Yin Xiao Developing “osteoimmune-smart” bone substitute materials have become the forefront of research in bone regeneration. Biocompatible polymer coatings are applied widely to improve the bioactivity of bone substitute materials. In this context, polyoxazolines (Pox) have attracted substantial attention recently due to properties such as biocompatibility, stability, and low biofouling. In view of these useful properties, it is interesting to explore the capacity of Pox as an osteoimmunomodulatory agent to generate a favorable osteoimmune environment for osteogenesis. We applied a technique called plasma polymerization and succeeded in preparing Pox-like coatings (Ppox) and engineered their nanotopography at the nanoscale. We found that Ppox switched macrophages towards M2 extreme, thus inhibiting the release of inflammatory cytokines. The underlying mechanism may be related to the suppression of TLR pathway. The generated osteoimmune environment improved osteogenesis while inhibited osteoclastogenesis. This may be related to the release of osteogenic factors, especially Wnt10b from macrophages. The addition of nanotopography (16nm, 38nm, 68nm) can tune the Ppox-mediated inhibition on inflammation and osteoclastic activities, while no significant effects were observed within the tested nano sizes on the Ppox-mediated osteogenesis. These results collectively suggest that Ppox can be useful as an effective osteoiumunomodulatory agent to endow bone substitute materials with favourable osteoimmunomodulatory property.Statement of significanceIn this study, we succeeded in preparing plasma deposited Pox-like nano-coatings (Ppox) via plasma polymerization and found that Ppox nanotopographies are useful osteoimmunomodulatory tools. Their osteoimmunodolatory effects and underlying mechanisms are unveiled. It is the first investigation into the feasibility of applying poly-oxazoline as an osteoimmunomodulatory agent. This expand the application of poly-oxazoline into the forefront in bone regeneration area for the development of advanced “osteoimmune-smart” bone substitute materials.Graphical abstractGraphical abstract for this article
       
  • A Bioink Blend for Rotary 3D Bioprinting Tissue Engineered Small-Diameter
           Vascular Constructs
    • Abstract: Publication date: Available online 2 July 2019Source: Acta BiomaterialiaAuthor(s): Sebastian Freeman, Rafael Ramos, Paul Alexis Chando, Luxi Zhou, Kyle Reeser, Sha Jin, Pranav Soman, Kaiming Ye 3D bioprinted vascular constructs have gained increased interest due to their significant potential for creating customizable alternatives to autologous vessel grafts. In this study, we developed a new approach for biofabricating fibrin-based vascular constructs using a novel rotary 3D bioprinter developed in our lab. We formulated a new bioink by incorporating fibrinogen with gelatin to achieve a desired shear-thinning property for rotary bioprinting. The blending of heat-treated gelatin with fibrinogen turned unprintable fibrinogen into a printable biomaterial for vessel bioprinting by leveraging the favorable rheological properties of gelatin. We discovered that the heat-treatment of gelatin remarkably affects the rheological properties of a gelatin-fibrinogen blended bioink, which in turn influences the printability of the ink. Further characterizations revealed that not only concentration of the gelatin but the heat treatment also affects cell viability during printing. Notably, the density of cells included in the bioinks also influenced printability and tissue volumetric changes of the printed vessel constructs during cultures. We observed increased collagen deposition and construct mechanical strength during two months of the cultures. The burst pressure of the vessel constructs reached 1,110 mmHg, which is about 52% of the value of the human saphenous vein. An analysis of the tensile mechanical properties of the printed vessel constructs unveiled an increase in both the circumferential and axial elastic moduli during cultures. This study highlights important considerations for bioink formulation when bioprinting vessel constructs.Statement of SignificanceThere has been an increased demand for small-diameter tissue-engineered vascular grafts. Vascular 3D bioprinting holds the potential to create equivalent vascular grafts but with the ability to tailor them to meet patient’s needs. Here, we presented a new and innovative 3D rotary bioprinter and a new bioink formulation for printing vascular constructs using fibrinogen, a favorable biomaterial for vascular tissue engineering. The bioink was formulated by blending fibrinogen with a more printable biomaterial, gelatin. The systematic characterization of the effects of heat treatment and gelatin concentration as well as bioink cell concentration on the printability of the bioink offers new insight into the development of printable biomaterials for tissue biofabrication.Graphical abstractGraphical abstract for this article
       
  • The effect of biomimetic calcium deficient hydroxyapatite and sintered
           β-tricalcium phosphate on osteoimmune reaction and osteogenesis
    • Abstract: Publication date: Available online 30 June 2019Source: Acta BiomaterialiaAuthor(s): Joanna M. Sadowska, Fei Wei, Jia Guo, Jordi Guillem-Marti, Zhengmei Lin, Maria-Pau Ginebra, Yin Xiao Biomaterial implantation triggers inflammatory reactions. Understanding the effect of physicochemical features of biomaterials on the release of inflammatory cytokines from immune cells would be of great interest in view of designing bone graft materials to enhance the healing of bone defects. The present work investigated the interactions of two chemically and texturally different calcium phosphate (CaPs) substrates with macrophages, one of the main innate immune cells, and its further impact on osteogenic differentiation of bone forming cells. The behaviour of macrophages seeded on biomimetic calcium deficient hydroxyapatite (CDHA) and sintered β-tricalcium phosphate (β-TCP) was assessed in terms of the release of inflammatory cytokines and osteoclastogenic factors. The osteogenic differentiation of bone progenitor cells (bone marrow stromal cells (BMSCs) and osteoblastic cell line (SaOS-2)) were subsequently studied by incubating with the conditioned medium induced by macrophage-CaPs interaction in order to reveal the effect of immune cell reaction to CaPs on osteogenic differentiation. It was found that the incubation of macrophages with CaPs substrates caused a decrease of pro-inflammatory cytokines, more pronounced for β-TCP compared with CDHA showing significantly decreased IL-6, TNF-a, and iNOS. However, the macrophage-CDHA interaction resulted in a more favourable environment for osteogenic differentiation of osteoblasts with more collagen type I production and osteogenic genes (Runx2, BSP) expression, suggesting that osteogenic differentiation of bone cells is not only determined by the nature of biomaterials, but also significantly influenced by the inflammatory environment generated by the interaction of immune cells and biomaterials.Statement of significanceThe field of osteoimmunology highlights the importance of the cross-talk between immune and bone cells for effective bone regeneration. This tight interaction opens the door to new strategies that encompass the development of smart cell-instructive biomaterials which performance covers the events from early inflammation to osteogenesis. The present work links the anti-inflammatory and osteoimmunomodulatory features of synthetic bone grafts to their chemistry and texture, focussing on the cross-talk between macrophages and two major orchestrators of bone healing, namely primary mesenchymal stem cells and osteoblasts. The results emphasize the importance of the microenvironment created through the interaction between the substrate and the immune cells as it can stimulate osteogenic events and subsequently foster bone healing.Graphical abstractGraphical abstract for this article
       
  • Glycosaminoglycan Functionalization of Electrospun Scaffolds Enhances
           Schwann Cell activity
    • Abstract: Publication date: Available online 29 June 2019Source: Acta BiomaterialiaAuthor(s): Michela Idini, Paul Wieringa, Silvia Rocchiccioli, Gabriele Nieddu, Nadia Ucciferri, Marilena Formato, Antonio Lepedda, Lorenzo Moroni Nerve fibers of the peripheral nervous system (PNS) have a remarkable ability to regenerate up to an almost complete recovery of normal function following a crush or a Sunderland Type II injury. This process is governed by glial cells, known as Schwann cells, through their unique capacity to dedifferentiate into cells that drive the healing process. Despite that many progresses have occurred in restorative medicine and microsurgery, the regenerative process after a severe lesion of a major nerve trunk (e.g., Sunderland Types III-V) is often incomplete and functional recovery is unsatisfactory. In this aspect, it is known that glycosaminoglycans (GAGs) of the extracellular matrix are involved in proliferation, synaptogenesis, neural plasticity, and regeneration of the PNS. Here, we developed poly(caprolactone) (PCL) fibrous scaffolds functionalized with GAGs, which allowed us to assess their influence on the adhesion, proliferation, and differentiation of Schwann cells. We found that both aligned and random fiber scaffolds functionalized with GAGs resulted in increased cell proliferation on day 1. In addition, aligned functionalized scaffolds also resulted in increased GAG presence on day 1, probably because of cell extracellular matrix (ECM) formation and an increased syndecan-4 expression on day 7. A different modification and activation of Schwann cells in the presence of GAG versus no-GAG scaffolds was underlined by proteomic comparative analysis, where a general downregulation of the expression of intracellular/structural and synthetic proteins was shown on day 7 for GAG-functionalized scaffolds with regard to the nonfunctionalized ones. In conclusion, we have shown that GAG-functionalized scaffolds are effective in modulating Schwann cell behavior in terms of adhesion, proliferation, and differentiation and should be considered in strategies to improve PNS repair.Statement of significanceNerve fibers functional recovery following a severe trauma of Peripheral Nervous System (PNS) still represents a huge challenge for neurosurgery nowadays. In this respect, tissue engineering is committed to develop new constructs able to guide Schwann cells by mimicking the natural extracellular matrix environment. To this purpose, we successfully fabricated polycaprolactone (PCL) scaffolds with two well-defined fiber deposition patterns, functionalized with glycosaminoglycans (GAGs) and assessed for their potential as support for Schwann cells adhesion, growth and differentiation, by both classical biochemistry and LC-MSMS-based proteomic profiling. By this way, we showed as PCL–GAGs scaffolds could represent a promising artificial substrate that closely mimics the recently established pattern of Schwann cells migration into the regenerating nerve and, therefore, it should be considered in strategies to improve PNS repair.Graphical abstractGraphical abstract for this article
       
  • An investigation of layer-specific tissue biomechanics of porcine
           atrioventricular valve anterior leaflets
    • Abstract: Publication date: Available online 29 June 2019Source: Acta BiomaterialiaAuthor(s): Katherine E. Kramer, Colton J. Ross, Devin W. Laurence, Anju R. Babu, Yi Wu, Rheal A. Towner, Arshid Mir, Harold M. Burkhart, Gerhard A. Holzapfel, Chung-Hao Lee Atrioventricular heart valves (AHVs) are composed of structurally complex and morphologically heterogeneous leaflets. The coaptation of these leaflets during the cardiac cycle facilitates unidirectional blood flow. Valve regurgitation is treated preferably by surgical repair if possible or replacement based on the disease state of the valve tissue. A comprehensive understanding of valvular morphology and mechanical properties is crucial to refining computational models, serving as a patient-specific diagnostic and surgical tool for preoperative planning. Previous studies have modeled the stress distribution throughout the leaflet’s thickness, but validations with layer-specific biaxial mechanical experiments are missing. In this study, we sought to fill this gap in literature by investigating the impact of microstructure constituents on mechanical behavior throughout the thickness of the AHVs’ anterior leaflets. Porcine mitral valve anterior leaflets (MVAL) and tricuspid valve anterior leaflets (TVAL) were micro-dissected into three layers (atrialis/spongiosa, fibrosa, and ventricular) and two layers (atrialis/spongiosa and fibrosa/ventricularis), respectively, based on their relative distributions of extracellular matrix components as quantified by histological analyses: collagen, elastin, and glycosaminoglycans. Our results suggest that (i) for both valves, the atrialis/spongiosa layer is the most extensible and anisotropic layer, possibly due to its relatively low collagen content as compared to other layers, (ii) the intact TVAL response is stiffer than the atrialis/spongiosa layer but more compliant than the fibrosa/ventricularis layer, and (iii) the MVAL fibrosa and ventricularis layers behave nearly isotropic. These novel findings emphasize the biomechanical variances throughout the AHV leaflets, and our results could better inform future AHV computational model developments.Statement of SignificanceThis study, which is the first of its kind for atrioventricular heart valve (AHV) leaflet tissue layers, rendered a mechanical characterization of the biaxial mechanical properties and distributions of extracellular matrix components (collagen, elastin, and glycosaminoglycans) of the mitral and tricuspid valve anterior leaflet layers. The novel findings from the present study emphasize the biomechanical variances throughout the thickness of AHV leaflets, and our results indicate that the previously adopted homogenous leaflet in the AHV biomechanical modeling may be an oversimplification of the complex leaflet anatomy. Such improvement in the understanding of valvular morphology and tissue mechanics is crucial to future refinement of AHV computational models, serving as a patient-specific diagnostic and surgical tool, at the preoperative stage, for treating valvular heart diseases.Graphical abstractGraphical abstract for this article
       
  • In vitro–in vivo correlation of inhalable budesonide-loaded large porous
           particles for sustained treatment regimen of asthma
    • Abstract: Publication date: Available online 29 June 2019Source: Acta BiomaterialiaAuthor(s): Jiaqi Li, Huangliang Zheng, Lu Qin, En-Yu Xu, Linglong Yang, Lan Zhang, Xiaofei Zhang, Linlin Fan, Moritz Beck-Broichsitter, Uwe Muenster, Linc Chen, Yuyang Zhang, Shirui Mao Large porous particles (LPPs) are well-known vehicles for drug delivery to the lungs. However, it remains uncertain whether or to which extent the in vitro drug release behavior of LPPs can be predictive of their in vivo performance (e.g., systemic exposure and therapeutic efficacy). With regard to this, three budesonide-loaded LPP formulations with identical composition but distinct in vitro drug release profiles were studied in vivo for their pharmacokinetic and pharmacodynamic behavior after delivery to rat lung, and finally, an in vitro/in vivo correlation (IVIVC) was established. All formulations reduced approximately 75% of the uptake by RAW264.7 macrophages compared with budesonide/lactose physical mixture and showed a drug release-dependent retention behavior in the lungs of rats. Likewise, the highest budesonide plasma concentration was measured for the formulation revealing the fastest in vitro drug release. After deconvolution of the plasma concentration/time profiles, the calculated in vivo drug release data were successfully utilized for a point-to-point IVIVC with the in vitro release profiles and the predictability of the developed IVIVC was acceptable. Finally, effective therapy was observed in an allergic asthma rat model for the sustained drug release formulations. Overall, the obtained in vitro results correlate well with the systemic drug exposure and the therapeutic performance of the investigated lung-delivered formulations, which can provide an experimental basis for IVIVC development in the pulmonary-controlled delivery system.Statement of significanceLarge porous particles (LPPs) are well-known vehicles for drug delivery to the lungs. However, it remains uncertain whether or to which extent the in vitro drug release behavior of LPPs can be predicted by their in vivo performance (e.g., systemic exposure and therapeutic efficacy). With regard to this, three budesonide-loaded PLGA-based LPP formulations with identical composition but distinct in vitro drug release profiles were studied in vivo for their pharmacokinetic and pharmacodynamic behavior, and finally, an in vitro/in vivo correlation (IVIVC) was established. It was demonstrated that the influence of the in vitro drug release profile was obvious during lung retention, systemic exposure, and therapeutic efficacy measurements. An IVIVC (Level A) was successfully established for the budesonide-loaded LPPs delivered to the airspace of rats for the first time. Taken together, the present work will clearly support research and development activities in the field of controlled drug delivery to the lungs.Graphical abstractGraphical abstract for this article
       
