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Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 20)
Achievements in the Life Sciences     Open Access   (Followers: 4)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 23)
Acta Biologica Colombiana     Open Access   (Followers: 7)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 25)
Acta Biotheoretica     Hybrid Journal   (Followers: 5)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales : The Journal of Silesian Museum in Opava     Open Access  
Acta Neurobiologiae Experimentalis     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 9)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Studies in Biology     Open Access  
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Bioinformatics     Open Access   (Followers: 19)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 6)
Advances in Cell Biology     Open Access   (Followers: 24)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Ecological Research     Full-text available via subscription   (Followers: 45)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 1)
Advances in Life Science and Technology     Open Access   (Followers: 14)
Advances in Life Sciences     Open Access   (Followers: 5)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
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: 1)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 6)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 1)
Ageing Research Reviews     Hybrid Journal   (Followers: 8)
Aging Cell     Open Access   (Followers: 11)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
Al-Kauniyah : Jurnal Biologi     Open Access  
Alasbimn Journal     Open Access   (Followers: 1)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Biology Teacher     Full-text available via subscription   (Followers: 13)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 10)
American Journal of Bioethics     Hybrid Journal   (Followers: 10)
American Journal of Biostatistics     Open Access   (Followers: 9)
American Journal of Human Biology     Hybrid Journal   (Followers: 12)
American Journal of Medical and Biological Research     Open Access   (Followers: 7)
American Journal of Plant Sciences     Open Access   (Followers: 19)
American Journal of Primatology     Hybrid Journal   (Followers: 15)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 73)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 10)
Anatomical Science International     Hybrid Journal   (Followers: 2)
Animal Cells and Systems     Hybrid Journal   (Followers: 4)
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 UMCS, Biologia     Open Access   (Followers: 1)
Annals of Applied Biology     Hybrid Journal   (Followers: 7)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Human Biology     Hybrid Journal   (Followers: 4)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 17)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 25)
Annual Review of Cancer Biology     Full-text available via subscription   (Followers: 1)
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: 16)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 20)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 10)
Anthropological Review     Open Access   (Followers: 24)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antibiotics     Open Access   (Followers: 9)
Antioxidants     Open Access   (Followers: 4)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 8)
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: 8)
Applied Bionics and Biomechanics     Open Access   (Followers: 8)
Applied Vegetation Science     Full-text available via subscription   (Followers: 9)
Aquaculture Environment Interactions     Open Access   (Followers: 2)
Aquaculture International     Hybrid Journal   (Followers: 22)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 6)
Aquatic Biology     Open Access   (Followers: 5)
Aquatic Ecology     Hybrid Journal   (Followers: 32)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 14)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 20)
Archaea     Open Access   (Followers: 3)
Archiv für Molluskenkunde: International Journal of Malacology     Full-text available via subscription   (Followers: 3)
Archives of Biomedical Sciences     Open Access   (Followers: 7)
Archives of Microbiology     Hybrid Journal   (Followers: 8)
Archives of Natural History     Hybrid Journal   (Followers: 8)
Archives of Oral Biology     Hybrid Journal   (Followers: 2)
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: 2)
Artificial Photosynthesis     Open Access   (Followers: 1)
Asian Bioethics Review     Full-text available via subscription   (Followers: 2)
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: 6)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 2)
Asian Journal of Nematology     Open Access   (Followers: 3)
Asian Journal of Poultry Science     Open Access   (Followers: 4)
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 6)
Autophagy     Hybrid Journal   (Followers: 2)
Avian Biology Research     Full-text available via subscription   (Followers: 5)
Avian Conservation and Ecology     Open Access   (Followers: 13)
Bacteriology Journal     Open Access   (Followers: 2)
Bacteriophage     Full-text available via subscription   (Followers: 4)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Plant Taxonomy     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 2)
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  
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
Biochemistry and Cell Biology     Hybrid Journal   (Followers: 14)
Biochimie     Hybrid Journal   (Followers: 7)
BioControl     Hybrid Journal   (Followers: 5)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 5)
Biodemography and Social Biology     Hybrid Journal   (Followers: 1)
BioDiscovery     Open Access   (Followers: 2)
Biodiversity : Research and Conservation     Open Access   (Followers: 28)
Biodiversity and Natural History     Open Access   (Followers: 6)
Biodiversity Data Journal     Open Access   (Followers: 3)
Biodiversity Informatics     Open Access   (Followers: 1)
Biodiversity Information Science and Standards     Open Access  
Bioedukasi : Jurnal Pendidikan Biologi FKIP UM Metro     Open Access  
Bioeksperimen : Jurnal Penelitian Biologi     Open Access  
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 1)
Bioenergy Research     Hybrid Journal   (Followers: 2)
Bioengineering and Bioscience     Open Access   (Followers: 1)
BioEssays     Hybrid Journal   (Followers: 10)
Bioethics     Hybrid Journal   (Followers: 14)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 3)
Biogeosciences (BG)     Open Access   (Followers: 10)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 1)
Bioinformatics     Hybrid Journal   (Followers: 274)
Bioinformatics and Biology Insights     Open Access   (Followers: 15)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 7)
Biointerphases     Open Access   (Followers: 1)
Biojournal of Science and Technology     Open Access  
Biologia     Hybrid Journal  
Biologia on-line : Revista de divulgació de la Facultat de Biologia     Open Access  
Biological Bulletin     Partially Free   (Followers: 5)
Biological Control     Hybrid Journal   (Followers: 4)
Biological Invasions     Hybrid Journal   (Followers: 17)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 16)
Biological Letters     Open Access   (Followers: 4)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 43)
Biological Psychology     Hybrid Journal   (Followers: 6)
Biological Research     Open Access  
Biological Rhythm Research     Hybrid Journal   (Followers: 2)
Biological Theory     Hybrid Journal   (Followers: 2)
Biological Trace Element Research     Hybrid Journal  
Biologicals     Full-text available via subscription   (Followers: 9)
Biologics: Targets & Therapy     Open Access   (Followers: 1)
Biologie Aujourd'hui     Full-text available via subscription  
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42)
Biologija     Open Access  
Biology     Open Access   (Followers: 5)
Biology and Philosophy     Hybrid Journal   (Followers: 17)
Biology Bulletin     Hybrid Journal   (Followers: 1)
Biology Bulletin Reviews     Hybrid Journal  
Biology Direct     Open Access   (Followers: 7)
Biology Letters     Full-text available via subscription   (Followers: 36)

        1 2 3 4 5 6 7 8 | Last

Journal Cover Acta Biomaterialia
  [SJR: 2.02]   [H-I: 104]   [25 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7061
   Published by Elsevier Homepage  [3089 journals]
  • Biomaterials for articular cartilage tissue engineering: Learning from
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): A.R. Armiento, M.J. Stoddart, M. Alini, D. Eglin
      Articular cartilage is commonly described as a tissue that is made of up to 80% water, is devoid of blood vessels, nerves, and lymphatics, and is populated by only one cell type, the chondrocyte. At first glance, an easy tissue for clinicians to repair and for scientists to reproduce in a laboratory. Yet, chondral and osteochondral defects currently remain an open challenge in orthopedics and tissue engineering of the musculoskeletal system, without considering osteoarthritis. Why do we fail in repairing and regenerating articular cartilage? Behind its simple and homogenous appearance, articular cartilage hides a heterogeneous composition, a high level of organisation and specific biomechanical properties that, taken together, make articular cartilage a unique material that we are not yet able to repair or reproduce with high fidelity. This review highlights the available therapies for cartilage repair and retraces the research on different biomaterials developed for tissue engineering strategies. Their potential to recreate the structure, including composition and organisation, as well as the function of articular cartilage, intended as cell microenvironment and mechanically competent replacement, is described. A perspective of the limitations of the current research is given in the light of the emerging technologies supporting tissue engineering of articular cartilage. Statement of Significance The mechanical properties of articular tissue reflect its functionally organised composition and the recreation of its structure challenges the success of in vitro and in vivo reproduction of the native cartilage. Tissue engineering and biomaterials science have revolutionised the way scientists approach the challenge of articular cartilage repair and regeneration by introducing the concept of the interdisciplinary approach. The clinical translation of the current approaches are not yet fully successful, but promising results are expected from the emerging and developing new generation technologies.