  • Interfacial characterization of poly (vinyl alcohol) fibers embedded in a
           calcium phosphate cement matrix: An experimental and numerical
           investigation
    • Abstract: Publication date: Available online 29 June 2019Source: Acta BiomaterialiaAuthor(s): Ali Paknahad, Daniela G. Petre, Sander C.G. Leeuwenburgh, Lambertus J. Sluys Because of their chemical similarity to the mineral phase of bone and teeth, calcium phosphate cements (CPCs) are extensively investigated for applications in biomedicine. Nevertheless, their applicability in load-bearing anatomical sites is restricted by their brittleness. Reinforcement of calcium phosphate cements with polymeric fibers can overcome this mechanical limitation provided that the affinity between these fibers and the surrounding matrix is optimal. To date, the effects of the fiber-matrix affinity on the mechanical properties of fiber-reinforced calcium phosphate cements are still poorly understood. The goal of this study is therefore to investigate the interfacial properties and bond-slip response between the CPC matrix and polymeric fibers. To this end, we selected poly (vinyl alcohol) (PVA) fibers as reinforcing agents because of their high strength and stiffness and their effective reinforcement of cementitious matrices. Micromechanical pull-out experiments were combined with numerical simulations based on an dedicated constitutive interfacial law to characterize the interfacial properties of PVA fibers embedded in a CPC matrix at the single fiber pull-out level. The computational model developed herein is able to predict all three main phases of pull-out response, i.e. the elastic, debonding and frictional pull-out phases. The resulting interfacial constitutive law is validated experimentally and predicts the pull-out response of fibers with different diameters and embedded lengths.Statements of significanceTo date, the effects of the fiber-matrix affinity on the mechanical properties of fiber-reinforced calcium phosphate cements are still poorly understood. In this study, we present a novel experimental protocol to investigate the affinity between poly (vinyl alcohol) PVA fibers and the calcium phosphate cement (CPC) matrix by means of single-fiber pull out tests. We determine the critical embedded length for PVA fibers with two different diameters; and we design a numerical FE model including a distinct representation of fiber, matrix and interface with a predictive interfacial constitutive law which is capable of capturing all three main phases of single-fiber pull-out, i.e. elastic, debonding and frictional stages. The resulting interfacial constitutive law is validated experimentally and predicts the pull-out response of fibers with different diameters and embedded lengths.Graphical abstractGraphical abstract for this article
       
  • Aligned Conductive Core-Shell Biomimetic Scaffolds Based on Nanofiber
           
    • Abstract: Publication date: Available online 29 June 2019Source: Acta BiomaterialiaAuthor(s): Ling Wang, Yaobin Wu, Tianli Hu, Peter X. Ma, Baolin Guo Aligned topographical cue has been demonstrated as a critical role in neuronal guidance, and it is highly beneficial to develop a scaffold with aligned structure for peripheral nerve tissue regeneration. Although considerable efforts have been devoted to guiding neurite alignment and extension, it remains a remarkable challenge for developing a biomimetic scaffold for enhancing 3D aligned neuronal outgrowth. Herein, we present a core-shell scaffold based on aligned conductive nanofiber yarns (NFYs) within the hydrogel to mimic the 3D hierarchically aligned structure of the native nerve tissue. The aligned NFYs assembled by a bundle of aligned nanofibers composed of polycaprolactone (PCL), silk fibroin (SF), and carbon nanotubes (CNTs) are prepared by a developed dry–wet electrospinning method, which has the ability to induce neurite alignment and elongation when PC12 cells and dorsal root ganglia (DRG) cells are cultured on their 3D peripheral surface. Particularly, such an aligned nanofibrous structure also induces aligned neurite extension and cell migration from DRG explants along the direction of nanofibers. 3D core-shell scaffolds are fabricated by encapsulating NFYs within the hydrogel shell after photocrosslinking, and these 3D aligned scaffolds are able to control cellular alignment and elongation of nerve cells in this 3D environment. Our results suggest that such 3D hierarchically aligned core-shell scaffold consists of NFYs that mimic the aligned nerve fiber structure to induce neurite alignment and extension and a hydrogel shell that mimics the epineurium layer to protect nerve cell organization within a 3D environment, which is largely promising for the design of biomimetic scaffolds in nerve tissue engineering.Statement of significanceDesigning scaffolds with 3D aligned structure has been paid more attention for peripheral nerve tissue regeneration, because the aligned topographical cue is able to induce neurites alignment and extension. However, developing scaffolds mimicking the hierarchically aligned structure of native nerve tissue for directing 3D aligned neuronal outgrowth without external stimulation remains challenging. This work presented a simple and efficient strategy to prepare a 3D biomimetic core-shell scaffold based on electrospun aligned conductive nanofiber yarns within photocurable hydrogel shell to mimic the hierarchically aligned structure of native nerve tissue. These 3D aligned composite scaffolds performed the ability to direct 3D cellular alignment and elongation of nerve cells along with the nanofiber yarn direction, and the hydrogel shell mimicking the epineurium layer was able to protect nerve cells organization within the 3D environment, which indicated their great potential in peripheral nerve tissue engineering applications.Graphical abstractGraphical abstract for this article
       
  • A bioinspired hyperthermic macrophage-based polypyrrole-polyethylenimine
           (Ppy-PEI) nanocomplex carrier to prevent and disrupt thrombotic fibrin
           clots
    • Abstract: Publication date: Available online 29 June 2019Source: Acta BiomaterialiaAuthor(s): Thierry Burnouf, Chih-Hwa Chen, Shun-Jen Tan, Ching-Li Tseng, Kun-Ying Lu, Lee-Hsin Chang, Batzaya Nyambat, Shao-Chan Huang, Pei-Ru Jheng, Robby Nur Aditya, Fwu-Long Mi, Er-Yuan Chuang Fibrinolytic treatments for venous or arterial thrombotic syndromes using systemic administration of thrombolytics, such as streptokinase, can induce life-threatening bleeding complications. In this study, we offer the first proof of concept for a targeted photothermal fibrin clot prevention and reduction technology using macrophages loaded with polypyrrole-polyethylenimine nanocomplexes (Ppy-PEI NCs) and subjected to near-infrared radiation (NIR). We first show that the developed Ppy-PEI NCs could be taken up by defensive macrophages in vitro through endocytosis. The Ppy-PEI NCs generated local hyperthermia upon NIR treatment, which appeared to produce reactive oxygen species in Ppy-PEI NC-loaded macrophages. Preliminary evidence of efficacy as an antithrombotic tool is provided, in vitro, using fibrinogen-converted fibrin clots, and in vivo, in a rat femoral vascular thrombosis model generated by exposure to ferric chloride substance. The in vivo biocompatibility, photothermal behavior, biodistribution, and histological observation of cellular interactions with the Ppy-PEI NCs in the rat model provide rationale in support of further preclinical studies. This Ppy-PEI NC/NIR-based method, which uses a unique macrophage-guided targeting approach to prevent and lyse fibrin clots, may potentially overcome some of the disadvantages of current thrombolytic treatments.Statement of significanceFibrinolytic treatments for venous or arterial thrombotic syndromes using systemic administration of thrombolytics, such as streptokinase, can induce life-threatening bleeding complications. In this study, we offer the first proof of concept for a targeted photothermal fibrin clot reduction technology using macrophages loaded with polypyrrole-polyethylenimine nanocomplexes (Ppy-PEI NCs) and subjected to near-infrared radiation (NIR). We first show that the developed Ppy-PEI NCs can be taken up by defensive macrophages in vitro through endocytosis. The Ppy-PEI NCs generated local hyperthermia upon NIR treatment, which appeared to produce reactive oxygen species in Ppy-PEI NC-loaded macrophages. Preliminary evidence of efficacy as an antithrombotic tool is provided, in vitro, using fibrinogen-converted fibrin clots, and in vivo, in a rat femoral vascular thrombosis model generated by exposure to ferric chloride substance. The in vivo biocompatibility, photothermal behavior, biodistribution, and histological observation of cellular interactions with the Ppy-PEI NCs in the rat model provide rationale in support of further preclinical studies. This Ppy-PEI NC/NIR-based method, which uses a unique macrophage-guided targeting approach to disintegrate fibrin clots, may potentially overcome some of the disadvantages of current thrombolytic treatments.Graphical abstractGraphical abstract for this article
       
  • Low density lipoprotein-inspired nanostructured lipid nanoparticles
           containing pro-doxorubicin to enhance tumor-targeted therapeutic
           efficiency
    • Abstract: Publication date: Available online 28 June 2019Source: Acta BiomaterialiaAuthor(s): Wenpan Li, Jia Fu, Ying Ding, Dan Liu, Nan Jia, Dawei Chen, Haiyang Hu Inefficient tumor accumulation and controlling drug release at the tumor site are two major obstacles limiting the antitumor efficacy of nanoparticle delivery systems. Inspired by the biological structure and function of low-density lipoprotein (LDL), a pH-sensitive ApoB-100/Oleic acid-DOX/NLC (AODN) nanoparticle based on nanostructured lipid carrier (NLC) was prepared in this study. The biological composition of ApoB-containing NLC nanoparticles is similar to that of LDL, which can effectively increase the cycle time and targeting efficiency of nanoparticles. Meantime, the doxorubicin prodrug strategy was used to increase the drug loading of the nanoparticles and achieve drug-sensitive release. In vitro results indicated that AODN nanoparticles can cause more drugs to be phagocytosed by LDL receptor-mediated endocytosis, thus showing high cytotoxicity in 4T1 cells. In vivo experiments have shown that pH-sensitive AODN nanoparticles can cause more drugs to accumulate in the tumor site, reducing systemic toxicity and effectively inhibiting orthotopic breast cancer. These data provide strong evidence that the strategy of combining bionics and prodrug technology provides a new approach to improving the efficiency of chemotherapy drugs in cancer treatment.Statement of SignificanceInefficient tumor accumulation and controlling drug release at the tumor site are two major obstacles limiting the antitumor efficacy of nanoparticle delivery systems. Inspired by low density lipoprotein, a pH-sensitive ApoB-100/oleic acid-DOX/NLC (AODN) nanoparticle based on nanostructured lipid carrier (NLC) was prepared. Its biological composition is similar to that of LDL, which can effectively increase the cycle time and targeting efficiency of drugs. Then, the doxorubicin prodrug strategy was used to increase the drug loading of the nanoparticles and achieve drug-sensitive release. AODN nanoparticles can effectively inhibit tumor by effectively accumulating at tumor site and controlling release. The strategy of combining bionics and prodrug technology provides a new approach to improving the efficiency of chemotherapy drugs in cancer treatment.Graphical abstractGraphical abstract for this article
       
  • Extracellular matrix type modulates mechanotransduction of stem cells
    • Abstract: Publication date: Available online 28 June 2019Source: Acta BiomaterialiaAuthor(s): Alice E. Stanton, Xinming Tong, Fan Yang Extracellular matrix (ECM) is comprised of different types of proteins, which change in composition and ratios during morphogenesis and disease progression. ECM proteins provide cell adhesion and impart mechanical cues to the cells. Increasing substrate stiffness has been shown to induce Yes-associated protein (YAP) translocation from the cytoplasm to the nucleus, yet these mechanistic studies used fibronectin only as the biochemical cue. How varying the types of ECM modulates mechanotransduction of stem cells remains largely unknown. Using polyacrylamide hydrogels with tunable stiffness as substrates, here we conjugated four major ECM proteins commonly used for cell adhesion: fibronectin, collagen I, collagen IV and laminin, and assessed the effects of varying ECM type and density on YAP translocation in human mesenchymal stem cells (hMSCs). For all four ECM types, increasing ECM ligand density alone can induce YAP nuclear translocation without changing substrate stiffness. The ligand threshold for such biochemical ligand-induced YAP translocation differs across ECM types. While stiffness-dependent YAP translocation can be induced by all four ECM types, each ECM requires a different optimized ligand density for this to occur. Using antibody blocking, we further identified integrin subunits specifically involved in mechanotransduction of different ECM types. Finally, we demonstrated that altering ECM type further modulates hMSC osteogenesis without changing substrate stiffness. These findings highlight the important role of ECM type in modulating mechanotransduction and differentiation of stem cells, and call for future mechanistic studies to further elucidate the role of changes in ECM compositions in mediating mechanotransduction during morphogenesis and disease progression.Statement of SignificanceOur study addresses a critical gap of knowledge in mechanobiology. Increasing substrate stiffness has been shown to induce nuclear YAP translocation, yet only on fibronectin-coated substrates. However, extracellular matrix (ECM) is comprised of different protein types. How varying the type of ECM modulates stem cell mechanotransduction remains largely unknown.We here reveal that the choice of ECM type can directly modulate stem cell mechanotransduction, filling this critical gap.This work has broad impacts in mechanobiology and biomaterials, as it provides the first evidence that varying ECM type can impact YAP translocation independent of substrate stiffness, opening doors for a more rational biomaterials design tuning ECM properties to control cell fate for promoting normal development and for preventing disease progression.Graphical abstractGraphical abstract for this article
       
  • Screening of Perfused Combinatorial 3D Microenvironments for Cell Culture
    • Abstract: Publication date: Available online 27 June 2019Source: Acta BiomaterialiaAuthor(s): Diana Lopes, C. Fernandes, J. Miguel Nóbrega, Sónia G. Patrício, Mariana B. Oliveira, João F. Mano Biomaterials combining biochemical and biophysical cues to establish close-to-extracellular matrix (ECM) models have been explored for cell expansion and differentiation purposes. Multivariate arrays are used as material-saving and rapid-to-analyze platforms, which enable selecting hit-spotted formulations targeting specific cellular responses. However, these systems often lack the ability to emulate dynamic mechanical aspects that occur in specific biological milieus and affect physiological phenomena including stem cells differentiation, tumor progression, or matrix modulation. We report a tailor-made strategy to address the combined effect of flow and biochemical composition of three-dimensional (3D) biomaterials on cellular response. We suggest a simple-to-implement device comprising (i) a perforated platform accommodating miniaturized 3D biomaterials and (ii) a bioreactor that enables the incorporation of the biomaterial-containing array into a disposable perfusion chamber. The system was upscaled to parallelizable setups, increasing the number of analyzed platforms per independent experiment. As a proof-of-concept, porous chitosan scaffolds with 1 mm diameter were functionalized with combinations of 5 ECM and cell-cell contact-mediating proteins, relevant for bone and dental regeneration, corresponding to 32 protein combinatorial formulations. Mesenchymal stem cells adhesion and production of an early osteogenic marker were assessed on-chip on static and under-flow dynamic perfusion conditions. Different hit-spotted biomaterial formulations were detected for the different flow regimes using direct image analysis. Cell-binding proteins still poorly explored as biomaterials components – amelogenin and E-cadherin – were here shown as relevant cell response modulators. Their combination with ECM cell-binding proteins – fibronectin, vitronectin, and type 1 collagen – rendered specific biomaterial combinations with high cell adhesion and ALP production under flow. The developed versatile system may be targeted at widespread tissue regeneration applications, and as a disease model/drug screening platform.Statement of SignificanceA perfusion system that enables cell culture in arrays of three-dimensional biomaterials under dynamic flow is reported. The effect of 31 cell-binding protein combinations in the adhesion and alkaline phosphatase (ALP) production of mesenchymal stem cells was assessed using a single bioreactor chamber. Flow perfusion was not only assessed as a classical enhancer/accelerator of cell growth and early osteogenic differentiation. We hypothesized that flow may affect cell-protein interactions, and that key components driving cell response may differ under static or dynamic regimes. Indeed, hit-spotted formulations that elicited highest cell attachment and ALP production on static cell culture differed from the ones detected for dynamic flow assays. The impacting role of poorly studied proteins as E-cadherin and amelogenin as biomaterial components was highlighted.Graphical abstractGraphical abstract for this article
       
  • Mechanical properties of stingray tesserae: High-resolution correlative
           analysis of mineral density and indentation moduli in tessellated
           cartilage
    • Abstract: Publication date: Available online 27 June 2019Source: Acta BiomaterialiaAuthor(s): Ronald Seidel, Andreas Roschger, Ling Li, Joseph J. Bizzarro, Qiuting Zhang, Jie Yin, Ting Yang, James C. Weaver, Peter Fratzl, Paul Roschger, Mason N. Dean Skeletal tissues are built and shaped through complex, interacting active and passive processes. These spatial and temporal variabilities make interpreting growth mechanisms from morphology difficult, particularly in bone, where the remodeling process erases and rewrites local structural records of growth throughout life. In contrast to the majority of bony vertebrates, the elasmobranch fishes (sharks, rays, and their relatives) have skeletons made of cartilage, reinforced by an outer layer of mineralized tiles (tesserae), and are believed to grow only by deposition, without remodeling. We exploit this structural permanence, performing the first fine-scale correlation of structure and material properties in an elasmobranch skeleton. Our characterization across an age series of stingray tesserae allows unique insight into the growth processes and mechanical influences shaping the skeleton. Correlated quantitative backscattered electron imaging (qBEI) and nanoindentation measurements show a positive relationship between mineral density and tissue stiffness/hardness. Although tessellated cartilage as a whole (tesserae plus unmineralized cartilage) is considerably less dense than bone, we demonstrate that tesserae have exceptional local material properties, exceeding those of (mammal) bone and calcified cartilage. We show that the finescale ultrastructures recently described in tesserae have characteristic material properties suggesting distinct mechanical roles and that regions of high mineral density/stiffness in tesserae are confined predominantly to regions expected to bear high loads. In particular, tesseral spokes (laminated structures flanking joints) exhibit particularly high mineral densities and tissue material properties, more akin to teeth than bone or calcified cartilage. We conclude that these spokes toughen tesserae and reinforce points of contact between them. These toughening and reinforcing functions are supported by finite element simulations incorporating our material data. The high stresses predicted for spokes, and evidence we provide that new spoke laminae are deposited according to their local mechanical environment, suggest tessellated cartilage is both mutable and responsive, despite lacking remodeling capability.Statement of SignificanceThe study of vertebrate skeletal materials is heavily biased toward mammal bone, despite evidence that bone and cartilage are extremely diverse. We broaden the perspective on vertebrate skeleton materials and evolution in an investigation of stingray tessellated cartilage, a curious type of unmineralized cartilage with a shell of mineralized tiles (tesserae). Combining high-resolution imaging and material testing, we demonstrate that tesserae have impressive local material properties for a vertebrate skeletal tissue, arguing for unique tissue organization relative to mammalian calcified cartilage and bone. Incorporating our materials data into mechanical models, we show that finescale material arrangements allow this cartilage to act as a functional and responsive alternative to bone, despite lacking bone’s ability to remodel. These results are relevant to a diversity of researchers, from skeletal, developmental, and evolutionary biologists, to materials scientists interested in high-performance, low-density composites.Graphical abstractGraphical abstract for this article
       
  • Role of charge reversal in the hemo/immunocompatibility of polycationic
           gene delivery systems
    • Abstract: Publication date: Available online 27 June 2019Source: Acta BiomaterialiaAuthor(s): Qi Yang, Shuo Liu, Xin Liu, Zonghua Liu, Wei Xue, Yi Zhang As an effective and well-recognized strategy used in many delivery systems, such as polycation gene vectors, charge reversal refers to the alternation of vector surface charge from negative (in blood circulation) to positive (in the targeted tissue) in response to specific stimuli to simultaneously satisfy the requirements of biocompatibility and targeting. Although charge reversal vectors are intended to avoid interactions with blood in their application, no overall or systematic investigation has been carried out to verify the role of charge reversal in the blood compatibility. Herein, we comprehensively mapped the effects of a typical charge-reversible polycation gene vector based on pH-responsive 2,3-dimethylmaleic anhydride (DMMA)-modified polyethylenimine (PEI)/pDNA complex in terms of blood components, coagulation function, and immune response as compared to conventional PEGylated modification. The in vitro and in vivo results displayed that charge-reversal modification significantly improves the PEI/pDNA-induced abnormal effect on vascular endothelial cells, platelet activation, clotting factor activity, fibrinogen polymerization, blood coagulation process, and pro-inflammatory cytokine expression. Unexpectedly, (PEI/pDNA)-DMMA induced the cytoskeleton impairment-mediated erythrocyte morphological alternation and complement activation even more than PEI/pDNA. Further, transcriptome sequencing demonstrated that the overexpression of pro-inflammatory cytokines was correlated with vector-induced differentially expressed gene number and mediated by inflammation-related signaling pathways (MAPK, NF-κB, Toll-like receptor, and JAK-STAT) activation. By comparison, charge-reversal modification improved the hemocompatibility to a greater extent than dose PEGylation except for erythrocyte rupture. Nevertheless, it is inferior to mPEG modification in terms of immunocompatibility. These findings provide comprehensive insights to understand the molecular mechanisms of the effects of charge reversal on blood components and their function and to provide valuable information for its potential applications from laboratory to clinic.Statement of SignificanceThe seemingly revolutionary charge reversal strategy has been believed to possess stealth character with negative charge eluding interaction with blood components during circulation. However to date, no overall or systematic investigation has been carried out to verify the role of charge-reversal on the blood/immune compatibility, which impede their development from laboratory to bedside. Therefore, we comprehensively mapped the effects of a typical charge-reversible polycationic gene vector on blood components (vascular endothelial cell, platelet, clotting factors, fibrinogen, RBCs and coagulation function) and immune response (complement and pro-inflammatory cytokines) at cellular and molecular level in comparison to PEGylation modification. These findings help to elucidate the molecular mechanisms for the effects of charge-reversal on blood components and functions, and provide valuable information for the possible application in clinical settings.Graphical abstractGraphical abstract for this article
       
  • Towards refining microstructures of biodegradable magnesium alloy WE43 by
           spark plasma sintering
    • Abstract: Publication date: Available online 27 June 2019Source: Acta BiomaterialiaAuthor(s): Julie Soderlind, Martina Cihova, Robin Schäublin, Subhash Risbud, Jörg F. Löffler Microstructural refinement of magnesium (Mg) alloys is beneficial for mechanical and corrosion properties, both of which are critical for their successful application as temporary implant materials. One method of achieving a refined microstructure is through rapid solidification via gas-atomization-powder production. In this study we investigated spark plasma sintering (SPS) as a potential processing method for maintaining this refined microstructure while achieving a range of porosities up to full densification. We characterized the microstructural evolution as a function of sintering temperature from 250 to 450 °C for the alloy WE43 using multi-scale correlative microscopy techniques, including light microscopy and scanning and transmission electron microscopy-based methods. The spatial distribution of the two major alloying elements, neodymium (Nd) and yttrium (Y), was determined and the intermetallic phases they form identified using energy dispersive X-ray spectroscopy in conjunction with electron diffraction. The gas-atomized powder microstructure consists of Mg-rich dendrites and a percolating interdendritic Mg–Nd–Y ternary phase with structure Mg14Nd2Y, surrounded by a high Nd and Y content in solid solution. This microstructure is maintained up to a sintering temperature of 350 °C, while with higher sintering temperatures segregation of Nd and Y dominates. The percolating ternary phase breaks up into faceted globular precipitates with structure Mg5Nd, which is isomorphous to Mg14Nd2Y. Y comes out of solution and migrates to previous powder-particle surfaces, possibly forming Y2O3. Sample densities ranged from 64 to 100% for sintering temperatures of 250 to 450 °C, respectively, and the grain size remained constant at about 10 µm. SPS is demonstrated to be an attractive alternative method for processing Mg alloys to a wide range of porosities and fine microstructures. The microstructural refinement achieved by SPS holds the potential for slow and homogeneous corrosion.Statement of SignificanceThis study presents the impact spark plasma sintering (SPS) has on the microstructure of WE43, a magnesium alloy used for biodegradable implants. SPS is of great interest in this context as it is scalable, rapid, and has the potential for tuning density while maintaining a refined microstructure. The microstructure and density are explored from the gas-atomized powder to the densified material using electron microscopy and chemical mapping from the macro- to the nano-level. The insights gained reveal an original evolution of rare-earth element distribution with an isomorphous chemistry change, while the microstructure develops from the non-equilibrium state (powder) towards an equilibrium structure upon sintering. This study, including measurements of mechanical performance, sets the premises of SPS for the fabrication of Mg-based implants with tunable characteristics.Graphical abstractGraphical abstract for this article
       
  • Synthesis and characterization of electrospun nanofibrous tissue
           engineering scaffolds generated from in situ polymerization of ionomeric
           polyurethane composites
    • Abstract: Publication date: Available online 27 June 2019Source: Acta BiomaterialiaAuthor(s): Jennifer PY. Chan, Kyle G. Battiston, J. Paul Santerre Tissue scaffolds need to be engineered to be cell compatible, have timely biodegradable character, be functional with respect to providing niche cell support for tissue repair and regeneration, readily accommodate multiple cell types, and have mechanical properties that enable the simulation of the native tissue. In this study, electrospun degradable polar hydrophobic ionic polyurethane (D-PHI) scaffolds were generated in order to yield an extracellular matrix-like structure for tissue engineering applications. D-PHI oligomers were synthesized, blended with a degradable linear polycarbonate polyurethane (PCNU), and electrospun with simultaneous in situ UV cross-linking in order to generate aligned nanofibrous scaffolds in the form of elastomeric composite materials. The D-PHI/PCNU scaffold fibre morphology, cross-linking efficiency, surface nature, mechanical properties, in vivo degradation and integration, as well as in vitro cell compatibility were characterized. The results showed that D-PHI/PCNU scaffolds had a high cross-linking efficiency, stronger polar nature, and lower stiffness relative to PCNU scaffolds. In vivo, the D-PHI/PCNU scaffold degraded relatively slowly, thereby enabling new tissue time to form and yielding very good integration with the latter tissue. Based on a study with A10 vascular smooth muscle cells, the D-PHI/PCNU scaffold was able to support high cell viability, adhesion, and expression of typical smooth muscle cell markers after a 7-day culture period, which was comparable to PCNU scaffolds. These characterization results demonstrate that the unique properties of a D-PHI/PCNU scaffold, combined with the benefits of electrospinning, could allow for the generation of a tissue engineered scaffold that mimics important aspects of the native extracellular matrix and could be used for functional tissue regeneration.Statement of significanceTissue engineered scaffolds should recapitulate native extracellular matrix features. This study investigates the processing of a classical polycarbonate polyurethane (PCNU) with a cross-linked and degradable ionomeric polyurethane (D-PHI), polymerized via in-situ rapid light curing to yield a 3-dimensional co-electrospun nanofibre matrix with chemical diversity and low modulus character. This research advances the use of D-PHI for tissue engineering applications by providing a facile means of changing physical and chemical properties in classical PCNUs without the need to adjust spinning viscosities of the base polymer. Further, the in vivo and cell culture findings set the stage for introducing unique elastic materials which inherently support wound healing, repair, and regeneration in tissues, for applications that require the recapitulation of native extracellular matrix physical features.Graphical abstractGraphical abstract for this article
       
  • Anisotropic Crack Propagation and Deformation in Dentin Observed by
           Four-Dimensional X-ray Nano-Computed Tomography
    • Abstract: Publication date: Available online 26 June 2019Source: Acta BiomaterialiaAuthor(s): Xuekun Lu, Marta Peña Fernández, Robert S Bradley, Shelley D Rawson, Marie O'Brien, Benjamin Hornberger, Marty Leibowitz, Gianluca Tozzi, Philip J Withers Understanding the cracking behaviour of biological composite materials is of practical importance. This paper presents the first study to track the interplay between crack initiation, microfracture and plastic deformation in three dimensions (3D) as a function of tubule and collagen fibrils arrangement in elephant dentin using in situ X-ray nano-computed tomography (nano-CT). A nano-indenter with a conical tip has been used to incrementally indent three test-pieces oriented at 0°, 45° and 70° to the long axis of the tubules (i.e. radial to the tusk). For the 0° sample two significant cracks formed, one of which linked up with microcracks in the axial-radial plane of the tusk originating from the tubules and the other one occurred as a consequence of shear deformation at the tubules. The 70° test-piece was able to bear the greatest loads despite many small cracks forming around the indenter. These were diverted by the microstructure and did not propagate significantly. The 45° test-piece showed intermediate behaviour. In all cases strains obtained by digital volume correlation were well in excess of the yield strain (0.9%), indeed some plastic deformation could even be seen through bending of the tubules. The hoop strains around the conical indenter were anisotropic with the smallest strains correlating with the primary collagen orientation (axial to the tusk) and the largest strains aligned with the hoop direction of the tusk.Statement of SignificanceThis paper presents the first comprehensive study of the anisotropic nature of microfracture, crack propagation and deformation in elephant dentin using time-lapse X-ray nano-computed tomography. To unravel the interplay of collagen fibrils and local deformation, digital volume correlation (DVC) has been applied to map the local strain field while the crack initiation and propagation is tracked in real time. Our results highlight the intrinsic and extrinsic shielding mechanisms and correlate the crack growth behavior in nature to the service requirement of dentin to resist catastrophic fracture. This is of wide interest not just in terms of understanding dentin fracture but also can extend beyond dentin to other anisotropic structural composite biomaterials such as bone, antler and chitin.Graphical abstractGraphical abstract for this article
       
  • The influence of body temperature on tissue stiffness, blood perfusion,
           and water diffusion in the mouse brain
    • Abstract: Publication date: Available online 25 June 2019Source: Acta BiomaterialiaAuthor(s): Gergely Bertalan, Philipp Boehm-Sturm, Stefanie Schreyer, Anna-Sophie Morr, Barbara Steiner, Heiko Tzschätzsch, Jürgen Braun, Jing Guo, Ingolf Sack While hypothermia of the brain is used to reduce neuronal damage in patients with conditions such as traumatic brain injury or stroke, little is known about how temperature affects the biophysical properties of in vivo brain tissue. Therefore, we measured shear wave speed (SWS), apparent diffusion coefficient (ADC), and cerebral blood flow (CBF) in the mouse brain at different body temperatures to investigate the relationship between temperature and tissue stiffness, water diffusion, and blood perfusion in the living brain. Multifrequency magnetic resonance elastography (MRE), diffusion-weighted imaging (DWI), and arterial spin labeling (ASL) were performed in seven mice while increasing and recording body temperature from hypothermia (28–30°C) to normothermia (36–38°C). SWS, ADC, and CBF were analyzed in regions of whole brain, cortex, hippocampus, and diencephalon. Our results show that SWS decreases while ADC and CBF increase from hypothermia to normothermia (whole brain SWS: -6.2%, ADC: +34.0%, CBF: +80.2%; cortex SWS: -10.1%, ADC: +30.9%, CBF: +82.4%; all p>0.05). We found a significant inverse correlation between SWS and both ADC and CBF in all analyzed regions except diencephalon (whole brain SWS-ADC: r=-0.8, p
       