      Graphical abstract image

      PubDate: 2017-12-12T15:12:08Z
  • Native and synthetic scaffolds for limbal epithelial stem cell
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Kim N. Nguyen, Samantha Bobba, Alexander Richardson, Mijeong Park, Stephanie L. Watson, Denis Wakefield, Nick Di Girolamo
      Limbal stem cell deficiency (LSCD) is a complex blinding disease of the cornea, which cannot be treated with conventional corneal transplants. Instead, a stem cell (SC) graft is required to replenish the limbal epithelial stem cell (LESC) reservoir, which is ultimately responsible for regenerating the corneal epithelium. Current therapies utilize limbal tissue biopsies that harbor LESCs as well as tissue culture expanded cells. Typically, this tissue is placed on a scaffold that supports the formation of corneal epithelial cell sheets, which are then transferred to diseased eyes. A wide range of biological and synthetic materials have been identified as carrier substrates for LESC, some of which have been used in the clinic, including amniotic membrane, fibrin, and silicon hydrogel contact lenses, each with their own advantages and limitations. This review will provide a brief background of LSCD, focusing on bio-scaffolds that have been utilized in limbal stem cell transplantation (LSCT) and materials that are being developed as potentially novel therapeutics for patients with this disease. Statement of Significance The outcome of patients with corneal blindness that receive stem cell grafts to restore eye health and correct vision varies considerably and may be due to the different biological and synthetic scaffolds used to deliver these cells to the ocular surface. This review will highlight the positive attributes and limitations of the myriad of carriers developed for clinical use as well as those that are being trialled in pre-clinical models. The overall focus is on developing a standardized therapy for patients, however due to the multiple causes of corneal blindness, a personal regenerative medicine approach may be the best option.
      Graphical abstract image

      PubDate: 2017-12-12T15:12:08Z
  • Effect of stem cell niche elasticity/ECM protein on the self-beating
           cardiomyocyte differentiation of induced pluripotent stem (iPS) cells at
           different stages
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Mitsuhi Hirata, Tetsuji Yamaoka
      Stem cell-based myocardial regeneration therapies have emerged as alternative strategies to heart transplantation for serious heart diseases, but autologous beating mature cardiomyocytes are not available. Here we investigated the effect of culture substrates on the cardiomyocyte differentiation of induced pluripotent stem cells (iPSs) in vitro by separately evaluating the following continuous three steps: (1) cardiac marker gene expression, (2) contractile gene expression and self-beating, and (3) beating duration. To this end, we used iPS cells to study the cardiac differentiation, and neonatal rat cardiomyocytes (NCMs) to study beating behavior. These cells were cultured on substrates with different natures, i.e., an elastic substrate (Es) with the modulus of 9, 20, or 180 kPa, and hard tissue culture polystyrene dishes (TCPS) coated with collagen type I (Col), gelatin (Gel), or fibronectin (FN). The results revealed that the effective niches in each step were very different. The cardiac marker gene (GATA4, Tbx5, MEF2C) expression of iPSs at the 1st step was very high on the TCPS coated with FN or Gel, whereas on the FN-coated Es (especially with the 9 kPa modulus), the undifferentiated marker gene (Nanog) expression of iPSs was maintained. The expression of the contractile genes α-MHC, TnC1, and TnT2 and the self-beating (the 2nd step) of the NCMs were high on FN-coated TCPS and Col-coated Es. The 3rd step (beating duration) of the NCMs was effective on the Es, and at 21 days both the iPSs and NCMs stopped beating on the TCPS but were still beating on the Es. Overall, cardiac differentiation ‘preferred’ ECM-rigid culture substrates, and beating-behavior ‘preferred’ Col-soft culture substrates. These results are important for understanding and designing cardiac differentiation niches for regenerative medicine, and they suggest that a single culture substrate is not suitable for preparing self-beating cardiomyocytes. Statement of Significance The transplantation of beating cardiomyocytes (BCMs) is expected to be made more effective for serious heart diseases. The identification of the appropriate engineering processes and suitable culture substrates for inducing stem cell differentiation into BCMs is thus indispensable. The differentiation can be divided into three major processes, the cardiac differentiation step, the beating-induction step and the beating-duration step. A protocol with the higher efficiency in all of the steps must be useful. In this study, we separately evaluated the effect of culture substrates at each three step. We clarified that the biological and the physical properties of the culture substrates required at these steps were different. We found useful criteria for effective cardiac cell niche systems design.
      Graphical abstract image

      PubDate: 2017-12-12T15:12:08Z
  • Synthesis and evaluation of dual crosslinked alginate microbeads
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Sami I. Somo, Kelly Langert, Chin-Yu Yang, Marcella K. Vaicik, Veronica Ibarra, Alyssa A. Appel, Banu Akar, Ming-Huei Cheng, Eric M. Brey
      Alginate hydrogels have been investigated for a broad variety of medical applications. The ability to assemble hydrogels at neutral pH and mild temperatures makes alginate a popular choice for the encapsulation and delivery of cells and proteins. Alginate has been studied extensively for the delivery of islets as a treatment for type 1 diabetes. However, poor stability of the encapsulation systems after implantation remains a challenge. In this paper, alginate was modified with 2-aminoethyl methacrylate hydrochloride (AEMA) to introduce groups that can be photoactivated to generate covalent bonds. This enabled formation of dual crosslinked structure upon exposure to ultraviolet light following initial ionic crosslinking into bead structures. The degree of methacrylation was varied and in vitro stability, long term swelling, and cell viability examined. At low levels of the methacrylation, the beads could be formed by first ionic crosslinks followed by exposure to ultraviolet light to generate covalent bonds. The methacrylated alginate resulted in more stable beads and cells were viable following encapsulation. Alginate microbeads, ionic (unmodified) and dual crosslinked, were implanted into a rat omentum pouch model. Implantation was performed with a local injection of 100 µl of 50 µg/ml of Lipopolysaccharide (LPS) to stimulate a robust inflammatory challenge in vivo. Implants were retrieved at 1 and 3 weeks for analysis. The unmodified alginate microbeads had all failed by week 1, whereas the dual-crosslinked alginate microbeads remained stable up through 3 weeks. The modified alginate microbeads may provide a more stable alternative to current alginate-based systems for cell encapsulation. Statement of Significance Alginate, a naturally occurring polysaccharide, has been used for cell encapsulation to prevent graft rejection of cell transplants for people with type I diabetes. Although some success has been observed in clinical trials, the lack of reproducibility and failure to reach insulin dependence for longer periods of time indicates the need for improvements in the procedure. A major requirement for the long-term function of alginate encapsulated cells is the mechanical stability of microcapsules. Insufficient mechanical integrity of the capsules can lead to immunological reactions in the recipients. In this work, alginate was modified to allow photoactivatable groups in order to allow formation of covalent crosslinks in addition to ionic crosslinking. The dual crosslinking design prevents capsule breakdown following implantation in vivo.
      Graphical abstract image

      PubDate: 2017-12-12T15:12:08Z
  • Enhancing immunogenicity of antigens through sustained intradermal
           delivery using chitosan microneedles with a patch-dissolvable design
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Mei-Chin Chen, Kuan-Ying Lai, Ming-Hung Ling, Chun-Wei Lin
      Reducing the dosage required for vaccination is highly desirable, particularly in cases of epidemic emergencies. This study evaluated the potential of a chitosan microneedle (MN) system with a patch-dissolvable design for low-dose immunization. This system comprises antigen-loaded chitosan MNs and a hydrophilic polyvinyl alcohol/polyvinyl pyrrolidone supporting array patch, which provides extra strength to achieve complete MN insertion and then quickly dissolves in the skin to reduce patch-induced skin irritation. After insertion, MNs could be directly implanted in the dermal layer as an intradermal (ID) depot to allow a sustained release of the model antigen ovalbumin (OVA) for up to 28 days. We found that rats immunized with MNs containing low-dose OVA (approximately 200 μg) had persistently high antibody levels for 18 weeks, which were significantly higher than those observed after an intramuscular injection of full-dose OVA (approximately 500 μg), demonstrating at least 2.5-fold dose sparing. Moreover, OVA-encapsulated chitosan MNs had superior immunogenicity to OVA plus chitosan solution, indicating that MN-based delivery and prolonged skin exposure can further enhance chitosan’s adjuvanticity. Therefore, this patch-dissolvable MN system offers a needle-free, accurate, and reliable ID delivery of antigens and has potential as a sustained ID delivery device to improve vaccine efficacy and facilitate dose sparing with existing vaccines. Statement of Significance This study developed implantable chitosan microneedles (MNs) with a patch-dissolvable design for the sustained intradermal (ID) delivery of antigens and demonstrated their antigen dose-sparing potential. We found that rats immunized with chitosan MNs containing low-dose OVA had persistently high antibody levels for 18 weeks, which were significantly higher than those observed after an intramuscular injection of full-dose OVA, demonstrating at least 2.5-fold dose sparing. Our results indicate that chitosan MNs can not only serve as an efficient vaccine delivery system but also exert their promising adjuvant activity by forming an ID depot for prolonged antigen exposure and activating dendritic cells for promoting immune responses.
      Graphical abstract image

      PubDate: 2017-12-12T15:12:08Z
  • Fabrication of dense anisotropic collagen scaffolds using biaxial
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Jared L. Zitnay, Shawn P. Reese, Garvin Tran, Niloofar Farhang, Robert D. Bowles, Jeffrey A. Weiss
      We developed a new method to manufacture dense, aligned, and porous collagen scaffolds using biaxial plastic compression of type I collagen gels. Using a novel compression apparatus that constricts like an iris diaphragm, low density collagen gels were compressed to yield a permanently densified, highly aligned collagen material. Micro-porosity scaffolds were created using hydrophilic elastomer porogens that can be selectively removed following biaxial compression, with porosity modulated by using different porogen concentrations. The resulting scaffolds exhibit collagen densities that are similar to native connective tissues (∼10% collagen by weight), pronounced collagen alignment across multiple length scales, and an interconnected network of pores, making them highly relevant for use in tissue culture, the study of physiologically relevant cell-matrix interactions, and tissue engineering applications. The scaffolds exhibited highly anisotropic material behavior, with the modulus of the scaffolds in the fiber direction over 100 times greater than the modulus in the transverse direction. Adipose-derived mesenchymal stem cells were seeded onto the biaxially compressed scaffolds with minimal cell death over seven days of culture, along with cell proliferation and migration into the pore spaces. This fabrication method provides new capabilities to manufacture structurally and mechanically relevant cytocompatible scaffolds that will enable more physiologically relevant cell culture studies. Further improvement of manufacturing techniques has the potential to produce engineered scaffolds for direct replacement of dense connective tissues such as meniscus and annulus fibrosus. Statement of Significance In vitro studies of cell-matrix interactions and the engineering of replacement materials for collagenous connective tissues require biocompatible scaffolds that replicate the high collagen density (15–25%/wt), aligned fibrillar organization, and anisotropic mechanical properties of native tissues. However, methods for creating scaffolds with these characteristics are currently lacking. We developed a new apparatus and method to create high density, aligned, and porous collagen scaffolds using a biaxial compression with porogens technique. These scaffolds have a highly directional structure and mechanical properties, with the tensile strength and modulus up to 100 times greater in the direction of alignment. We also demonstrated that the scaffolds are a suitable material for cell culture, promoting cell adhesion, viability, and an aligned cell morphology comparable to the cell morphology observed in native aligned tissues.
      Graphical abstract image

      PubDate: 2017-12-12T15:12:08Z
  • Selecting the correct cellular model for assessing of the biological
           response of collagen-based biomaterials
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Natalia Davidenko, Samir Hamaia, Daniel V. Bax, Jean-Daniel Malcor, Carlos F. Schuster, Donald Gullberg, Richard W. Farndale, Serena M. Best, Ruth E. Cameron
      Accurate evaluation of the biological performance of biomaterials requires the correct assessment of their native-like cell ligation properties. However, cell attachment studies often overlook the details of the substrate-cell binding mechanisms, be they integrin-mediated or non-specific, and ignore the class- and species-specificities of the cell adhesion receptor involved. In this work we have used different collagen (Col) substrates (fibrillar collagens I, II and III and network-forming Col IV), containing different affinity cell-recognition motifs, to establish the influence of the receptor identity and species-specificity on collagen-cell interactive properties. Receptor expression was varied by using cells of different origin, or transfecting collagen-binding integrins into integrin-null cells. These include mouse C2C12 myoblasts transfected with human α1, α2, α10 or α11; human fibrosarcoma HT1080 cells which constitutively express only human α2β1, and rat glioma Rugli cells, with only rat α1β1. Using these lines, the nature of integrin binding sites was studied in order to delineate the bioactivity of different collagen substrates. Integrin ligation was studied on collagen coatings alongside synthetic (GFOGER/GLOGEN) and Toolkit (Col II-28/Col III-7) triple-helical peptides to evaluate (1) their affinity towards different integrins and (2) to confirm the activity of the inserted integrin in the transfected cells. Thin films of dermal and tendon Col I were used to evaluate the influence of the carbodiimide (EDC)-based treatment on the cellular response on Col of different origin. The results showed that the binding properties of transfected C2C12 cells to collagens depend on the identity of inserted integrin. Similar ligation characteristics were observed using α1+ and α10+ cells, but these were distinct from the similar binding features of α2+ and α11+ cells. Recombinant human and rat-α1 I domain binding to collagens and peptides correlated with the cell adhesion results, showing receptor class- and species-specificities. The understanding of the physiologically relevant cell anchorage characteristics of bio-constructs may assist in the selection of (1) the optimum collagen source for cellular supports and (2) the correct cellular model for their biological assessment. This, in turn, may allow reliable prediction of the biological performance of bio-scaffolds in vivo for specific TE applications. Statement of Significance Integrins play a vital role in cellular responses to environmental cues during early-stage cell-substrate interaction. We describe physiologically relevant cell anchorage to collagen substrates that present different affinity cell-recognition motifs, to provide experimental tools to assist in understanding integrin binding. Using different cell types and recombinant integrin α1-I-domains, we found that cellular response was highly dependent on collagen type, origin and EDC-crosslinking status, as well as on the integrin class and species of origin. This comprehensive study establishes selectivity amongst the four collagen-binding integrins and species-specific properties that together may influence choice of cell type and receptor in different experimental settings. This work offers key guidance in selecting of the correct cellular model for the biological testing of collagen-based biomaterials.
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      PubDate: 2017-12-12T15:12:08Z
  • A low friction, biphasic and boundary lubricating hydrogel for cartilage
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Piers E. Milner, Maria Parkes, Jennifer L. Puetzer, Robert Chapman, Molly M. Stevens, Philippa Cann, Jonathan R.T. Jeffers
      Partial joint repair is a surgical procedure where an artificial material is used to replace localised chondral damage. These artificial bearing surfaces must articulate against cartilage, but current materials do not replicate both the biphasic and boundary lubrication mechanisms of cartilage. A research challenge therefore exists to provide a material that mimics both boundary and biphasic lubrication mechanisms of cartilage. In this work a polymeric network of a biomimetic boundary lubricant, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), was incorporated into an ultra-tough double network (DN) biphasic (water phase + polymer phase) gel, to form a PMPC triple network (PMPC TN) hydrogel with boundary and biphasic lubrication capability. The presence of this third network of MPC was confirmed using ATR-FTIR. The PMPC TN hydrogel had a yield stress of 26 MPa, which is an order of magnitude higher than the peak stresses found in the native human knee. A preliminary pin on plate tribology study was performed where both the DN and PMPC TN hydrogels experienced a reduction in friction with increasing sliding speed which is consistent with biphasic lubrication. In the physiological sliding speed range, the PMPC TN hydrogel halved the friction compared to the DN hydrogel indicating the boundary lubricating PMPC network was working. A biocompatible, tough, strong and chondral lubrication imitating PMPC TN hydrogel was synthesised in this work. By complementing the biphasic and boundary lubrication mechanisms of cartilage, PMPC TN hydrogel could reduce the reported incidence of chondral damage opposite partial joint repair implants, and therefore increase the clinical efficacy of partial joint repair. Statement of Significance This paper presents the synthesis, characterisation and preliminary tribological testing of a new biomaterial that aims to recreate the primary chondral lubrication mechanisms: boundary and biphasic lubrication. This work has demonstrated that the introduction of an established zwitterionic, biomimetic boundary lubricant can improve the frictional properties of an ultra-tough hydrogel. This new biomaterial, when used as a partial joint replacement bearing material, may help avoid damage to the opposing chondral surface—which has been reported as an issue for other non-biomimetic partial joint replacement materials. Alongside the synthesis of a novel biomaterial focused on complementing the lubrication mechanisms of cartilage, your readership will gain insights into effective mechanical and tribological testing methods and materials characterisation methods for their own biomaterials.