  • The Exoskeleton of Scorpions’ Pincers: Structure and
           Micro-Mechanical Properties
    • Abstract: Publication date: Available online 25 June 2019Source: Acta BiomaterialiaAuthor(s): Israel Kellersztein, Sidney R. Cohen, Benny Bar-On, H. Daniel Wagner Since scorpions exist almost all over the world, some expected body differences exist among the species: undoubtedly, the most evident is the shape and size of their pincers or chelae. The scorpion chela is a multifunctional body component (e.g. attack/defense, mating and protection from the environment) that leads to the development of different stresses in the cuticle. How such stresses in the cuticle are accommodated by different chelae shape and size is largely unknown. Here we provide new comparative data on the hierarchical structure and mechanical properties of the chela cuticle in two scorpion species: Scorpio Maurus Palmatus (SP) that has a large chela and Buthus Occitanus Israelis (BO), with a slender chela. We found that the SP exocuticle is composed of four different sublayers whereas the BO exocuticle displays only two sublayers. These structures are different from the exocuticle morphologies in crustaceans, where the Bouligand morphology is present throughout the entire layer. Moreover, the scorpion chela cuticle presents an exclusive structural layer made of unidirectional fibers arranged vertically towards the normal direction of the cuticle. Nanoindentation measurements were performed under dry conditions on transversal and longitudinal planes to evaluate the stiffness and hardness of the different chela cuticle layers in both scorpions. The chela cuticle structure is a key factor towards the decision of the scorpion whether to choose to sting or use the chela for other mechanical functions.Statement of significanceMany arthropods such as lobsters, crabs, stomatopods, isopods, and spiders have been the subject of research in recent years, and their hierarchical structure and mechanical properties extensively investigated. Yet, except for a limited number of pre-1980 publications, comparatively little work has been devoted to the terrestrial scorpion. The scorpion chela is a multifunctional part of the body (e.g. attack/defense, mating and protection from the environment) that involves the development of various stresses in the cuticle. How these stresses in the chela cuticle are managed by different chelae shape and size is still unknown. The lack of a single study that integrates morphological characterization of the entire hierarchical structure of the scorpion chela cuticle, and local mechanical properties, significantly affects the scientific knowledge regarding important structural approaches that can be used by nature to maximize functionality.Graphical abstractGraphical abstract for this article
       
  • Permeability and mechanical properties of gradient porous PDMS scaffolds
           fabricated by 3D-printed sacrificial templates designed with minimal
           surfaces
    • Abstract: Publication date: Available online 25 June 2019Source: Acta BiomaterialiaAuthor(s): H. Montazerian, M.G.A. Mohamed, M. Mohaghegh Montazeri, S. Kheiri, A.S. Milani, K. Kim, M. Hoorfar In the present study, polydimethylsiloxane (PDMS) porous scaffolds are designed based on minimal surface architectures and fabricated through a low-cost and accessible sacrificial mold printing approach using a fused deposition modeling (FDM) 3D printer. The effects of pore characteristics on compressive properties and fluid permeability are studied. The results suggest that radially gradient pore distribution (as a potential way to enhance mechanically-efficient scaffolds with enhanced cell/scaffold integration) has higher elastic modulus and fluid permeability compared to their uniform porosity counterparts. Also, the scaffolds are fairly strain-reversible under repeated loading of up to 40% strain. Among different triply periodic minimal surface pore architectures, P-surface was observed to be stiffer, less permeable and have lower densification strain compared to the D-surface and G-surface-based pore shapes. The biocompatibility of the created scaffolds is assessed by filling the PDMS scaffolds using mouse embryonic fibroblasts with cell-laden gelatin methacryloyl which was cross-linked in situ by UV light. Cell viability is found to be over 90% after 4 days in 3D culture. This method allows for effectively fabricating biocompatible porous organ-shaped scaffolds with detailed pore features which can potentially tailor tissue regenerative applications.Statement of SignificancePrinting polymers with chemical curing mechanism required for materials such as PDMS is challenging and impossible to create high-resolution uniformly cured structures due to hard control on the base polymer and curing process. An interconnected porous mold with ordered internal architecture with complex geometries were 3D printed using low-cost and accessible FDM technology. The mold acted as a 3D sacrificial material to form internally architected flexible PDMS scaffolds for tissue engineering applications. The scaffolds are mechanically stable under high strain cyclic loads and provide enough pore and space for viably integrating cells within the gradient architecture in a controllable manner.Graphical abstractGraphical abstract for this article
       
  • The Blood Compatibility Challenge: Editorial introduction
    • Abstract: Publication date: Available online 25 June 2019Source: Acta BiomaterialiaAuthor(s): Michael V. Sefton, Claudia Sperling, Manfred F. Maitz, Carsten Werner
       
  • An Injectable and Tumor-specific Responsive Hydrogel with Tissue-adhesive
           and Nanomedicine-releasing Abilities for Precise Locoregional Chemotherapy
           
    • Abstract: Publication date: Available online 25 June 2019Source: Acta BiomaterialiaAuthor(s): Di Wu, Xiaoguang Shi, Fuli Zhao, Sergio Tomas Fernando Chilengue, Liandong Deng, Anjie Dong, Deling Kong, Weiwei Wang, Jianhua Zhang Locoregional chemotherapy, especially using implantable hydrogel depots to sustainably deliver chemotherapeutics at tumor site, has shown great potential for improving antitumor efficacy and reducing systemic toxicity. However, the hydrogel applications are limited by some intrinsic constraints, especially the contradiction between increasing drug penetration and accumulation in tumor and decreasing random drug diffusion into surrounding normal tissues. Herein, we report a unique “Jekyll and Hyde” nanoparticle-hydrogel (NP-gel) hybrid platform, which can keep dormant in adjacent normal tissues but be activated by mildly acidic and hyaluronidase-rich microenvironment in malignant tumor tissues to unidirectionally release tumor-targeting and penetrative doxorubicin (DOX)-loaded NPs. Apart from tumor-specific recognition, penetration, internalization and release, NP-gel features: shear-thinning behavior for injection, tissue-adhesiveness for continuous on-site activation, and full biodegradability for safe use. Precise delivery was clearly demonstrated in both tumor-grafted and tumor-resected mice. A single peritumoral injection of DOX-loaded NP-gel exhibited a significantly higher drug accumulation in tumor for 3 weeks than in nontarget organs and thus long-term tumor remission. More importantly, significant inhibition in tumor recurrence without detectable toxicity to healthy organs was demonstrated when applied after tumor resection. The designed system displayed long-acting and precise anticancer efficacy, paving the way toward effective tumor locoregional treatment.Statement of SignificanceInjectable hydrogels, allowing sustained drug delivery directly at tumor site, has shown great potential for locoregional chemotherapy. However, how to achieve tumor-specific drug accumulation but meanwhile impede the random drug diffusion into surrounding normal tissues remains an insurmountable challenge, especially considering high drug concentration gradient, higher interstitial fluid pressure and denser extracellular matrix in tumor than adjacent normal tissue. Herein, a ‘Jekyll and Hyde’ nanoparticle-hydrogel hybrid formulation was designed to keep dormant in adjacent normal tissues but be activated by mildly acidic and hyaluronidase-rich microenvironment in malignant tumor tissues to unidirectionally release tumor-targeting and penetrative DOX-loaded nanoparticles, leading to a significant tumor inhibition and antirecurrence efficiency without detectable toxicity to healthy organs, thus presenting great potential for precise locoregional chemotherapy.Graphical abstractGraphical abstract for this article
       
  • Microporous scaffolds support assembly and differentiation of pancreatic
           progenitors into β-cell clusters
    • Abstract: Publication date: Available online 25 June 2019Source: Acta BiomaterialiaAuthor(s): Richard L. Youngblood, Joshua P. Sampson, Kimberly R. Lebioda, Lonnie D. Shea Human pluripotent stem cells (hPSCs) represent a promising cell source for the development of β-cells for use in therapies for type 1 diabetes. Current culture approaches provide signals to mimic a temporal control of organogenesis to drive the differentiation towards β-cells. However, spatial control may represent an opportunity to improve the efficiency and manufacturing of β-cells. Herein, we adapted the current culture systems to microporous biomaterials with the hypothesis that the pores can guide the assembly of pancreatic progenitors into clusters of defined size that can influence maturation. The scaffold culture allowed hPSC-derived pancreatic progenitors to form clusters at a consistent size as cells differentiated. By modulating the scaffold pore sizes, we observed 250–425 µm pore size scaffold cultures augmented insulin expression and key β-cell maturation markers compared to cells cultured in suspension. Furthermore, when compared to suspension cultures, the scaffold culture showed increased insulin secretion in response to glucose stimulus indicating the development of functional β-cells. In addition, scaffolds facilitated cell-cell interactions enabled by the scaffold design and supported cell-mediated matrix deposition of extracellular matrix (ECM) proteins associated with the basement membrane of islet cells. We further investigated the influence of ECM on cell development by incorporating an ECM matrix on the scaffold prior to cell seeding; however, their presence did not further enhance maturation. These results suggest the microporous scaffold culture provides a conducive environment that drives in vitro differentiation of hPSC-derived insulin-producing glucose-responsive β-cells and demonstrates the feasibility of these scaffolds as a biomanufacturing platform.Statement of SignificanceCell therapy for diabetes is a promising strategy, yet generating limitless insulin-producing mature β-cells from human pluripotent stem cells (hPSCs) remains a challenge. Current hPSC differentiation methods involve media containing signals to drive maturation toward β-cells and spontaneous cluster formation. Herein, we sought to provide spatial cues to guide assembly of cells into 3D structures by culture within the pores of a microporous scaffold. The scaffolds direct cell-cell interactions within the pores and provide a support for cell-mediated matrix deposition that collectively creates a niche to promote functional hPSC-derived β-cell clusters. These scaffolds for 3D culture may contribute to hPSC differentiation methods for the generation of β-cells that can treat patients with diabetes.Graphical abstractGraphical abstract for this article
       
  • Acta Biomaterialia Outstanding Reviewers in 2018
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s):
       
  • In vivo study of the efficacy, biosafety, and degradation of a zinc alloy
           osteosynthesis system
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Xiang Wang, Xiaoxi Shao, Taiqiang Dai, Fangfang Xu, Jack G. Zhou, Gongqi Qu, Lei Tian, Bin Liu, Yanpu Liu In this study, a comprehensive analysis of a novel zinc alloy osteosynthesis system in a canine mandibular fracture model is presented. The efficacy of the system was compared for PLLA (poly-l-lactic acid) and titanium materials using X-ray radiography, micro-CT tomography, undecalcified bone histomorphometry, and a three-point bending test. Histology, blood normal, blood biochemical, and serum zinc concentration tests were also performed to assess the biosafety of the zinc alloy osteosynthesis system. The degradability of the zinc alloy was evaluated using a micro-CT and scanning electron microscope during the 24-week post operation period. The results showed that zinc alloy possesses good mechanical properties that support fracture healing. Its uniform and slow corrosion leads to adequate degradation behavior in 24 weeks. Additionally, the zinc alloy proved to be biocompatible, indicating that this novel osteosynthesis system is safe for use in the body. The results of the study demonstrate that this zinc alloy-based osteosynthesis system is a promising candidate for a new generation of osteosynthesis systems, with further improvements required in the future.Graphical abstractGraphical abstract for this article
       
  • Cisplatin-loaded polymeric complex micelles with a modulated
           drug/copolymer ratio for improved in vivo performance
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Qiuyue Chen, Lifeng Luo, Yingyan Xue, Jian Han, Yi Liu, Yu Zhang, Tian Yin, LiHui Wang, Dongmei Cun, Jingxin Gou, Haibing He, Xing Tang This study aimed to evaluate the performance of cisplatin-loaded polymeric micelles (CDDP-PMs) with different drug/copolymer ratios of 1:1, 1:3 and 1:6 (w/w) prepared by coordinated complexation and self-assembly method. The mass ratio influenced the self-assembly behaviors and the complex degree, where both single- and double- complexation existed in CDDP-PMs. With the increase of CDDP/copolymer ratio, the particle size and drug loading increased, while encapsulation efficiency decreased. The PEG density of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 were 0.20, 0.61 and 0.38 PEG/nm2, respectively. CDDP-PM1-3 and CDDP-PM1-6 had similar sustained release behavior, while CDDP-PM1-1 showed burst release. Pharmacokinetics showed the AUC of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 27.2, 76.6 and 13.0 fold higher than CDDP solution. Tissue distribution presented the platinum concentration of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 1.03, 0.80 and 0.48 times of CDDP solution in kidney at 10 min, and 17.61, 28.63 and 16.6 times in tumor at 48 h respectively, indicating CDDP-PMs significantly reduced nephrotoxicity and increased tumor-targeting accumulation. In vivo antitumor test showed that CDDP-PMs exhibited an improved antitumor efficacy and lower systemic toxicity compared with CDDP solution. From CDDP-PM1-1 to CDDP-PM1-6, the toxicity decreased with the increase of copolymer ratio, but the tumor inhibition rate also decreased. CDDP-PM1-3 had relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot. This work provides an effective strategy by modulating drug/copolymer ratio of CDDP-PMs to balance the antitumor efficacy and toxicity for better payoff.Statement of SignificanceCancer chemotherapy always exists a contradiction between antitumor efficacy and toxicity. Higher efficacy against tumor often associated with larger toxicity for normal tissues. This work provides an important strategy by modulating the drug/copolymer ratios to balance the antitumor efficacy and toxicity to obtain better payoff. The cisplatin-loaded polymeric micelles (CDDP-PMs) based on the complexation between CDDP and copolymer with different mass ratios make differences in vitro and in vivo because of the single- or double-complexation degree. Most importantly, we found the balance at CDDP/copolymer ratio of 1:3, which has relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot.Graphical abstractGraphical abstract for this article
       
  • A collagen scaffold loaded with human umbilical cord-derived mesenchymal
           stem cells facilitates endometrial regeneration and restores fertility
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Liaobing Xin, Xiaona Lin, Yibin Pan, Xiaowen Zheng, Libing Shi, Yanling Zhang, Lie Ma, Changyou Gao, Songying Zhang In women of reproductive age, severe injuries to the endometrium are often accompanied by endometrial scar formation or intrauterine adhesions (IUAs), which can result in infertility or miscarriage. Although many approaches have been used to treat severe IUAs, high recurrence rates and endometrial thinning have limited therapeutic efficiency. In this study, a collagen scaffold (CS) loaded with human umbilical cord-derived mesenchymal stem cells (UC-MSCs) was fabricated and applied for endometrial regeneration. The CS/UC-MSCs promoted human endometrial stromal cell proliferation and inhibited apoptosis in vitro through paracrine effects. In a model of endometrial damage, transplantation with the CS/UC-MSCs maintained normal luminal structure, promoted endometrial regeneration and collagen remodeling, induced intrinsic endometrial cell proliferation and epithelium recovery, and enhanced the expression of estrogen receptor α and progesterone receptor. An improved ability of the regenerated endometrium to receive embryos was confirmed. Together, our results indicate that the CS/UC-MSCs promoted endometrial structural reconstruction and functional recovery. Topical administration of the CS/UC-MSCs after trans-cervical resection of adhesions might prevent re-adhesion, promote endometrium regeneration and improve pregnancy outcomes for patients with severe IUAs.Statement of SignificanceIntrauterine adhesions due to severe endometrium injuries happen frequently in clinic and become one of the crucial reasons for women’s infertility or miscarriage. Therefore, how to regenerate the damaged endometrium is a big challenge. In this study, a collagen scaffold (CS) loaded with human umbilical cord-derived mesenchymal stem cells (UC-MSCs) was fabricated and applied for endometrium regeneration. Herein, UC-MSCs, known for low immunogenicity and high proliferative potential, exhibit promising potential for endometrium regeneration; and collagen scaffolds provide suitable physical support. It was proved that transplantation with CS/UC-MSCs promoted endometrial regeneration and fertility restoration. It suggested that topical administration of CS/UC-MSCs in uterus could be a promising strategy for patients suffering severe intrauterine adhesion and infertility.Graphical abstractGraphical abstract for this article
       