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      PubDate: 2017-12-12T15:12:08Z
  • Gelatin promotes rapid restoration of the blood brain barrier after acute
           brain injury
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Lucas S. Kumosa, Valdemar Zetterberg, Jens Schouenborg
      Gelatin coating of brain implants is known to provide considerable benefits in terms of reduced inflammatory sequalae and long-term neuroprotective effects. However, the mechanisms for gelatin’s protective role in brain injury are still unknown. To address this question, cellular and molecular markers were studied with quantitative immunohistochemical microscopy at acute (<2hours, 1, 3days), intermediate (1–2 weeks) and long-term time points (6 weeks) after transient insertion of stainless steel needles into female rat cortex cerebri with or without gelatin coating. Compared to non-coated controls, injuries caused by gelatin coated needles showed a significantly faster resolution of post-stab bleeding/leakage and differential effects on different groups of microglia cells. While similar levels of matrix metalloproteinase (MMP-2 and MMP-9, two gelatinases) was found for coated and noncoated needle stabs during the first week, markedly increased levels of both MMPs was seen for gelatin-coated but not non-coated needle stabs after 2weeks. Neuronal populations and activated astrocytes were largely unaffected. In conclusion, the beneficial effects of gelatin may be the combined results of faster healing of the blood brain barrier curtailing leakage of blood borne molecules/cells into brain parenchyma and to a modulation of the microglial population response favoring restitution of the injured tissue. These findings present an important therapeutic potential for gelatin coatings in various disease, injury and surgical conditions. Statement of Significance The neural interfaces field holds great promise to enable elucidation of neural information processing and to develop new implantable devices for stimulation based therapy. Currently, this field is struggling to find solutions for reducing tissue reactions to implanted micro and nanotechnology. Prior studies have recently shown that gelatin coatings lower activation of digestive microglia and mitigate the ubiquitous loss of neurons adjacent to implanted probes, both of which impede implant function. The underlying mechanisms remain to be elucidated, however. Our findings demonstrate for the first time that gelatin has a significant effect on the BBB by promoting rapid restoration of integrity after injury. Moreover, gelatin alters microglia phenotypes and modulates gelatinase activity for up to 2weeks favoring anti-inflammation and restoration of the tissue. Given the key importance of the BBB for normal brain functions, we believe our findings have substantial significance and will be highly interesting to researchers in the biomaterial field.
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      PubDate: 2017-12-12T15:12:08Z
  • A PEGylated platelet free plasma hydrogel based composite scaffold enables
           stable vascularization and targeted cell delivery for volumetric muscle
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Amit Aurora, Nicole Wrice, Thomas J. Walters, Robert J. Christy, Shanmugasundaram Natesan
      Extracellular matrix (ECM) scaffolds are being used for the clinical repair of soft tissue injuries. Although improved functional outcomes have been reported, ECM scaffolds show limited tissue specific remodeling response with concomitant deposition of fibrotic tissue. One plausible explanation is the regression of blood vessels which may be limiting the diffusion of oxygen and nutrients across the scaffold. Herein we develop a composite scaffold as a vasculo-inductive platform by integrating PEGylated platelet free plasma (PFP) hydrogel with a muscle derived ECM scaffold (m-ECM). In vitro, adipose derived stem cells (ASCs) seeded onto the composite scaffold differentiated into two distinct morphologies, a tubular network in the hydrogel, and elongated structures along the m-ECM scaffold. The composite scaffold showed a high expression of ITGA5, ITGB1, and FN and a synergistic up-regulation of ang1 and tie-2 transcripts. The in vitro ability of the composite scaffold to provide extracellular milieu for cell adhesion and molecular cues to support vessel formation was investigated in a rodent volumetric muscle loss (VML) model. The composite scaffold delivered with ASCs supported robust and stable vascularization. Additionally, the composite scaffold supported increased localization of ASCs in the defect demonstrating its ability for localized cell delivery. Interestingly, ASCs were observed homing in the injured muscle and around the perivascular space possibly to stabilize the host vasculature. In conclusion, the composite scaffold delivered with ASCs presents a promising approach for scaffold vascularization. The versatile nature of the composite scaffold also makes it easily adaptable for the repair of soft tissue injuries. Statement of Significance Decellularized extracellular matrix (ECM) scaffolds when used for soft tissue repair is often accompanied by deposition of fibrotic tissue possibly due to limited scaffold vascularization, which limits the diffusion of oxygen and nutrients across the scaffold. Although a variety of scaffold vascularization strategies has been investigated, their limitations preclude rapid clinical translation. In this study we have developed a composite scaffold by integrating bi-functional polyethylene glycol modified platelet free plasma (PEGylated PFP) with adipose derived stem cells (ASCs) along with a muscle derived ECM scaffold (m-ECM). The composite scaffold provides a vasculo-inductive and an effective cell delivery platform for volumetric muscle loss.
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      PubDate: 2017-12-12T15:12:08Z
  • A cyclo-trimer of acetonitrile combining fluorescent property with ability
           to induce osteogenesis and its potential as multifunctional biomaterial
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Xujie Liu, Yong Xie, Rui Liu, Ranran Zhang, Hao Yan, Xing Yang, Qianli Huang, Wei He, Bo Yu, Qingling Feng, Shengli Mi, Qiang Cai
      A biomaterial combining fluorescent property with ability to induce osteogenesis can serve as an ideal multifunctional scaffold in bone tissue engineering. However, the frequently used fluorescent agents can only serve as imaging probes. The polymer or oligomer with a conjugated system containing nitrogen atoms will fulfill these criteria. In this study, a cyclo-trimer of acetonitrile is synthesized using a facile method, which is proved to be 4-amino-2,6-dimethylpyrimidine. The cyclo-trimer of acetonitrile demonstrates strong intrinsic photoluminescence and has the potential for in vivo imaging. The cyclo-trimer of acetonitrile shows no toxicity both in vitro and in vivo. Moreover, the cyclo-trimer of acetonitrile significantly promotes the osteogenesis of SaOS-2 cells by improving alkaline phosphatase activity, collagen type I and osteocalcin expression, as well as expressions of osteoblastic genes, and enhances the matrix mineralization of rBMSCs. Thus, the cyclo-trimer of acetonitrile synthesized in present study illustrates the employment of this kind multifunctional biomaterial in bone tissue engineering and may offer great potential in biomedical applications where bioimaging and osteogenesis are both required. Statement of significance A conjugated cyclo-trimer of acetonitrile combining intrinsic fluorescent property with ability to induce osteogenesis was reported. Different from the traditional fluorescent dye or quantum dots, which are just “imaging agents”, the cyclo-trimer of acetonitrile can serve as a multifunctional biomaterial and offer great potential in biomedical applications where bioimaging and osteogenesis are both required. To our best knowledge, the fluorescent property, especially fluorescent property in vivo and the ability of this molecule to induce osteogenesis have not been reported before. Our work illustrates the employment of this kind multifunctional biomaterial in bone tissue engineering and will highlight the importance of multifunctional biomaterial in biomedical applications.
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      PubDate: 2017-12-12T15:12:08Z
  • Three-dimensional fabrication of thick and densely populated soft
           constructs with complex and actively perfused channel network
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Rodrigo Pimentel C., Suk Kyu Ko, Claudia Caviglia, Anders Wolff, Jenny Emnéus, Stephan Sylvest Keller, Martin Dufva
      One of the fundamental steps needed to design functional tissues and, ultimately organs is the ability to fabricate thick and densely populated tissue constructs with controlled vasculature and microenvironment. To date, bioprinting methods have been employed to manufacture tissue constructs with open vasculature in a square-lattice geometry, where the majority lacks the ability to be directly perfused. Moreover, it appears to be difficult to fabricate vascular tissue constructs targeting the stiffness of soft tissues such as the liver. Here we present a method for the fabrication of thick (e.g. 1 cm) and densely populated (e.g. 10 million cells·mL−1) tissue constructs with a three-dimensional (3D) four arm branch network and stiffness in the range of soft tissues (1–10 kPa), which can be directly perfused on a fluidic platform for long time periods (>14 days). Specifically, we co-print a 3D four-arm branch using water-soluble Poly(vinyl alcohol) (PVA) as main material and Poly(lactic acid) (PLA) as the support structure. The PLA support structure was selectively removed, and the water soluble PVA structure was used for creating a 3D vascular network within a customized extracellular matrix (ECM) targeting the stiffness of the liver and with encapsulated hepatocellular carcinoma (HepG2) cells. These constructs were directly perfused with medium inducing the proliferation of HepG2 cells and the formation of spheroids. The highest spheroid density was obtained with perfusion, but overall the tissue construct displayed two distinct zones, one of rapid proliferation and one with almost no cell division and high cell death. The created model, therefore, simulate gradients in tissues of necrotic regions in tumors. This versatile method could represent a fundamental step in the fabrication of large functional and complex tissues and finally organs. Statement of Significance Vascularization within hydrogels with mechanical properties in the range of soft tissues remains a challenge. To date, bioprinting have been employed to manufacture tissue constructs with open vasculature in a square-lattice geometry that are most of the time not perfused. This study shows the creation of densely populated tissue constructs with a 3D four arm branch network and stiffness in the range of soft tissues, which can be directly perfused. The cells encapsulated within the construct showed proliferation as a function of the vasculature distance, and the control of the micro-environment induced the encapsulated cells to aggregate in spheroids in specific positions. This method could be used for modeling tumors and for fabricating more complex and densely populated tissue constructs with translational potential.
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      PubDate: 2017-12-12T15:12:08Z
  • Enhanced oxygen permeability in membrane-bottomed concave microwells for
           the formation of pancreatic islet spheroids
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): GeonHui Lee, Yesl Jun, HeeYeong Jang, Junghyo Yoon, JaeSeo Lee, MinHyung Hong, Seok Chung, Dong-Hwee Kim, SangHoon Lee
      Oxygen availability is a critical factor in regulating cell viability that ultimately contributes to the normal morphogenesis and functionality of human tissues. Among various cell culture platforms, construction of 3D multicellular spheroids based on microwell arrays has been extensively applied to reconstitute in vitro human tissue models due to its precise control of tissue culture conditions as well as simple fabrication processes. However, an adequate supply of oxygen into the spheroidal cellular aggregation still remains one of the main challenges to producing healthy in vitro spheroidal tissue models. Here, we present a novel design for controlling the oxygen distribution in concave microwell arrays. We show that oxygen permeability into the microwell is tightly regulated by varying the poly-dimethylsiloxane (PDMS) bottom thickness of the concave microwells. Moreover, we validate the enhanced performance of the engineered microwell arrays by culturing non-proliferated primary rat pancreatic islet spheroids on varying bottom thickness from 10 μm to 1050 μm. Morphological and functional analyses performed on the pancreatic islet spheroids grown for 14 days prove the long-term stability, enhanced viability, and increased hormone secretion under the sufficient oxygen delivery conditions. We expect our results could provide knowledge on oxygen distribution in 3-dimensional spheroidal cell structures and critical design concept for tissue engineering applications. Statement of Significance In this study, we present a noble design to control the oxygen distribution in concave microwell arrays for the formation of highly functional pancreatic islet spheroids by engineering the bottom of the microwells. Our new platform significantly enhanced oxygen permeability that turned out to improve cell viability and spheroidal functionality compared to the conventional thick-bottomed 3-D culture system. Therefore, we believe that this could be a promising medical biotechnology platform to further develop high-throughput tissue screening system as well as in vivo-mimicking customised 3-D tissue culture systems.
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      PubDate: 2017-12-12T15:12:08Z
  • Injectable iodine-125 labeled tissue marker for radioactive localization
           of non-palpable breast lesions
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Henrik Schaarup-Jensen, Andreas Ingemann Jensen, Anders Elias Hansen, Henrik H. El Ali, Peter Hammershøj, Rasmus Irming Jølck, Andreas Kjær, Thomas L. Andresen, Mads H. Clausen
      We have developed a 125I-radiolabeled injectable fiducial tissue marker with the potential to replace current methods used for surgical guidance of non-palpable breast tumors. Methods in routine clinical use today such as radioactive seed localization, radio-guided occult lesion localization and wire-guided localization suffers from limitations that this injectable fiducial tissue marker offers solutions to. The developed 125I-radiolabeled injectable fiducial tissue marker is based on highly viscous sucrose acetate isobutyrate. The marker was readily inserted in NMRI mice and proved to be spatially well-defined and stable over a seven day period with excellent CT contrast (>1500 HU), enabling fluoroscopic visualization of the marker during placement. The radioactivity remains strongly associated with the marker during the implantation period, which limits exposure to healthy tissue. Biodistribution studies show that there is negligible radioactivity in all non-tumor tissues sampled, with the exception of the thyroid gland, where limited accumulation was observed (0.06% of injected dose after 7 days). Based on the excellent performance of the marker and the fact that it can be delivered through thin hypodermic needles (≥27G), the marker holds great promise for clinical application, since patient discomfort is reduced significantly compared to current methods. Statement of Significance A new type of tissue marker for local administration to non-palpable breast tumors has been developed. The surgical guidance marker is based on derivatives of the biomaterial sucrose acetate isobutyrate and unlike currently used markers it is injectable in the tissue using thin needles, reducing the discomfort to the patients significantly. The marker confers CT contrast and has radioactive properties, meaning it also could find use in brachytherapy. The design of the iodine-125 labeled fiducial tissue marker enables control of dosimetry as well as a choice of iodine isotope used. The marker is anticipated to be clinical applicable due to its contrast performance in mice and its potential for enhanced flexibility in surgical procedures, compared to current methods.
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      PubDate: 2017-12-12T15:12:08Z
  • Water effects on the deformation and fracture behaviors of the
           multi-scaled cellular fibrous bamboo
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Guowei Chen, Hongyun Luo, Haoyu Yang, Tao Zhang, Sijie Li
      Natural bamboo with different water weight contents (0%, 6% and 22%) had distinguishingly different mechanical properties, where samples with water contents of 22% had tensile strength and elongations increased by ∼30% and ∼200% than the dry (0%), respectively. The deformation and fracture process was synchronously recorded and analyzed with the aid of the acoustic emission (AE), during which there were three kinds of real time fracture behaviors recognized: matrix (multi-walled parenchyma cells) failure, interfacial (fiber/fiber or fiber/parenchyma cell walls) dissociations and fiber breakage. More interfacial dissociations and higher fracture energy were detected as more water was added, since water molecules can make great differences on the bamboo’s inner micro-structures and the mechanical properties. During the fracture process of the wet bamboo detected by AE, matrix failure and interfacial dissociations contributed most of the elongation, and the strength were mainly depended on the fiber breakage and interfacial dissociations. The discovered structural toughening mechanisms within the multi-scaled structures were microfiber bridging, multi-walled fiber pull-out, micro warts buckling and crack deflection. The micro-structural toughening effects were strengthened by the cellulose-hemicellulose-lignin complexes and a certain content of water molecules within the multi-scaled fibrous cellular structures, which are collaboratively working and ensuring the high mechanical performance of the natural bamboo. Statement of Significance The mechanical behaviors during the whole fracture process of bamboo were investigated by acoustic emission (AE). During the fracture process there were three kinds of fracture behaviors recognized by AE: matrix (parenchyma cells) failure, interfacial (fiber/fiber or fiber/parenchyma cell walls) dissociations and fiber breakage. The mechanical performance was greatly influenced by water contents (0%, 6% and 22%). Wet bamboos had higher fracture energy than the dry ones. There was more interfacial dissociation behaviors detected as more water was absorbed within the multi-scaled structures. The micro structural toughening mechanisms were strengthened by the macromolecular complexes and water molecules, which are working together and ensuring the excellent mechanical properties of the natural bamboo.
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      PubDate: 2017-12-12T15:12:08Z
  • The mechanical fingerprint of murine excisional wounds
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Marco Pensalfini, Eric Haertel, Raoul Hopf, Mateusz Wietecha, Sabine Werner, Edoardo Mazza
      A multiscale mechanics approach to the characterization of murine excisional wounds subjected to uniaxial tensile loading is presented. Local strain analysis at a physiological level of tension uncovers the presence of two distinct regions within the wound: i) a very compliant peripheral cushion and ii) a core area undergoing modest deformation. Microstructural visualizations of stretched wound specimens show negligible engagement of the collagen located in the center of a 7-day old wound; fibers remain coiled despite the applied tension, confirming the existence of a mechanically isolated wound core. The compliant cushion located at the wound periphery appears to protect the newly-formed tissue from excessive deformation during the phase of new tissue formation. The early remodeling phase (day 14) is characterized by a restored mechanical connection between far field and wound center. The latter remains less deformable, a characteristic possibly required for cell activities during tissue remodeling. The distribution of fibrillary collagens at these two time points corresponds well to the identified heterogeneity of mechanical properties of the wound region. This novel approach provides new insight into the mechanical properties of wounded skin and will be applicable to the analysis of compound-treated wounds or wounds in genetically modified tissue. Statement of Significance Biophysical characterization of healing wounds is crucial to assess the recovery of the skin barrier function and the associated mechanobiological processes. For the first time, we performed highly resolved local deformation analysis to identify mechanical characteristics of the wound and its periphery. Our results reveal the presence of a compliant cushion surrounding a stiffer wound core; we refer to this heterogeneous mechanical behavior as “mechanical fingerprint” of the wound. The mechanical response is shown to progress towards that of the intact skin as healing takes place. Histology and multiphoton microscopy suggest that wounded skin recovers its mechanical function via progressive reconnection of the newly-deposited collagen fibers with the surrounding intact matrix.