  • Nitric oxide-releasing vascular grafts: A therapeutic strategy to promote
           angiogenic activity and endothelium regeneration
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Fatemeh Kabirian, Peiman Brouki Milan, Ali Zamanian, Ruth Heying, Masoud Mozafari Small-diameter vascular grafts (SDVGs) are associated with a high incidence of failure due to infection and obstruction. Although several vascular grafts are commercially available, specific anatomical differences of defect sites require patient-based design and fabrication. Design and fabrication of such custom-tailored grafts are possible with 3d-printing technology. The aim of this study is to develop 3d-printed SDVGs with a nitric oxide (NO)-releasing coating to improve the success rate of implantation. The SDVGs were printed from polylactic acid and coated with blending of 10 wt% S-nitroso-N-acetyl-D-penicillamine into the polymeric substrate consisting of poly (ethylene glycol) and polycaprolactone. Our results show that NO is released in the physiological range (0.5–4 × 10−10 mol·cm−2·min−1) for 14 days and NO-releasing coating showed significant antibacterial potential against Gram-positive and Gram-negative strains. It was shown that both NO-releasing and control grafts are biocompatible in-vitro and in-vivo. Interestingly, the NO-releasing SDVGs dramatically enhanced ECs proliferation and significantly enhanced ECs migration in-vitro compared to control grafts. In addition, the NO-releasing SDVGs showed angiogenic potential in-vivo which can further prove the results of our in-vitro study. These findings are expected to facilitate tissue regeneration and integration of custom-made vascular implants with enhanced clinical success.Statement of significanceA series of 3d-printed small-diameter vascular grafts (SDVGs,
       
  • 4D printing and stimuli-responsive materials in biomedical aspects
    • Abstract: Publication date: 1 July 2019Source: Acta Biomaterialia, Volume 92Author(s): Yuan Siang Lui, Wan Ting Sow, Lay Poh Tan, Yunlong Wu, Yuekun Lai, Huaqiong Li Three-dimensional (3D) printing has revolutionized the world manufacturing production. In biomedical applications, however, 3D printed constructs fell short of expectations mainly due to their inability to adequately mimic the dynamic human tissues. To date, most of the 3D printed biomedical structures are largely static and inanimate as they lack the time-dependant dimension. To adequately address the dynamic healing and regeneration process of human tissues, 4D printing emerges as an important development where “time” is incorporated into the conventional concept of 3D printing as the fourth dimension. As such, additive manufacturing (AM) evolves from 3D to 4D printing and in the process putting stimulus-responsive materials in the limelight. In this review, the state-of-the-art efforts in integrating the time-dependent behaviour of stimulus-responsive materials in 4D printing will be discussed. In addition, current literatures on the interactions between various types of stimuli (categorized under physical, chemical and biological signals) with the associated stimulus-responsive materials will be the major focus in this review. Lastly, potential usage of 4D printing in biomedical applications will also be discussed, followed by technical considerations as well as outlook for future discoveries.Statement of SignificanceIn this Review, we have demonstrated the significance of 4D printing in biomedical applications, in which “time” has been incorporated into the conventional concept of 3D printing as the 4th dimension. As such, 4D printing differentiates and evolves from 3D printing using stimulus-responsive materials which can actively respond to external stimuli and more sophisticated “hardware”-printer which can achieve multi-printing via mathematical-predicted designs that are programmed to consider the transformation of 3D constructs over time. The emphasize will be on the interactions between various types of stimuli (categorized under physical, chemical and biological signals) with the associated stimulus-responsive materials, followed by technical considerations as well as outlook for future discoveries.Graphical abstractGraphical abstract for this article
       
  • Delivery of Bupivacaine from UHMWPE and its implications for managing pain
           after joint arthroplasty
    • Abstract: Publication date: Available online 5 June 2019Source: Acta BiomaterialiaAuthor(s): Scott C. Grindy, Dmitry Gil, Jeremy V. Suhardi, Orhun K. Muratoglu, Hany Bedair, Ebru Oral Total joint replacement is a widely used and successful surgical approach. Approximately 7 million US adults are currently living with a hip or knee replacement. However, the surgical procedures for total joint replacement are associated with significant postoperative pain, and current strategies do not adequately address this pain, which leads to patient dissatisfaction, reduced mobility, and increased risk of opioid addiction. We hypothesized that the ultra-high-molecular-weight polyethylene (UHMWPE)-bearing surfaces used in total joint prosthetics could provide sustained release of the local anesthetic bupivacaine, to provide relief from joint pain for an extended period of time after surgery. In this paper, we describe the production of bupivacaine-loaded UHMWPE (BPE) and measure the in vitro bupivacaine release kinetics of BPE. We found that bupivacaine could be released from BPE at clinically relevant rates for up to several days and that BPE possesses antibacterial effects. Therefore, bupivacaine-loaded UHMWPE is a promising material for joint replacement prostheses, and future studies will evaluate its safety and efficacy in in vivo models.Statement of SignificanceTotal joint replacement is associated with significant pain and risk of infection. In our paper, we introduce bupivacaine-loaded ultra-high molecular weight polyethylene (BPE) which releases bupivacaine, a pain-treating drug, at levels comparable to currently-used doses. Additionally, BPE inhibits growth of infection-causing bacteria. Therefore, BPE may be able to reduce both post-surgical pain and risk of infection, treating two of the most prominent complications associated with total joint replacement. To our knowledge, this is the first development of a material that can address both complications, and devices incorporating BPE would represent a significant advance in joint arthroplasty prosthetics. More generally, the incorporation of therapeutic agents into ultra-high molecular weight polyethylene could impact many orthopedic procedures due its ubiquity.Graphical abstractGraphical abstract for this article
       
  • Formation of Stable Strontium-Rich Amorphous Calcium Phosphate: Possible
           Effects on Bone Mineral
    • Abstract: Publication date: Available online 22 May 2019Source: Acta BiomaterialiaAuthor(s): Camila B. Tovani, Alexandre Gloter, Thierry Azaïs, Mohamed Selmane, Ana P. Ramos, Nadine Nassif Bone, tooth enamel, and dentin accumulate Sr2+, a natural trace element in the human body. Sr2+ comes from dietary and environmental sources and is thought to play a key role in osteoporosis treatments. However, the underlying impacts of Sr2+on bone mineralization remain unclear and the use of synthetic apatites (which are structurally different from bone mineral) and non-physiological conditions have led to contradictory results. Here, we report on the formation of a new Sr2+-rich and stable amorphous calcium phosphate phase, Sr(ACP). Relying on a bioinspired pathway, a series of Sr2+ substituted hydroxyapatite (HA) that combines the major bone mineral features is depicted as model to investigate how this phase forms and Sr2+ affects bone. In addition, by means of a comprehensive investigation the biomineralization pathway of Sr2+ bearing HA is described showing that not more than 10 at% of Sr2+, i.e. the physiological limit incorporated in bone, can be incorporated into HA without phase segregation. A combination of 31P and 1H solid state NMR, energy electron loss spectromicroscopy, transmission electron microscopy, electron diffraction, and Raman spectroscopy shows that Sr2+ introduces disorder in the HA culminating with the unexpected Sr(ACP), which co-exists with the HA under physiological conditions. These results suggest that heterogeneous Sr2+ distribution in bone is associated with regions of low structural organization. Going further, such observations give clues from the physicochemical standpoint to understand the defects in bone formation induced by high Sr2+ doses.Statement of significanceUnderstanding the role played by Sr2+ has a relevant impact in physiological biomineralization and provides insights for its use as osteoporosis treatments. Previous studies inspired by the bone remodelling pathway led to the formation of biomimetic HA in terms of composition, structures and properties in water. Herein, by investigating different atomic percentage of Sr2+ related to Ca2+ in the synthesis, we demonstrate that 10% of Sr2+ is the critical loads into the biomimetic HA phase; percent being the limited amount incorporated into bone. Unexpectedly, using higher amount leads to the formation of a stable Sr2+-rich amorphous calcium phosphate phase that may high-dose related pathologies. Our results provide further understanding of the different ways Sr2+ impacts bone.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Anti-infective efficacy, cytocompatibility and
           biocompatibility of a 3D-printed osteoconductive composite scaffold
           functionalized with quaternized chitosan” [Acta Biomater. 46 (2016)
           112–128]
    • Abstract: Publication date: Available online 21 May 2019Source: Acta BiomaterialiaAuthor(s): Ying Yang, Shengbing Yang, Yugang Wang, Zhifeng Yu, Haiyong Ao, Hongbo Zhang, Ling Qin, Olivier Guillaume, David Eglin, R. Geoff Richards, Tingting Tang
       
  • Targeted delivery of ibrutinib to tumor-associated macrophages by sialic
           acid-stearic acid conjugate modified nanocomplexes for cancer
           immunotherapy
    • Abstract: Publication date: Available online 17 May 2019Source: Acta BiomaterialiaAuthor(s): Qiujun Qiu, Cong Li, Yanzhi Song, Tao Shi, Xiang Luo, Hongxia Zhang, Ling Hu, Xinyang Yan, Huangliang Zheng, Mengyang Liu, Mingqi Liu, Min Liu, Shuaishuai Yang, Xinrong Liu, Guoliang Chen, Yihui Deng Ibrutinib (IBR), an irreversible Bruton’s tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)–stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted immunotherapy. Amphiphilic egg phosphatidylglycerol (EPG) structure and strong IBR-EPG interactions render these nanocomplexes high IBR loading capacity, prolonged blood circulation, and optimal particle sizes (∼30 nm), which can effectively deliver IBR to the tumor, followed by subsequent internalization of IBR by TAMs through SA-mediated active targeting. In vitro and in vivo tests showed that the prepared SA/IBR/EPG nanocomplexes could preferentially accumulate in TAMs and exert potent antitumor activity. Immunofluorescence staining analysis further confirmed that SA/IBR/EPG remarkably inhibited angiogenesis and tumorigenic cytokines released by TAM and eventually suppressed tumor progression, without eliciting any unwanted effect. Thus, SA-decorated IBR nanocomplexes present a promising strategy for cancer immunotherapy.Statement of SignificanceIbrutinib (IBR), an irreversible Bruton’s tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)–stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted delivery of IBR to TAMs. The developed SA/IBR/EPG nanocomplexes exhibited high efficiency in targeting TAMs and inhibiting BTK activation, consequently inhibiting Th2 tumorigenic cytokines release, reducing angiogenesis, and suppressing tumor growth. These results implied that SA/IBR/EPG nanocomplex could be a promising strategy for TAM-targeting immunotherapy with minimal systemic side effects.Graphical abstractGraphical abstract for this article
       
  • 3D printing of hydrogel scaffolds for future application in photothermal
           therapy of breast cancer and tissue repair
    • Abstract: Publication date: Available online 17 May 2019Source: Acta BiomaterialiaAuthor(s): Yongxiang Luo, Xiaoyue Wei, Yilin Wan, Xin Lin, Zhiyong Wang, Peng Huang Surgical removal remains the main clinical approach to treat breast cancer, although risks including high local recurrence of cancer and loss of breast tissues are the threats for the survival and quality of life of patients after surgery. In this study, bifunctional scaffold based on dopamine-modified alginate and polydopamine (PDA) was fabricated using 3D printing with an aim to treat breast cancer and fill the cavity, thereby achieving tissue repair. The as-prepared alginate-polydopamine (Alg-PDA) scaffold exhibited favorable photothermal effect both in vitro and in vivo upon 808 nm laser irradiation. Further, the Alg-PDA scaffold showed great flexibility and similar modulus with normal breast tissues and facilitated the adhesion and proliferation of normal breast epithelial cells. Moreover, the in vivo performance of the Alg-PDA scaffold could be tracked by magnetic resonance and photoacoustic dual-modality imaging. The scaffold that was fabricated using simple and biocompatible materials with individual-designed structure and macropores, as well as outstanding photothermal effect and enhanced cell proliferation ability, might be a potential option for breast cancer treatment and tissue repair after surgery.Statement of SignificanceIn this study, a three-dimensional porous scaffold was developed using 3D printing for the treatment of local recurrence of breast cancer and the following tissue repair after surgery. In this approach, easily available materials (dopamine-modified alginate and PDA) with excellent biocompatibility were selected and prepared as printing inks. The fabricated scaffold showed effective photothermal effects for cancer therapy, as well as matched mechanical properties with breast tissues. Furthermore, the scaffold supported attachment and proliferation of normal breast cells, which indicates its potential ability for adipose tissue repair. Together, the 3D-printed scaffold might be a promising option for the treatment of locally recurrent breast cancer cells and the following tissue repair after surgery.Graphical abstractGraphical abstract for this article
       
  • The degradation and performance of electrospun supramolecular vascular
           scaffolds examined upon in vitro enzymatic exposure
    • Abstract: Publication date: Available online 17 May 2019Source: Acta BiomaterialiaAuthor(s): E.E. van Haaften, R. Duijvelshoff, B.D. Ippel, S.H.M. Söntjens, M.H.C.J. van Houtem, H.M. Janssen, A.I.P.M. Smits, N.A. Kurniawan, P.Y.W. Dankers, C.V.C. Bouten To maintain functionality during in situ vascular regeneration, the rate of implant degradation should be closely balanced by neo-tissue formation. It is unknown, however, how the implant’s functionality is affected by the degradation of the polymers it is composed of. We therefore examined the macro- and microscopic features as well as the mechanical performance of vascular scaffolds upon in vitro enzymatic degradation. Three candidate biomaterials with supramolecularly interacting bis-urea (BU) hard blocks (‘slow-degrading’ polycarbonate-BU (PC-BU), ‘intermediate-degrading’ polycarbonate-ester-BU (PC(e)-BU), and ‘fast-degrading’ polycaprolactone-ester-BU (PCL-BU)) were synthesized and electrospun into microporous scaffolds. These materials possess a sequence-controlled macromolecular structure, so their susceptibility to degradation is tunable by controlling the nature of the polymer backbone. The scaffolds were incubated in lipase and monitored for changes in physical, chemical, and mechanical properties. Remarkably, comparing PC-BU to PC(e)-BU, we observed that small changes in macromolecular structure led to significant differences in degradation kinetics. All three scaffold types degraded via surface erosion, which was accompanied by fiber swelling for PC-BU scaffolds, and some bulk degradation and a collapsing network for PCL-BU scaffolds. For the PC-BU and PC(e)-BU scaffolds this resulted in retention of mechanical properties, whereas for the PCL-BU scaffolds this resulted in stiffening. Our in vitro study demonstrates that vascular scaffolds, electrospun from sequence-controlled supramolecular materials with varying ester contents, not only display different susceptibilities to degradation, but also degrade via different mechanisms.Statement of SignificanceOne of the key elements to successfully engineer vascular tissues in situ, is to balance the rate of implant degradation and neo-tissue formation. Due to their tunable properties, supramolecular polymers can be customized into attractive biomaterials for vascular tissue engineering. Here, we have exploited this tunability and prepared a set of polymers with different susceptibility to degradation. The polymers, which were electrospun into microporous scaffolds, displayed not only different susceptibilities to degradation, but also obeyed different degradation mechanisms. This study illustrates how the class of supramolecular polymers continues to represent a promising group of materials for tissue engineering approaches.Graphical abstractGraphical abstract for this article
       