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      PubDate: 2017-12-12T15:12:08Z
  • Transmural capillary ingrowth is essential for confluent vascular graft
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Timothy Pennel, Deon Bezuidenhout, Josepha Koehne, Neil H. Davies, Peter Zilla
      Spontaneous endothelialization of synthetic vascular grafts may occur via three independent or concurrent modalities: transanastomotic (TA) outgrowth, transmural (TM) ingrowth or fallout (FO) from the blood. The limited TA and FO endothelialization, which occurs in humans, results in poor long-term patency in the small diameter position, where TM ingrowth may offer a clinically relevant alternative. To achieve sequential analysis of each mode of healing, loop grafts comprising anastomotically isolated angiopermissive polyurethane control grafts were abluminally sealed using either ePTFE wraps or solid polyurethane skins and implanted in the rat infrarenal aortic loop model for twelve weeks. Positive control grafts showed improved endothelialization and patency compared to the abluminally isolated mid-grafts. Furthermore, the mid-graft healing was accelerated with surface heparin and heparin-growth factor (VEGF, PDGF) modification in a three-week sub-study. We are thus able to distinguish between the three vascular graft endothelialization modes, and conclude that fallout plays a secondary role to TM healing. The increased endothelialisation for growth factor presenting grafts indicates the promise of this simple approach but further optimization is required. Statement of Significance In addition to the full elucidation of, and differentiation between, the three healing/endothelialisation modes of vascular grafts, the significance of the work relates to the near-complete lack of endothelialisation of small diameter vascular grafts in humans (1–2 cm transanastomotic outgrowth on a graft that may be 60 cm long) even after decades of implantation. The concomitant retained midgraft thrombogenicity leads, together with anastomotic hyperplastic responses, to poor long-term outcomes. The large impact of successful translation of the current research to the achievement of full endothelialisation of long peripheral grafts in humans via transmural ingrowth (half a millimetre distance; thickness of the graft wall), is evident, and supported by the large improvements in clinical patencies achievable in by pre-seeding of ePTFE grafts with confluent endothelia.
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      PubDate: 2017-12-12T15:12:08Z
  • Tissue processing techniques for fabrication of covered stents for
           small-diameter vascular intervention
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Shahar Cohen, Smadar Magal, Itay Yakov, Evyatar Sirabella, Anna Bitman, Gabriel Groisman, Chaim Lotan
      Animal-derived pericardial tissue is a widely used biomaterial typically treated with glutaraldehyde (GA) to achieve immunological acceptance and long-term durability. However, GA fixation of biological tissue is associated with long-term failure due to degeneration and calcification. In this study, we evaluated two alternative tissue processing methods for the fabrication of pericardial tissue covered stents: detergent-based decellularization (decell) and limited exposure to GA (gentle-glut). Processed pericardial tissues were extensively characterized both in-vitro and in-vivo. Small-diameter covered stents were fabricated and the ability to seal perforation was evaluated in a flow circuit under physiological blood flow conditions. Results indicate that decell-treated tissue appeared with preserved architecture, tissue strength and stability. Gentle-glut tissue appeared with preserved architecture and increased tissue stability, compared to fresh, unprocessed tissue. Reduction of bioburden was demonstrated for both types of alternative treatments, as for GA fixation. Tensile testing demonstrated that both decell- and gentle-glut treated tissues respond better to low strain, as may occur during balloon inflation and stent deployment. Upon subcutaneous implantation in mice, gentle-glut and to a greater degree decell-treated tissue, elicit better host response, with evidence of active tissue remodeling and no detectable calcification, as compared with GA-treated tissue. Small-diameter stents covered with tissues from all groups successfully sealed perforation under physiological blood flow conditions in-vitro, without compromising flow. In summary, covered stents may perform better with pericardial tissue processed according to the methods described in this study. Adopting this methodology to other types of cardiovascular implants and tissues is also suggested. Statement of Significance Pericardial tissue is a widely used biomaterial for cardiovascular implants, such as covered stents. The use of glutaraldehyde (GA) has become the method of choice for pericardial tissue fixation, making it immunologically acceptable in humans. However, GA-treated tissue is prone to several problems, such as degeneration and calcification that may lead to long-term failure. Here, we studied two alternative tissue processing techniques: fixative-free decellularization and limited exposure to GA. We've shown that both methods achieve better mechanical properties and promote better host acceptance, tissue remodeling and long-term durability. Since the availability of autologous tissue for transplantation is limited, these methods should be adopted for other types of cardiovascular devices, such as bioprosthetic valves, ultimately achieving better long-term results for patients.
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      PubDate: 2017-12-12T15:12:08Z
  • Monomer sequence in PLGA microparticles: Effects on acidic microclimates
           and in vivo inflammatory response
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Michael A. Washington, Stephen C. Balmert, Morgan V. Fedorchak, Steven R. Little, Simon C. Watkins, Tara Y. Meyer
      Controlling the backbone architecture of poly(lactic-co-glycolic acid)s (PLGAs) is demonstrated to have a strong influence on the production and release of acidic degradation by-products in microparticle matrices. Previous efforts for controlling the internal and external accumulation of acidity for PLGA microparticles have focused on the addition of excipients including neutralization and anti-inflammatory agents. In this report, we utilize a sequence-control strategy to tailor the microstructure of PLGA. The internal acidic microclimate distributions within sequence-defined and random PLGA microparticles were monitored in vitro using a non-invasive ratiometric two-photon microscopy (TPM) methodology. Sequence-defined PLGAs were found to have minimal changes in pH distribution and lower amounts of percolating acidic by-products. A parallel scanning electron microscopy study further linked external morphological events to internal degradation-induced structural changes. The properties of the sequenced and random copolymers characterized in vitro translated to differences in in vivo behavior. The sequence alternating copolymer, poly LG, had lower granulomatous foreign-body reactions compared to random racemic PLGA with a 50:50 ratio of lactic to glycolic acid. Statement of Significance This paper demonstrates that changing the monomer sequence in poly(lactic-co-glycolic acid)s (PLGAs) leads to dramatic differences in the rate of degradation and the internal acidic microclimate of microparticles degrading in vitro. We note that the acidic microclimates within these particles were imaged for the first time with two-photon microscopy, which gives an extremely clear and detailed picture of the degradation process. Importantly, we also document that the observed sequence-controlled in vitro processes translate into differences in the in vivo behavior of polymers which have the same L to G composition but differing microstructures. These data, placed in the context of our prior studies on swelling, erosion, and MW loss (Biomaterials 2017, 117, 66 and other references cited within the manuscript), provide significant insight not only about sequence effects in PLGAs but into the underlying mechanisms of PLGA degradation in general.
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      PubDate: 2017-12-12T15:12:08Z
  • Manipulation of the response of human endothelial colony-forming cells by
           focal adhesion assembly using gradient nanopattern plates
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Long-Hui Cui, Hyung Joon Joo, Dae Hwan Kim, Ha-Rim Seo, Jung Suk Kim, Seung-Cheol Choi, Li-Hua Huang, Ji Eun Na, I-Rang Lim, Jong-Ho Kim, Im Joo Rhyu, Soon Jun Hong, Kyu Back Lee, Do-Sun Lim
      Nanotopography plays a pivotal role in the regulation of cellular responses. Nonetheless, little is known about how the gradient size of nanostructural stimuli alters the responses of endothelial progenitor cells without chemical factors. Herein, the fabrication of gradient nanopattern plates intended to mimic microenvironment nanotopography is described. The gradient nanopattern plates consist of nanopillars of increasing diameter ranges [120–200 nm (GP 120/200), 200–280 nm (GP 200/280), and 280–360 nm (GP 280/360)] that were used to screen the responses of human endothelial colony-forming cells (hECFCs). Nanopillars with a smaller nanopillar diameter caused the cell area and perimeter of hECFCs to decrease and their filopodial outgrowth to increase. The structure of vinculin (a focal adhesion marker in hECFCs) was also modulated by nanostructural stimuli of the gradient nanopattern plates. Moreover, Rho-associated protein kinase (ROCK) gene expression was significantly higher in hECFCs cultured on GP 120/200 than in those on flat plates (no nanopillars), and ROCK suppression impaired the nanostructural-stimuli-induced vinculin assembly. These results suggest that the gradient nanopattern plates generate size-specific nanostructural stimuli suitable for manipulation of the response of hECFCs, in a process dependent on ROCK signaling. This is the first evidence of size-specific nanostructure-sensing behavior of hECFCs. Significance Nano feature surfaces are of growing interest as materials for a controlled response of various cells. In this study, we successfully fabricated gradient nanopattern plates to manipulate the response of blood-derived hECFCs without any chemical stimulation. Interestingly, we find that the sensitive nanopillar size for manipulation of hECFCs is range between 120 nm and 200 nm, which decreased the area and increased the filopodial outgrowth of hECFCs. Furthermore, we only modulate the nanopillar size to increase ROCK expression can be an attractive method for modulating the cytoskeletal integrity and focal adhesion of hECFCs.
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      PubDate: 2017-12-12T15:12:08Z
  • Rapid fabrication of microneedles using magnetorheological drawing
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Zhipeng Chen, Lei Ren, Jiyu Li, Lebin Yao, Yan Chen, Bin Liu, Lelun Jiang
      Microneedles are micron-sized needles that are widely applied in biomedical fields owing to their painless, minimally invasive, and convenient operation. However, most microneedle fabrication approaches are costly, time consuming, involve multiple steps, and require expensive equipment. In this study, we present a novel magnetorheological drawing lithography (MRDL) method to efficiently fabricate microneedle, bio-inspired microneedle, and molding-free microneedle array. With the assistance of an external magnetic field, the 3D structure of a microneedle can be directly drawn from a droplet of curable magnetorheological fluid. The formation process of a microneedle consists of two key stages, elasto-capillary self-thinning and magneto-capillary self-shrinking, which greatly affect the microneedle height and tip radius. Penetration and fracture tests demonstrated that the microneedle had sufficient strength and toughness for skin penetration. Microneedle arrays and a bio-inspired microneedle were also fabricated, which further demonstrated the versatility and flexibility of the MRDL method. Statement of Significance Microneedles have been widely applied in biomedical fields owing to their painless, minimally invasive, and convenient operation. However, most microneedle fabrication approaches are costly, time consuming, involve multiple steps, and require expensive equipment. Furthermore, most researchers have focused on the biomedical applications of microneedles but have given little attention to the optimization of the fabrication process. This research presents a novel magnetorheological drawing lithography (MRDL) method to fabricate microneedle, bio-inspired microneedle, and molding-free microneedle array. In this proposed technique, a droplet of curable magnetorheological fluid (CMRF) is drawn directly from almost any substrate to produce a 3D microneedle under an external magnetic field. This method not only inherits the advantages of thermal drawing approach without the need for a mask and light irradiation but also eliminates the requirement for drawing temperature adjustment. The MRDL method is extremely simple and can even produce the complex and multiscale structure of bio-inspired microneedle.
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      PubDate: 2017-12-12T15:12:08Z
  • Synthesis and characterization of arginine-NIPAAm hybrid hydrogel as wound
           dressing: In vitro and in vivo study
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): De-Qun Wu, Jie Zhu, Hua Han, Jun-Zhi Zhang, Fei-Fei Wu, Xiao-Hong Qin, Jian-Yong Yu
      A multi-functional hybrid hydrogel P(M-Arg/NIPAAm) with temperature response, anti-protein adsorption and antibacterial properties was prepared and applied as wound dressing. The hydrogel was carried out by free radical copolymerization of methacrylate arginine (M-Arg) and N-isopropyl acrylamide (NIPAAm) monomers using N,N′-methylene bisacrylamide as a crosslinker, and ammonium persulfate/N,N,N′, N′-tetramethylethylenediamine as the redox initiator. To endow the antimicrobial property, chlorhexidine diacetate (CHX) was preloaded into the hydrogel and polyhexamethylene guanidine phosphate (PHMG) was grafted on the hydrogel surface, respectively. The antimicrobial property of two series of hydrogels was evaluated and compared. The successful synthesis of M-Arg, PHMG and hydrogels was proved by 13C NMR, 1H NMR and FTIR spectroscopy. The hydrogel morphology characterized by scanning electron microscopy confirmed that the homogeneous porous and interconnected structures of the hydrogels. The swelling, protein adsorption property, in vitro release of CHX, antimicrobial assessment, cell viability as well as in vivo wound healing in a mouse model were studied. The results showed the nontoxicity and antimicrobial P(M-Arg/NIPAAm) hydrogel accelerated the full-thickness wound healing process and had the potential application in wound dressing. Statement of Significance Despite the zwitterionic characteristic and biocompatible property of arginine based hydrogels, the brittle behavior and non-transparency still remain as a significant problem for wound dressing. Furthermore promoting the antibacterial property of the zwitterionic hydrogel is also necessary to prevent the bacterial colonization and subsequent wound infection. Therefore, we created a hybrid hydrogel combined methacrylate arginine (M-Arg) and N-isopropyl acrylamide (NIPAAm). NIPAAm improves transparency and mechanical property as well as acts as a temperature-response drug release system. Additionally, chlorhexidine (CHX) was preloaded into the hydrogels and polyhexamethylene guanidine phosphate (PHMG) was grafted on the hydrogel surface, respectively, which make the hydrogel useful as a favorable antibacterial dressing. The hybrid hydrogel has a combination effect of biocompatibility, environmentally responsive transformation behavior, biodegradability, anti-protein adsorption and antimicrobial properties. This report proposes the preparation of P(M-Arg/NIPAAm) hydrogel that has a great potential for wound healing.
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      PubDate: 2017-12-12T15:12:08Z
  • Determining the effects of PEI adsorption on the permeability of
           1,2-dipalmitoylphosphatidylcholine/bis(monoacylglycero)phosphate membranes
           under osmotic stress
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Scott R. Clark, Keel Yong Lee, Hoyoung Lee, Jawahar Khetan, Hyun Chang Kim, Yun Hwa Choi, Kwanwoo Shin, You-Yeon Won
      Polycations are used for a number of biological applications, including antibiotics and gene therapy. One aspect of the use of polycation gene carriers such as polyethylenemine (PEI) in gene therapy that is not well understood is their ability to escape from the vesicles they are internalized in. Here, in an attempt to gain a better understanding of PEI interaction with endosomal lipids under osmotic stress, we performed investigations using monolayers and vesicles derived from a mixture of neutral and negative lipids (1,2-dipalmitoylphosphatidylcholine (DPPC) and bis(monoacylglycero)phosphate (BMP), respectively). X-ray reflectivity (XR) and Langmuir trough measurements confirmed PEI adsorption to the negatively charged membrane. Confocal microscopy imaging indicated that PEI adsorption actually increases the overall integrity of the DPPC/BMP vesicle against osmotic stresses while also causing overall deformation and permeabilization of the lipid membrane, thus leading to leakage of contents from the interior of the vesicle. These confocal microscopy observations were also supported by data gathered by dynamic light scattering (DLS). Statement of Significance In recent decades, researchers have investigated polyamine-based gene delivery systems as useful alternatives to viral gene carriers. One step that is crucial to the performance of polyamine gene carriers such as polyethylenemine (PEI) is escape from late endosomal vesicles during intracellular delivery. However, the ability of polyamine/DNA polyplexes to effectively escape from endosomes is a little-understood part of the gene therapy techniques that use these polyplexes. Here, we performed investigations using monolayers and vesicles derived from a mixture of neutral and negative lipids (1,2-dipalmitoylphosphatidylcholine (DPPC) and bis(monoacylglycero)phosphate (BMP), respectively) as model systems for late endosomes in order to examine the interactions of PEI with the DPPC/BMP membranes and study the subsequent effects on the stability and permeability of these membranes.
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      PubDate: 2017-12-12T15:12:08Z
  • Pharmacodynamics in Alzheimer’s disease model rats of a bifunctional
           peptide with the potential to accelerate the degradation and reduce the
           toxicity of amyloid β-Cu fibrils
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Dan Wang, Qian Zhang, Xiaoyu Hu, Wei Wang, Xushan Zhu, Zhi Yuan
      The accumulation of the extracellular β-amyloid (Aβ) aggregates with metal ions in conjunction with reactive oxygen species (ROS) is closely related to the pathogenesis of Alzheimer’s disease (AD). Accounting on Cu ions chelating of our previously designed bifunctional peptide GGHRYYAAFFARR (GR) as well as Aβ-Cu fibrils (fAβ-Cu) dissociation potentials, we report herein an efficient route to synthetically minimize ROS toxicity and degrade fAβ-Cu. It is worth mentioning that GR combines the metal chelating agent GGH and β-sheet breaker RYYAAFFARR (RR). The in vitro results have showed that GR disassociates fAβ-Cu into smaller fragments (sAβ-Cu, 150–200 nm), easily assimilated by PC12 cell and subsequently degraded in the lysosomes; GR can also suppress the ROS generated by fAβ-Cu. The viability of PC12 cell treated with fAβ-Cu has increased, from 38% to about 70% after administration of GR, overwhelming the GGH chelator (46%) and single functional peptide RR (48%). The in vivo results indicated that GR has efficiently reduced Aβ deposition, ameliorated neurologic changes and rescued memory loss, thus, enhancing the cognitive and spatial memory in a AD rat model. This study confirms the superior effect of GR and paves the way toward its future employment in large scale AD treatment. Statement of Significance We have focused on accelerating the degradation of fAβ-Cu as well as synthetically reducing the ROS toxicity by GR, and, consequently, its benefits in vivo. The bifunctional peptide GR can not only disaggregate fAβ-Cu into smaller fragments to facilitate uptake and degradation by PC12 cell, but also suppresses the ROS generated by fAβ-Cu. Thus, the viability of PC12 cell treated with fAβ-Cu has increased from 38% to 70% after GR administration, overwhelming GGH (46%) and RR (48%). The in vivo studies have revealed that GR improves the spatial memory ability and reduce the amount of senile plaques within brain of AD model rats. Thus, we suppose the bifunctional inhibitor GR has good application prospects in the treatment of AD treatment.