  • Low-Toxicity Transferrin-Guided Polymersomal Doxorubicin for Potent
           Chemotherapy of Orthotopic Hepatocellular Carcinoma in Vivo
    • Abstract: Publication date: Available online 15 May 2019Source: Acta BiomaterialiaAuthor(s): Yaohua Wei, Xiaolei Gu, Liang Cheng, Fenghua Meng, Gert Storm, Zhiyuan Zhong Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies. The current chemotherapy with typically low tumor uptake and high toxicity reveals a poor anti-HCC efficacy. Here, we report transferrin-guided polycarbonate-based polymersomal doxorubicin (Tf-Ps-Dox) as a low-toxic and potent nanotherapeutic agent for effective treatment of liver tumor using a transferrin receptor (TfR)-positive human liver tumor SMMC-7721 model. Tf-Ps-Dox was facilely fabricated with small size of ca. 75 nm and varying Tf densities from 2.2% to 7.0%, by postmodification of maleimide-functionalized Ps-Dox (Dox loading content of 10.6 wt.%) with thiolated transferrin. MTT assays showed that Tf-Ps-Dox had an optimal Tf surface density of 3.9%. The cellular uptake, intracellular Dox level, and anticancer efficacy of Tf-Ps-Dox to SMMC-7721 cells were inhibited by supplementing free transferrin, which supports that Tf-Ps-Dox is endocytosed through TfR. Interestingly, Tf-Ps-Dox exhibited a high accumulation of 8.5%ID/g (percent injected dose per gram of tissue) in subcutaneous SMMC-7721 tumors, which was 2- and 3-fold higher than that of nontargeted Ps-Dox and clinically used liposomal Dox formulation (Lipo-Dox), respectively. The median survival times of mice bearing orthotopic SMMC-7721 tumors increased from 82, 88 to 96 days when treated with Tf-Ps-Dox at Dox doses from 8, 12 to 16 mg/kg, which was significantly longer than that of Ps-Dox at 8 mg/kg (58 days) and Lipo-Dox at 4 mg/kg (48 days) or PBS (36 days). Notably, unlike Lipo-Dox, no body weight loss and damage to major organs could be discerned for all Tf-Ps-Dox groups, indicating that Tf-Ps-Dox caused low systemic toxicity. This transferrin-dressed polymersomal doxorubicin provides a potent and low-toxic treatment modality for human hepatocellular carcinoma.Statement of SignificanceHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Vast work has focused on developing HCC-targeted nanotherapeutics. However, none of the nanotherapeutics has advanced to clinics, partly because the ligands used have not been validated in patients. Transferrin (Tf) is a natural ligand for transferrin receptor (TfR) that is overexpressed on cancerous cells, and it is currently under clinical trials (MBP-426 and CALAA-01) for the treatment of solid tumors. We designed Tf-functionalized polymersomal doxorubicin (Tf-Ps-Dox) for targeted therapy of orthotopic SMMC-7721 tumor in nude mice. Tf-Ps-Dox showed potent anti-HCC efficacy and significantly improved survival time with low toxicity as compared with nontargeted Ps-Dox and clinical liposomal Dox (Lipo-Dox). Hence, Tf-Ps-Dox is very appealing for targeted treatment of HCC.Graphical abstractGraphical abstract for this article
       
  • Polymer-Integrated Amnion Scaffold Significantly Improves Cleft Palate
           Repair
    • Abstract: Publication date: Available online 15 May 2019Source: Acta BiomaterialiaAuthor(s): Wuwei Li, Yuqian Fu, Bin Jiang, Aaron Y. Lo, Guillermo A. Ameer, Cleon Barnett, Bo Wang Cleft palate is a common oral and craniomaxillofacial birth defect. As the ideal surgery time is shortly after birth, clinical treatments should result in minimal disruption of the skeleton to allow tissue growth in children. A tissue-engineered graft was created in this study for cleft palate repair by integrating poly(1,8-octamethylene-citrate) (POC) with a decellularized amnion membrane (DAM-POC) to incorporate the advantages of both the synthetic polymer and the native tissue. The success of POC incorporation was confirmed by laser-induced breakdown spectroscopy and fluorescence detection. The DAM-POC scaffold showed a certain level of structure collapse and lower stiffness but better resistance to enzyme digestion than the native amnion and DAM scaffold. The DAM-POC scaffold is cell compatible when seeded with mesenchymal stem cells, as evidenced by adequate cell viability and improved alkaline phosphatase (ALP) activity and calcium deposit. A large palate defect was first surgically created in a young rat model and then repaired with the DAM-POC scaffold. Eight weeks postsurgery, histological study and CT scans showed nearly complete healing of both soft and hard tissues. In conclusion, we developed a cell-free, resorbable graft by incorporating and integrating a synthetic polymer with a human DAM. When the DAM-POC scaffold was applied to repair a large palate defect in young rats, it showed adequate biocompatibility as evidenced by its effectiveness in guiding hard and soft tissue regeneration and minimum interference with natural growth and palate development of rats.Statement of SignificanceProper restoration of severe cleft palate remains a major challenge because of insufficient autologous soft tissues to close the open wounds, thereby causing high tension at the surgical junction, secondary palatal fistulas, wound contraction, scar tissue formation, and facial growth disturbances. In this study, we have developed a tissue-engineered graft through incorporating and integrating a synthetic polymer with the human amnion membrane for cleft palate repair. The significance of this study lies in our ability to develop a cell-free, resorbable graft that can provide a less surgically invasive option to cover the open defect and support palate regeneration and tissue growth. This technique could potentially advance soft and hard tissue regeneration in children with birth craniomaxillofacial defects.Graphical abstractGraphical abstract for this article
       
  • Co-administration of combretastatin A4 nanoparticles and sorafenib for
           systemic therapy of hepatocellular carcinoma
    • Abstract: Publication date: Available online 14 May 2019Source: Acta BiomaterialiaAuthor(s): Yalin Wang, Haiyang Yu, Dawei Zhang, Guanyi Wang, Wantong Song, Yingmin Liu, Sheng Ma, Zhaohui Tang, Ziling Liu, Kazuo Sakurai, Xuesi Chen Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). In this study, a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is developed for the cooperative systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs. A significant decrease in tumor volume and prolonged survival time are observed in the combination group of CA4-NPs plus sorafenib compared with CA4-NPs or sorafenib monotherapy in subcutaneous and orthotopic H22 hepatic tumor models. Seventy-one percent of the mice are alive without residual tumor at 96 days post tumor inoculation for the subcutaneous models treated with CA4-NPs 30 or 35 mg·kg-1 plus sorafenib 30 mg·kg-1. Our findings suggest that co-administration of sorafenib and CA4-NPs possesses significant antitumor efficacy for HCC treatment.Statement of significanceEffective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). Herein, we demonstrate that a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is a promising synergistic approach for systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs.Graphical abstractGraphical abstract for this article
       
  • Acta Journals Editors Transitioning to Joint Appointments
    • Abstract: Publication date: Available online 13 May 2019Source: Acta BiomaterialiaAuthor(s):
       
  • Stimulus-Responsive Polymeric Nanogels as Smart Drug Delivery Systems
    • Abstract: Publication date: Available online 13 May 2019Source: Acta BiomaterialiaAuthor(s): Sakineh Hajebi, Navid Rabiee, Mojtaba Bagherzadeh, Sepideh Ahmadi, Mohammad Rabiee, Hossein Roghani-Mamaqani, Mohammadreza Tahriri, Lobat Tayebi, Michael R. Hamblin Nanogels are three-dimensional nanoscale networks formed by physically or chemically cross-linking polymers. Nanogels have been explored as drug delivery systems due to their advantageous properties, such as biocompatibility, high stability, tunable particle size, drug loading capacity, and possible modification of the surface for active targeting by attaching ligands that recognize cognate receptors on the target cells or tissues. Nanogels can be designed to be stimulus responsive, and react to internal or external stimuli such as pH, temperature, light and redox, thus resulting in the controlled release of loaded drugs. This “smart” targeting ability prevents drug accumulation in non-target tissues and minimizes the side effects of the drug. This review aims to provide an introduction to nanogels, their preparation methods,and to discuss the design of various stimulus-responsive nanogels that are able to provide controlled drug release in response to particular stimuli.Statement of significanceSmart and stimulus-responsive drug delivery is a rapidly growing area of biomaterial research. The explosive rise in nanotechnology and nanomedicine, has provided a host of nanoparticles and nanovehicles which may bewilder the uninitiated reader. This review will lay out the evidence that polymeric nanogels have an important role to play in the design of innovative drug delivery vehicles that respond to internal and external stimuli such as temperature, pH, redox, and light.Graphical abstractGraphical abstract for this article
       
  • Superhydrophobic hierarchical fiber/bead composite membranes for efficient
           burns treatment
    • Abstract: Publication date: Available online 13 May 2019Source: Acta BiomaterialiaAuthor(s): Weichang Li, Qianqian Yu, Hang Yao, Yue Zhu, Paul D. Topham, Kan Yue, Li Ren, Linge Wang One of the current challenges in burn wound care is the development of multifunctional dressings that can protect the wound from bacteria or organisms and promote skin regeneration and tissue reconstitution. To this end, we report the design and fabrication of a composite electrospun membrane, comprised of electrospun polylactide : poly(vinyl pyrrolidone)/polylactide : poly(ethylene glycol) (PLA:PVP/PLA:PEG) core/shell fibers loaded with bioactive agents, as a functionally integrated wound dressing for efficient burns treatment. Different mass ratios of PLA:PVP in the shell were screened to optimize mechanical, physicochemical, and biological properties, in addition to controlled release profiles of loaded antimicrobial peptides (AMPs) from the fibers for desirable antibacterial activity. Fibroblasts were shown to readily adhere and proliferate when cultured on the membrane, indicating good in vitro cytocompatibility. The introduction of PLA beads by electrospraying on one side of the membrane resulted in biomimetic micro-nanostructures similar to those of lotus leaves. This designer structure rendered the composite membranes with superhydrophobic property to inhibit the adhesion/spreading of exogenous bacteria and other microbes. The administration of the resulting composite fibrous membrane on burnt skin in an infected rat model led to faster healing than a conventional product (sterile silicone membrane) and control detailed herein. These composite fibrous membranes loaded with bioactive drugs provide an integrated strategy for promoting burn wound healing and skin regeneration.Statement of SignificanceTo address an urgent need in complex clinical requirements on developing a new generation of wound dressings with integrated functionalities. This article reports research work on a hierarchical fiber/bead composite membranes design, which combines a lotus-leaf-like superhydrophobic surface with drugs preloaded in the core and shell of fibers for effective burn treatment. This demonstrates a balance between simplified preparation processes and increased multifunctionality of the wound dressings. The creation of hierarchically structured surfaces can be readily achieved by electrospinning, and the composite dressings possessed a considerable mechanical strength, effective wound exudate absorption and permeability, good biocompatibility, broad antibacterial ability and promoting wound healing etc. Thus, our work unveils a promising strategy for the development of functionally integrated wound dressings for burn wound care.Graphical abstractGraphical abstract for this article
       
  • Graphene oxide containing self-assembling peptide hybrid hydrogels as a
           potential 3D injectable cell delivery platform for intervertebral disc
           repair applications
    • Abstract: Publication date: Available online 12 May 2019Source: Acta BiomaterialiaAuthor(s): Cosimo Ligorio, Mi Zhou, Jacek K. Wychowaniec, Xinyi Zhu, Cian Bartlam, Aline F. Miller, Aravind Vijayaraghavan, Judith A. Hoyland, Alberto Saiani Cell-based therapies have shown significant promise in tissue engineering with one key challenge being the delivery and retention of cells. As a result, significant efforts have been made in the past decade to design injectable biomaterials to host and deliver cells at injury sites. Intervertebral disc (IVD) degeneration, a major cause of back pain, is a particularly relevant example where a minimally-invasive cellular therapy could bring significant benefits specifically at the early stages of the disease, when a cell-driven process starts in the gelatinous core of the IVD, the nucleus pulposus (NP).In this present study we explore the use of graphene oxide (GO) as nano-filler for the reinforcement of FEFKFEFK (β-sheet forming self-assembling peptide) hydrogels. Our results confirm the presence of strong interactions between FEFKFEFK and GO flakes with the peptide coating and forming short thin fibrils on the surface of the flakes. These strong interactions were found to affect the bulk properties of hybrid hydrogels. At pH 4 electrostatic interactions between the peptide fibres and the peptide-coated GO flakes are thought to govern the final bulk properties of the hydrogels while at pH 7, after conditioning with cell culture media, electrostatic interactions are removed leaving the hydrophobic interactions to govern hydrogel final properties. The GO-F820 hybrid hydrogel, with mechanical properties similar to the NP, was shown to promote high cell viability and retained cell metabolic activity in 3D over the 7 days of culture and therefore shown to harbour significant potential as an injectable hydrogel scaffold for the in-vivo delivery of NP cells.Statement of significanceShort self-assembling peptide hydrogels (SAPHs) have attracted significant interest in recent years as they can mimic the natural extra-cellular matrix, holding significant promise for the ab-initio design of cells’ microenvironments. Recently the design of hybrid hydrogels for biomedical applications has been explored through the incorporation of specific nanofillers.In this study we exploited graphene oxide (GO) as nanofiller to design hybrid injectable 3Dscaffolds for the delivery of nucleus pulposus cells (NPCs) for intervertebral disc regeneration. Our work clearly shows the presence of strong interactions between peptide and GO, mimicking the mechanical properties of the NP tissue and promoting high cell viability and metabolic activity. These hybrid hydrogels therefore harbour significant potential as injectable scaffolds for the in-vivo delivery of NPCs.Graphical abstractGraphical abstract for this article
       
  • A Rapid Biofabrication Technique for Self-Assembled Collagen-based
           Multicellular and Heterogeneous 3D Tissue Constructs
    • Abstract: Publication date: Available online 11 May 2019Source: Acta BiomaterialiaAuthor(s): Alireza Shahin-Shamsabadi, P. Ravi Selvaganapathy Although monolayer cell culture models are considered as gold standard for in vitro modeling of pathophysiological events, they cannot reconstruct in vivo like gradient of gases and nutrients and lack proper cell-cell and cell-matrix interactions. Spherical cellular aggregates, otherwise known as multicellular spheroids, are widely used as three-dimensional in vitro models to mimic natural in vivo cellular microenvironment for applications such as drug screening. Although very useful, the previously established techniques are limited to low cell numbers, their processes are usually slow, and sometimes show limitations in terms of the cell type that can be used. Here, a versatile technique based on rapid self-assembly of cells and extracellular matrix material in different shapes using microfabricated molds is introduced to form multicellular tissue constructs. The self-assembly process takes less than 6 hrs and produces a mechanically robust tissue construct that could be handled easily. We demonstrate that a variety of shapes including spherical, cuboidal, dumbbell- and cross-like shapes could be fabricated using this approach. Interestingly, the structures formed with non-spherical shapes were able to retain that shape even after removal from the molds and during long term cell culture. This versatile approach is applicable to a variety of cell types (breast cancer cell lines MCF-7, MDA-MB-321, Hs-578T; osteosarcoma cell line SaOS-2; endothelial cell line HUVEC) as well as a range of cell numbers (104-106). Furthermore, we also show that the constructs could be spatially patterned to position various cell types in a precisely controlled way. Such heterogeneous constructs that are formed provide physiologically relevant cell densities, 3D structure as well as close positioning of multiple types of cells that are not possible using other fabrication approaches. This fabrication approach will find significant applications in developing 3D cell culture models for drug discovery as well as tissue grafts for implantation.Statement of significanceIn this manuscript we describe a method for rapid formation of tissue constructs (6 hrs as opposed to several days for current state of art methods). We also identify the essential factors needed for such a rapid consolidation into a construct. We demonstrate the ability to form non-spherical constructs of various shapes that retain their shape over long term as opposed to those formed with current state of art lose their shape during long time cell culture. We also show the ability to form precise heterogeneous constructs consisting of multiple cell types and with well-defined interfaces that are not possible with current state of art methods. This method could be used with a wide variety of cell types and are mechanically robust within 6 hrs to be handled with tweezers. We believe that such multicellular, heterogeneous constructs would be of significant use to biologists and drug discovery researchers investigating mechanisms involved in diseases processes or the effect of drug on them.Graphical abstractGraphical abstract for this article
       
  • Nonlinear elasticity of the lung extracellular microenvironment is
           regulated by macroscale tissue strain
    • Abstract: Publication date: Available online 11 May 2019Source: Acta BiomaterialiaAuthor(s): Ignasi Jorba, Gabriel Beltrán, Bryan Falcones, Béla Suki, Ramon Farré, José Manuel García-Aznar, Daniel Navajas The extracellular matrix (ECM) of the lung provides physical support and key mechanical signals to pulmonary cells. Although lung ECM is continuously subjected to different stretch levels, detailed mechanics of the ECM at the scale of the cell is poorly understood. Here, we developed a new polydimethylsiloxane (PDMS) chip to probe nonlinear mechanics of tissue samples with atomic force microscopy (AFM). Using this chip, we performed AFM measurements in decellularized rat lung slices at controlled stretch levels. The AFM revealed highly nonlinear ECM elasticity with the microscale stiffness increasing with tissue strain. To correlate micro- and macroscale ECM mechanics, we also assessed macromechanics of decellularized rat lung strips under uniaxial tensile testing. The lung strips exhibited exponential macromechanical behavior but with stiffness values one order of magnitude lower than at the microscale. To interpret the relationship between micro- and macromechanical properties, we carried out a finite element (FE) analysis which revealed that the stiffness of the alveolar cell microenvironment is regulated by the global strain of the lung scaffold. The FE modeling also indicates that the scale dependence of stiffness is mainly due to the porous architecture of the lung parenchyma. We conclude that changes in tissue strain during breathing result in marked changes in the ECM stiffness sensed by alveolar cells providing tissue-specific mechanical signals to the cells.Statement of significanceThe micromechanical properties of the extracellular matrix (ECM) are a major determinant of cell behavior. The ECM is exposed to mechanical stretching in the lung and other organs during physiological function. Therefore, a thorough knowledge of the nonlinear micromechanical properties of the ECM at the length scale that cells probe is required to advance our understanding of cell-matrix interplay. We designed a novel PDMS chip to perform atomic force microscopy measurements of ECM micromechanics on decellularized rat lung slices at different macroscopic strain levels. For the first time, our results reveal that the microscale stiffness of lung ECM markedly increases with macroscopic tissue strain. Therefore, changes in tissue strain during breathing result in variations in ECM stiffness providing tissue-specific mechanical signals to lung cells.Graphical abstractGraphical abstract for this article
       
  • Osteogenic and pH Stimuli-responsive Self-healing Coating on Biomedical
           Mg-1Ca Alloy
    • Abstract: Publication date: Available online 11 May 2019Source: Acta BiomaterialiaAuthor(s): Pan Xiong, Zhaojun Jia, Wenhao Zhou, Jianglong Yan, Pei Wang, Wei Yuan, Yangyang Li, Yan Cheng, Zhenpeng Guan, Yufeng Zheng Various coatings have been used to slow down the corrosion rate of biomedical magnesium alloys. However, these coatings usually act only as passive barriers. It is much more desirable to endow such coatings with active, biocorrosion-responsive self-repairing capacity. In the present work, a self-healing coating system (denoted as “silk-PA”) was constructed in the form of a sandwich architecture of fluoride precoating (bottom), silk-phytic acid (PA) coating (middle), and silk fibroin coating (top). Here, PA was loaded in the middle coating as a corrosion inhibitor by harnessing its strong chelating ability toward dissolving Mg2+ and Ca2+ ions. The self-healing property was evaluated by scratch and SVET tests, and the corrosion resistance was evaluated by in vitro immersion and electrochemical measurements. The results showed that the silk-PA manifested intriguing self-healing capacity with pH responsiveness, hence profiting the corrosion resistance of the Mg-1Ca alloy. The biocompatibility and osteogenic activity of the coating system were further evaluated using MC3T3-E1 cells, and it demonstrated favorable responses in multiple cellular behaviors, i.e., adherence, spreading, proliferation, and differentiation. These findings open new opportunities in the study of self-healing coatings for protection against corrosion in biomedical Mg alloys.Statement of significanceIn the present study, a self-healing coating system with pH stimuli-responsiveness as well as osteogenic activity was fabricated on Mg-1Ca alloy by integrating a silk fibroin barrier coating, a silk fibrin/phytic acid composite coating, and a fluoride pre-coating. This coating system demonstrated interesting self-healing ability in comparison to traditional surface modification layers. Furthermore, self-healing ability enhanced corrosion resistance of biomedical magnesium alloys, while effective compositions of the coating system endowed the substrate with osteogenic activity. This work gives some new insights into smart surface modification for biomedical Mg alloys.Graphical abstractGraphical abstract for this article
       
  • Synchrotron tomography of intervertebral disc deformation quantified by
           digital volume correlation reveals microstructural influence on strain
           patterns
    • Abstract: Publication date: Available online 11 May 2019Source: Acta BiomaterialiaAuthor(s): C.M. Disney, A. Eckersley, J.C. McConnell, H. Geng, A.J. Bodey, J.A Hoyland, P.D. Lee, M.J. Sherratt, B.K. Bay The intervertebral disc (IVD) has a complex and multiscale extracellular matrix structure which provides unique mechanical properties to withstand physiological loading. Low back pain has been linked to degeneration of the disc but reparative treatments are not currently available. Characterising the disc’s 3D microstructure and its response in a physiologically relevant loading environment is required to improve understanding of degeneration and to develop new reparative treatments. In this study, techniques for imaging the native IVD, measuring internal deformation and mapping volumetric strain were applied to an in situ compressed ex vivo rat lumbar spine segment. Synchrotron X-ray micro-tomography (synchrotron CT) was used to resolve IVD structures at microscale resolution. These image data enabled 3D quantification of collagen bundle orientation and measurement of local displacement in the annulus fibrosus between sequential scans using digital volume correlation (DVC). The volumetric strain mapped from synchrotron CT provided a detailed insight into the micromechanics of native IVD tissue. The DVC findings showed that there was no slipping at lamella boundaries, and local strain patterns were of a similar distribution to the previously reported elastic network with some heterogeneous areas and maximum strain direction aligned with bundle orientation, suggesting bundle stretching and sliding. This method has the potential to bridge the gap between measures of macro-mechanical properties and the local 3D micro-mechanical environment experienced by cells. This is the first evaluation of strain at the micro scale level in the intact IVD and provides a quantitative framework for future IVD degeneration mechanics studies and testing of tissue engineered IVD replacements.Statement of SignificanceSynchrotron in-line phase contrast X-ray tomography provided the first visualisation of native intact intervertebral disc microstructural deformation in 3D. For two annulus fibrosus volumes of interest, collagen bundle orientation was quantified and local displacement mapped as strain. Direct evidence of microstructural influence on strain patterns could be seen such as no slipping at lamellae boundaries and maximum strain direction aligned with collagen bundle orientation. Although disc elastic structures were not directly observed, the strain patterns had a similar distribution to the previously reported elastic network. This study presents technical advances and is a basis for future X-ray microscopy, structural quantification and digital volume correlation strain analysis of soft tissue.Graphical abstractGraphical abstract for this article
       
  • Zwitterionic poly-carboxybetaine coating reduces artificial lung
           thrombosis in sheep and rabbits
    • Abstract: Publication date: Available online 10 May 2019Source: Acta BiomaterialiaAuthor(s): Rei Ukita, Kan Wu, Xiaojie Lin, Neil M. Carleton, Noritsugu Naito, Angela Lai, Chi Chi Do-Nguyen, Caitlin T. Demarest, Shaoyi Jiang, Keith E. Cook Current artificial lungs fail in 1-4 weeks due to surface-induced thrombosis. Biomaterial coatings may be applied to anticoagulate artificial surfaces, but none have shown marked long-term effectiveness. Poly-carboxybetaine (pCB) coatings have shown promising results in reducing protein and platelet-fouling in vitro. However, in vivo hemocompatibility remains to be investigated. Thus, three different pCB-grafting approaches to artificial lung surfaces were first investigated: 1) graft-to approach using 3,4-dihydroxyphenylalanine (DOPA) conjugated with pCB (DOPA-pCB); 2) graft-from approach using the Activators ReGenerated by Electron Transfer method of atom transfer radical polymerization (ARGET-ATRP); and 3) graft-to approach using pCB randomly copolymerized with hydrophobic moieties. One device coated with each of these methods and one uncoated device were attached in parallel within a veno-venous sheep extracorporeal circuit with no continuous anticoagulation (N=5 circuits). The DOPA-pCB approach showed the least increase in blood flow resistance and the lowest incidence of device failure over 36-hours. Next, we further investigated the impact of tip-to-tip DOPA-pCB coating in a 4-hour rabbit study with veno-venous micro-artificial lung circuit at a higher activated clotting time of 220-300s (N≥5). Here, DOPA-pCB reduced fibrin formation (p=0.06) and gross thrombus formation by 59% (p
       
  • Biological Properties of ZnO, SiO2, and Ag2O Ternary Dopant Plasma Sprayed
           Hydroxyapatite Coating for Orthopaedic and Dental Applications
    • Abstract: Publication date: Available online 10 May 2019Source: Acta BiomaterialiaAuthor(s): Ashley A. Vu, Samuel Ford Robertson, Dongxu Ke, Amit Bandyopadhyay, Susmita Bose In this study, we explored a ternary dopant system utilizing 0.25 wt.% ZnO to induce osteogenesis, 0.50 wt.% SiO2 to induce angiogenesis, and 2.0 wt.% Ag2O to provide secondary infection control within a plasma assisted hydroxyapatite coating for orthopaedic or dental applications. The objective of this study was to understand the effects of ZnO, SiO2, and Ag2O dopants on the mechanical and biological properties of hydroxyapatite (HA) coatings on titanium (Ti). Coatings were deposited using a 30 kW plasma spray system equipped with a supersonic nozzle to produce above standard coating bond strengths of 24 ± 2 MPa on Ti6Al4V and 22 ± 1 MPa on commercially pure Ti substrates. Antibacterial properties were revealed in vitro against E. coli and S. aureus. The ternary dopant system was implanted in 18 male Sprague-Dawley rats with timepoints of 5 and 10 weeks. By week 5, ZnSiAg-HA produced 32% bone mineralization of 68% total bone formation compared to only 11% bone mineralization of 55% total bone formation in the undoped coating. This system can be employed for younger patient replacement surgeries and revision surgeries to lower healing time and enhance osseointegration.Statement of significanceTotal hip replacements increased 124% from 2000 to 2010 with an ever-increasing rate due to the rise in average life span and an escalation in surgeries for younger age patients. With all replacement surgeries comes the risk of rejection, poor integration, and infection. This study incorporates biologically relevant metallic oxides of ZnO, SiO2, and Ag2O within a hydroxyapatite coating on titanium deposited using a radio frequency induction plasma spray. A ternary dopant system has not been explored in the current literature and little is known about these particular dopants in vivo meaning ‘within a living organism.’ This proposed system can be employed for younger patient replacement surgeries to lower healing time and enhance osseointegration between implant and host tissue.Graphical abstractGraphical abstract for this article
       
  • Starvation-amplified CO generation for enhanced cancer therapy through
           erythrocyte membrane-biomimetic gas nanofactory
    • Abstract: Publication date: Available online 10 May 2019Source: Acta BiomaterialiaAuthor(s): Yuqian Wang, Zhangya Liu, Hao Wang, Zhengjie Meng, Yonglu Wang, Wenjun Miao, Xueming Li, Hao Ren Carbon monoxide (CO)-based gas therapy has emerged as an attractive therapeutic strategy for cancer therapy. However, the main challenges are the in situ-triggered and efficient delivery of CO in tumors, which limit its further clinical application. Herein, we developed an erythrocyte membrane-biomimetic gas nanofactory (MGP@RBC) to amplify the in situ generation of CO for combined energy starvation of cancer cells and gas therapy. This nanofactory was constructed by encapsulating glucose oxidase (GOx) and Mn2(CO)10 (CO-donor) into the biocompatible polymer poly(lactic-co-glycolic acid), obtaining MGP nanoparticles, which are further covered by red blood cell (RBC) membrane. Because of the presence of proteins on RBC membranes, the nanoparticles could effectively avoid immune clearance in macrophages (Raw264.7) and significantly prolong their blood circulation time, thereby achieving higher accumulation at the tumor site. After that, the GOx in GMP@RBC could effectively catalyze the conversion of endogenous glucose to hydrogen peroxide (H2O2) in the presence of oxygen. The concomitant generation of H2O2 could efficiently trigger CO release to cause dysfunction of mitochondria and activate caspase, thereby resulting in apoptosis of the cancer cells. In addition, the depletion of intratumoral glucose could starve tumor cells by shutting down the energy supply. Altogether, the in vitro and in vivo studies of our synthesized biomimetic gas nanofactory exhibited an augmentative synergistic efficacy of CO gas therapy and energy starvation to inhibit tumor growth. It provides an attractive strategy to amplify CO generation for enhanced cancer therapy in an accurate and more efficient manner.Statement of significationCarbon monoxide (CO) based gas therapy has emerged as an attractive therapeutic strategy for cancer therapy. In this study, we developed an erythrocyte membranebiomimetic gas nanofactory to amplify the in-situ generation of CO for combined cancer starvation and gas therapy. It is constructed by coating glucose oxidase (GOx) and CO donor-loaded nanoparticles with erythrocyte membrane. Due to the erythrocyte membrane, it can effectively prolong blood circulation time and achieve higher tumor accumulation. After accumulated in tumor, endogenous glucose can be effectively catalyzed to hydrogen peroxide, in-situ ampfied CO release to induce the apoptosis of cancer cells. In addition, depleting glucose can also starve tumor cells by shutting down the energy supply. Overall, our biomimetic gas nanofactory exhibits an augmentative synergistic efficacy of CO gas therapy and starvation to increased tumor inhibition. It provide a novel strategy to deliver CO in an accurate and more efficient manner, promising for combined cancer therapy in future clinical application.Graphical abstractGraphical abstract for this article
       
  • Substrate Stiffness- and Topography-dependent Differentiation of Annulus
           Fibrosus-derived Stem Cells Is Regulated by Yes-associated Protein (YAP)
    • Abstract: Publication date: Available online 9 May 2019Source: Acta BiomaterialiaAuthor(s): Genglei Chu, Zhangqin Yuan, Caihong Zhu, Pinghui Zhou, Huan Wang, Weidong Zhang, Yan Cai, Xuesong Zhu, Huilin Yang, Bin Li Annulus fibrosus (AF) tissue engineering has attracted increasing attention as a promising therapy for degenerative disc disease (DDD). However, regeneration of AF still faces many challenges due to the tremendous complexity of this tissue and lack of in-depth understanding of the structure-function relationship at cellular level within AF is highly required. In light of the fact that AF is composed of various types of cells and has gradient mechanical, topographical and biochemical features along the radial direction. In this study, we aimed to achieve directed differentiation of AF-derived stem cells (AFSCs) by mimicking the mechanical and topographical features of native AF tissue. AFSCs were cultured on four types of electrospun poly(ether carbonate urethane) urea (PECUU) scaffolds with various stiffness and fiber size (soft, small size; stiff, small size; soft, large size and stiff, large size). The results show that with constant fiber size, the expression level of the outer AF (oAF) phenotypic marker genes in AFSCs increased with the scaffold stiffness, while that of inner AF (iAF) phenotypic marker genes showed an opposite trend. When scaffold stiffness was fixed, the expression of oAF phenotypic marker genes in AFSCs increased with fiber size. While the expression of iAF phenotypic marker genes decreased. Such substrate stiffness- and topography- dependent changes of AFSCs was in accordance with the genetic and biochemical distribution of AF tissue from the inner to outer regions. Further, we found that the Yes-associated protein (YAP) was translocated to the nucleus in AFSCs cultured with increasing stiffness and fiber size of scaffolds, yet it remained mostly phosphorylated and cytosolic in cells on soft scaffolds with small fiber size. Inhibition of YAP down-regulated the expression of tendon/ligament-related genes, whereas expression of the cartilage-related genes was upregulated. The results illustrate that matrix stiffness is a potent regulator of AFSC differentiation. Moreover, we reveal that fiber size of scaffolds induced changes in cell adhesions and determined cell shape, spreading area, and extracellular matrix expression. In all, both mechanical property and topography features of scaffolds regulate AFSC differentiation, possibly through a YAP-dependent mechanotransduction mechanism.Graphical abstractMechanistic hypothesis linking the mechanical and topographical variation to AFSC differentiation via YAP activation. YAP mediates cell differentiation in concern with FAs assembly through integrin to maintain the integrity of actin fiber cytoskeleton. This triggers YAP nuclear shuttling. In the nucleus, YAP helps transcribe the tendon/ligament-related genes encoding for proteins participating in AFSC differentiation.Graphical abstract for this article
       
  • Photodynamic PEG-Coated ROS-Sensitive Prodrug Nanoassemblies for
           Core-Shell Synergistic Chemo-Photodynamic Therapy
    • Abstract: Publication date: Available online 9 May 2019Source: Acta BiomaterialiaAuthor(s): Bingjun Sun, Yao Chen, Han Yu, Chen Wang, Xuanbo Zhang, Hanqing Zhao, Qin Chen, Zhonggui He, Cong Luo, Jin Sun The combination of chemotherapy with photodynamic therapy (PDT) holds promising applications in cancer therapy. However, co-encapsulation of chemotherapeutic agents and photosensitizers (PS) into the conventional nanocarriers suffers from inefficient co-loading and aggregation-caused quenching (ACQ) effect of PS trapped in dense carrier materials. Herein, we report a light-activatable photodynamic PEG-coated prodrug nanoplatform for core-shell synergistic chemo-photodynamic therapy. A novel photodynamic polymer is rationally designed and synthesized by conjugating pyropheophorbide a (PPa) to polyethylene glycol 2000 (PEG2k). PPa is used as the hydrophobic and photodynamic moiety of the amphipathic PPa-PEG2k polymer. Then, a core-shell nanoassembly is prepared, with an inner core of a reactive oxygen species (ROS)-responsive oleate prodrug of paclitaxel (PTX) and an outer layer of PPa-PEG2k. PPa-PEG2k serves for both PEGylation and PDT. Instead of being trapped in the inner core, PPa in the outer PPa-PEG2k layer significantly alleviates the ACQ effect. Under laser irradiation, ROS generated by PPa-PEG2k not only is used for PDT but also synergistically promotes PTX release in combination with the endogenous ROS overproduced in tumor cells. The photodynamic PEG-coated nanoassemblies demonstrated synergistic antitumor activity in vivo. Such a unique nanoplatform, with an inner chemotherapeutic core and an outer photodynamic PEG shell, provides a new strategy for synergistic chemo-photodynamic therapy.Statement of significationThe combination of chemotherapy with photodynamic therapy (PDT) holds promising prospects in cancer therapy. However, it remains a tremendous challenge to effectively co-deliver chemotherapeutic drugs and photosensitizers into tumors. Herein, we construct a photodynamic PEGylation-coated prodrug-nanoplatform for high-efficiency synergistic cancer therapy, which is composed of a light-activatable PPa-PEG2k shell and a ROS-responsive paclitaxel (PTX) prodrug core. The PPa-PEG2k-generated ROS not only was used for synergistic PTX release but also synergistically facilitated tumor cell apoptosis in combination with PTX-initiated chemo-cytotoxicity. The light-activatable nanoassemblies exhibited multiple drug delivery advantages including high co-loading efficiency, self-enhanced PTX release, extended circulation time, favorable biodistribution, and potent synergistic anticancer activity. Our findings provide a new strategy for the rational design of advanced nano-DDS for high-efficiency combinational chemo-photodynamic therapy.Graphical abstractGraphical abstract for this article
       
  • Investigating the passive mechanical behaviour of skeletal muscle fibres:
           Micromechanical experiments and Bayesian hierarchical modelling
    • Abstract: Publication date: Available online 9 May 2019Source: Acta BiomaterialiaAuthor(s): Markus Böl, Rahul Iyer, Johannes Dittmann, Mayra Garcés-Schröder, Andreas Dietzel Characterisation of the skeletal muscle’s passive properties is a challenging task since its structure is dominated by a highly complex and hierarchical arrangement of fibrous components at different scales. The present work focuses on the micromechanical characterisation of skeletal muscle fibres, which consist of myofibrils, by realising three different deformation states, namely, axial tension, axial compression, and transversal compression. To the best of the authors’ knowledge, the present study provides a novel comprehensive data set representing of different deformation states. These data allow for a better understanding of muscle fibre load transfer mechanisms and can be used for meaningful modelling approaches. As the present study shows, axial tension and compression experiments reveal a strong tension-compression asymmetry at fibre level. In comparison to the tissue level, this asymmetric behaviour is more pronounced at the fibre scale, elucidating the load transfer mechanism in muscle tissue and aiding in the development of future modelling strategies. Further, a Bayesian hierarchical modelling approach was used to consider the experimental fluctuations in a parameter identification scheme, leading to more comprehensive parameter distributions that reflect the entire observed experimental uncertainty.Statement of significanceThis article examines for the first time the mechanical properties of skeletal muscle fibres under axial tension, axial compression, and transversal compression, leading to a highly comprehensive data set. Moreover, a Bayesian hierarchical modelling concept is presented to identify model parameters in a broad way. The results of the deformation states allow a new and comprehensive understanding of muscle fibres’ load transfer mechanisms; one example is the effect of tension-compression asymmetry. On the one hand, the results of this study contribute to the understanding of muscle mechanics and thus to the muscle’s functional understanding during daily activity. On the other hand, they are relevant in the fields of skeletal muscle multiscale, constitutive modelling.Graphical abstractGraphical abstract for this article
       
  • Transplantation of human meningioma stem cells loaded on a self-assembling
           peptide nanoscaffold containing IKVAV improves traumatic brain injury in
           rats
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Sajad Sahab Negah, Pardis Oliazadeh, Ali Jahanbazi Jahan-Abad, Arezou Eshaghabadi, Fariborz Samini, Sepideh Ghasemi, Amir Asghari, Ali Gorji Traumatic brain injury (TBI) can result in permanent brain function impairment due to the poor regenerative ability of neural tissue. Tissue engineering has appeared as a promising approach to promote nerve regeneration and to ameliorate brain damage. The present study was designed to investigate the effect of transplantation of the human meningioma stem-like cells (hMgSCs) seeded in a promising three-dimensional scaffold (RADA4GGSIKVAV; R-GSIK) on the functional recovery of the brain and neuroinflammatory responses following TBI in rats. After induction of TBI, hMgSCs seeded in R-GSIK was transplanted within the injury site and its effect was compared to several control groups. Application of hMgSCs with R-GSIK improved functional recovery after TBI. A significant higher number of hMgSCs was observed in the brain when transplanted with R-GSIK scaffold compared to the control groups. Application of hMgSCs seeded in R-GSIK significantly decreased the lesion volume, reactive gliosis, and apoptosis at the injury site. Furthermore, treatment with hMgSCs seeded in R-GSIK significantly inhibited the expression of Toll-like receptor 4 and its downstream signaling molecules, including interleukin-1β and tumor necrosis factor. These data revealed the potential for hMgSCs seeded in R-GSIK to improve the functional recovery of the brain after TBI; possibly via amelioration of inflammatory responses.Statement of significanceTissue engineered scaffolds that mimic the natural extracellular matrix of the brain may modulate stem cell fate and contribute to tissue repair following traumatic brain injury (TBI). Among several scaffolds, self-assembly peptide nanofiber scaffolds markedly promotes cellular behaviors, including cell survival and differentiation. We developed a novel three-dimensional scaffold (RADA16GGSIKVAV; R-GSIK). Transplantation of the human meningioma stem-like cells seeded in R-GSIK in an animal model of TBI significantly improved brain functional recovery, possibly via enhancement of stem cell survival as well as reduction of the lesion volume, inflammatory process, and reactive gliosis at the injury site. R-GSIK is a suitable microenvironment for human stem cells and could be a potential biomaterial for the reconstruction of the injured brain after TBI.Graphical abstractGraphical abstract for this article
       
  • Mechanical behavior of ctenoid scales: joint-like structures control the
           deformability of the scales in the flatfish Solea solea
           (Pleuronectiformes)
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Marlene Spinner, Clemens F. Schaber, Shao-Min Chen, Marco Geiger, Stanislav N. Gorb, Hamed Rajabi Ctenoid scales protect the fish body against predators and other environmental impacts. At the same time, they allow for sufficient degree of flexibility to perform species-specific locomotion. The scales of the flatfish Solea solea were chosen to elucidate the specific mechanical behavior and material properties of the ctenoid scales. Using scanning electron microscopy and micro-computed tomography, the three-dimensional asymmetric structures of the stacked mineralized ctenial spines in the posterior field, which is a part of the scales exposed to the environment, were examined in detail. Nanoindentations on the surface of the ctenial spines indicated that the elastic modulus and hardness of these mineralized structures are about 14 GPa and 0.4 GPa, respectively. The spines appeared to be connected to each other by means of joint-like structures containing soft tissues. Bending tests demonstrated that the ctenoid scales have two functional zones: a stiff supporting main body and an anisotropically deformable posterior field. While the stiff plate-like main body provides support for the whole scale, the deformable joint-like structures in the ctenial spines increase the deformability of the posterior field in downward bending. During upward bending, however, the spines prevent complete folding of the posterior field by an interlocking effect.Statement of significanceIn contrast to the continuously mineralized cycloid scales, ctenoid scales combine two conflicting properties: They are hard to protect the body of fish against predators and other environmental impacts, yet flexible enough to allow for sufficient degree of body bendability for locomotion. To understand the structural background underlying this specific biomechanical feature, here we investigated the scales of the flatfish Solea solea. For the first time, we demonstrated the presence of joint-like structures within the scales, which increase scale deformability during downward bending, but prevent scale deformation during upward bending by interlocking. Our results shed lights on the material-structure-function relationships in ctenoid scales, as well as on their functional adaptations to the specific environment.Graphical abstractGraphical abstract for this article
       
  • The Construction of Retinal Pigment Epithelium (RPE) Sheets with Enhanced
           RPE Characteristics and Cilium Assembly Using iPS Conditioned Medium and
           Small Incision Lenticule Extraction Derived Lenticules
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Jianing Gu, Yini Wang, Zekai Cui, Hong Li, Shenyang Li, Xu Yang, Xin Yan, Chengcheng Ding, Shibo Tang, Jiansu Chen In vitro generation of a functional retinal pigment epithelium (RPE) monolayer sheet is useful and promising for RPE cell therapy. Here, for the first time, we used induced pluripotent stem (iPS) supernatant as the conditioned medium (iPS-CM) and femtosecond laser intrastromal lenticule (FLI-lenticule) as a scaffold to construct an engineered RPE sheet. There are significant enhancements in RPE cell density, transepithelial electrical resistance (TER) and inhibitions of ultraviolet C (UVC)-irradiated apoptosis when RPE cells are cultured in iPS supernatant/Dulbecco’s modified Eagle’s medium (DMEM)-F12 of 1/2 (iPS-CM) compared with those in normal medium (NM, DMEM-F12). Using the assay of a panel of cytokines, combined with transcriptome and protein analyses, we discover that iPS-CM contains high levels of platelet-derived growth factor AA (PDGF-AA), insulin-like growth factor binding protein (IGFBP)-2, transforming growth factor (TGF)-α and IGFBP-6, which are responsible for the upregulation of gene and protein markers with RPE phenotypes and downregulation of gene and protein markers with epithelial-mesenchymal transition (EMT) phenotypes for RPE cells in iPS-CM when compared to those in NM. Moreover, compared to cultures on tissue culture plates (TCP), RPE cells on FLI-lenticule display more microvilli and cilium in accordance with the results in terms of RNA-Seq data, quantitative polymerase chain reaction (qPCR) expression, immunofluorescence staining, and western blot assays. Furthermore, acellular FLI-lenticule exhibits biocompatibility after rabbit subretinal implantation by 30 days through electroretinography and histological examination. Thus, we determined that engineered RPE sheets treated by iPS-CM in conjunction with FLI-lenticule scaffold aid in enhanced RPE characteristics and cilium assembly. Such a strategy to construct RPE sheets is a promising avenue for developing RPE cell therapy, disease models and drug screening tools.Statement of SignificanceIn vitro generation of a functional RPE monolayer sheet is useful and promising for RPE cell therapy. Here, we constructed engineered RPE sheets treated by iPS-CM in conjunction with FLI-lenticule scaffolds to help in enhanced RPE characteristics and cilium assembly. Such a strategy to generate RPE sheets is a promising avenue for developing RPE cell therapy, disease models and drug screening tools.Graphical abstractGraphical abstract for this article
       
  • Engineered Heart Tissue Models from hiPSC-Derived Cardiomyocytes and
           Cardiac ECM for Disease Modeling and Drug Testing Applications
    • Abstract: Publication date: Available online 7 May 2019Source: Acta BiomaterialiaAuthor(s): Idit Goldfracht, Yael Efraim, Rami Shinnawi, Ekaterina Kovalev, Irit Huber, Amira Gepstein, Gil Arbel, Naim Shaheen, Malte Tiburcy, Wolfram H. Zimmerman, Marcelle Machluf, Lior Gepstein Cardiac tissue engineering provides unique opportunities for cardiovascular disease modeling, drug testing, and regenerative medicine applications. To recapitulate human heart tissue, we combined human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a chitosan-enhanced extracellular-matrix (ECM) hydrogel, derived from decellularized pig hearts. Ultrastructural characterization of the ECM-derived engineered heart tissues (ECM-EHTs) revealed an anisotropic muscle structure, with embedded cardiomyocytes showing more mature properties than 2D-cultured hiPSC-CMs. Force measurements confirmed typical force-length relationships, sensitivity to extracellular calcium, and adequate ionotropic responses to contractility modulators. By combining genetically-encoded calcium and voltage indicators with laser-confocal microscopy and optical mapping, the electrophysiological and calcium-handling properties of the ECM-EHTs could be studied at the cellular and tissue resolutions. This allowed to detect drug-induced changes in contraction rate (isoproterenol, carbamylcholine), optical signal morphology (E-4031, ATX2, isoproterenol, ouabin and quinidine), cellular arrhythmogenicity (E-4031 and ouabin) and alterations in tissue conduction properties (lidocaine, carbenoxolone and quinidine). Similar assays in ECM-EHTs derived from patient-specific hiPSC-CMs recapitulated the abnormal phenotype of the long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. Finally, programmed electrical stimulation and drug-induced pro-arrhythmia led to the development of reentrant arrhythmias in the ECM-EHTs.In conclusion, a novel ECM-EHT model was established, which can be subjected to high-resolution long-term serial functional phenotyping, with important implications for cardiac disease modeling, drug testing and precision medicine.Statement of SignificanceOne of the main objectives of cardiac tissue engineering is to create an in-vitro muscle tissue surrogate of human heart tissue. To this end, we combined a chitosan-enforced cardiac-specific ECM hydrogel derived from decellularized pig hearts with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from healthy-controls and patients with inherited cardiac disorders. We then utilized genetically-encoded calcium and voltage fluorescent indicators coupled with unique optical imaging techniques and force-measurements to study the functional properties of the generated engineered heart tissues (EHTs). These studies demonstrate the unique potential of the new model for physiological/pathophysiological studies (assessing contractility, conduction and reentrant arrhythmias), novel disease modeling strategies (“disease-in-a-dish” approach for studying inherited arrhythmogenic disorders), and for drug testing applications (safety pharmacology).Graphical abstractGraphical abstract for this article
       
 
 
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