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      PubDate: 2017-12-12T15:12:08Z
  • Surface-adaptive zwitterionic nanoparticles for prolonged blood
           circulation time and enhanced cellular uptake in tumor cells
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Hanlin Ou, Tangjian Cheng, Yumin Zhang, Jinjian Liu, Yuxun Ding, Jingru Zhen, Wenzeng Shen, Yingjin Xu, Wenzeng Yang, Pei Niu, Jianfeng Liu, Yingli An, Yang Liu, Linqi Shi
      Recently, zwitterionic materials have been developed as alternatives to PEG for prolonging the circulation time of nanoparticles without triggering immune responses. However, zwitterionic coatings also hindered the interactions between nanoparticles and tumor cells, leading to less efficient uptake of nanoparticles by cancer cells. Such effect significantly limited the applications of zwitterionic materials for the purposes of drug delivery and the development to novel therapeutic agents. To overcome these issues, surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(β-amino ester) (PAE) heterogeneous surfaces were constructed. Owing to the synergistic effect of zwitterionic coatings and micro-phase-separated surfaces, PMPC mixed-shell micelles exhibited the improved blood circulation time compared to single-PEG-shell micelles (PEGSMs) and single-PMPC-shell micelles (PMPCSMs). Moreover, such MSMs can convert their surface to positively charged ones in response to the acidic tumor microenvironment, leading to a significant enhancement in cellular uptake of MSMs by tumor cells. This strategy demonstrated a general approach to enhance the cellular uptake of zwitterionic nanoparticles without compromising their long circulating capability, providing a practical method for improving the tumor-targeting efficiency of particulate drug delivery systems. Statement of Significance Herein we demonstrate a general strategy to integrate non-fouling zwitterionic surface on the nanoparticles without compromising their capability of tumor accumulation, by constructing a surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(β-amino ester) (PAE) heterogeneous surfaces. At the blood pH (7.4), PAE chains collapsed to the inner of the shell due to the deprotonation, and the forming micro-phase separation structure was synergistic with zwitterionic surface to prolong the circulation time of MSMs in the blood. While at the tumor sites, PAE was protonated, and the positively charged surface of MSMs enhanced cellular uptake. This self-assembly-based strategy is compatible to other zwitterionic materials, endowing a great flexibility for the construction of responsive drug delivery systems particularly to the novel chemotherapeutic agents.
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      PubDate: 2017-12-12T15:12:08Z
  • In situ dual-crosslinked nanoparticles for tumor targeting gene delivery
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Ying Zhang, Liang Liu, Lin Lin, Jie Chen, Huayu Tian, Xuesi Chen, Atsushi Maruyama
      The instability of gene delivery systems and their “off-target” features are among the major hurdles in gene therapy. In this study, a facile fabrication platform is constructed to endow the gene delivery system with high stability in the circulation system and achieve targeted delivery of plasmid DNA (pDNA) into cancer cells. Aldehyde groups-bearing hyaluronic acid (HA-CHO) is initially synthesized through oxidation, and is then shielded on polyethylenimine/DNA (PEI/DNA) complex particles to form dual-crosslinked nanoparticles in situ. These nanoparticles simultaneously possess electrostatic and chemical crosslinks between outer layers and cores. The dual-crosslinking system further offers the following advantages when used for gene delivery. First, the two different in situ crosslinking routes strengthen nanoparticle stability. Second, targeting ligands on HA layers mediate specific recognition toward cancer cells. Cell and animal experiments demonstrate that the as-prepared complex particles exhibit enhanced stability in serum and excellent long circulation behavior in vivo. Third, the dual-crosslinked nanoparticles present good accumulation ability in tumors after intravenous injection into nude mice bearing HeLa tumors. Overall, the dual-crosslinking strategy is a promising solution for constructing an efficient gene delivery system. Statement of Significance This manuscript focused on the in situ dual-crosslinked nanoparticles for tumor targeting pDNA delivery. The novel system is prepared by in situ shielding HA-CHO on PEI/DNA complexes. The electrostatic crosslink formed between carboxyl groups on HA-CHO and amine groups on PEI as well as the reaction between aldehyde groups on HA-CHO and amine groups on PEI contributes to the chemical crosslink. By introduction of HA-CHO on PEI/DNA complexes, they show promoting colloidal stability, enhanced cellular uptake and tumor targeting ability. The in vivo experiments further confirm the excellent ability of long circulation and tumor accumulation. Accordingly, HA-CHO2/PEI/DNA has great potential for tumor targeting antitumor therapy.
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      PubDate: 2017-12-12T15:12:08Z
  • Developmental refinement of synaptic transmission on micropatterned single
           layer graphene
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Sandeep Keshavan, Shovan Naskar, Alberto Diaspro, Laura Cancedda, Silvia Dante
      Interfacing neurons with graphene, a single atomic layer of sp2 hybridized C-atoms, is a key paradigm in understanding how to exploit the unique properties of such a two-dimensional system for neural prosthetics and biosensors development. In order to fabricate graphene-based circuitry, a reliable large area patterning method is a requirement. Following a previously developed protocol, we monitored the in vitro neuronal development of geometrically ordered neural network growing onto patterned Single Layer Graphene (SLG) coated with poly-D-lysine. The microscale patterns were fabricated via laser micromachining and consisted of SLG stripes separated by micrometric ablated stripes. A comprehensive analysis of the biointerface was carried out combining the surface characterization of SLG transferred on the glass substrates and Immunohistochemical (IHC) staining of the developing neural network. Neuronal and glial cells proliferation, as well as cell viability, were compared on glass, SLG and SLG-patterned surfaces. Further, we present a comparative developmental study on the efficacy of synaptic transmission on control glass, on transferred SLG, and on the micropatterned SLG substrates by recording miniature post synaptic currents (mPSCs). The mPSC frequencies and amplitudes obtained on SLG-stripes, SLG only and on glass were compared. Our results indicate a very similar developmental trend in the three groups, indicating that both SLG and patterned SLG preserve synaptic efficacy and can be potentially exploited for the fabrication of large area devices for neuron sensing or stimulation. Statement of significance This paper compares the morphological and functional development of neural networks forming on glass, on Single Layer Graphene (SLG) and on microsized patterned SLG substrates after neuron spontaneous migration. Neurons developing on SLG are viable after two weeks in vitro, and, on SLG, glial cell proliferation is enhanced. The functionality of the neural networks is demonstrated by measuring the development of neuron synapses in the first and second week in vitro. Preserving the neuron synaptic efficacy, both homogeneous and patterned interfaces based on graphene can be potentially exploited for the fabrication of large area devices for neuron sensing or stimulation, as well as for next generation of bio-electronic systems, to be used as brain-interfaces.
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      PubDate: 2017-12-12T15:12:08Z
  • Layer-by-layer assembly of graphene oxide on thermosensitive liposomes for
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Mohadeseh Hashemi, Meisam Omidi, Bharadwaj Muralidharan, Lobat Tayebi, Matthew J. Herpin, Mohammad Ali Mohagheghi, Javad Mohammadi, Hugh D.C. Smyth, Thomas E. Milner
      Stimuli responsive polyelectrolyte nanoparticles have been developed for chemo-photothermal destruction of breast cancer cells. This novel system, called layer by layer Lipo-graph (LBL Lipo-graph), is composed of alternate layers of graphene oxide (GO) and graphene oxide conjugated poly (l-lysine) (GO-PLL) deposited on cationic liposomes encapsulating doxorubicin. Various concentrations of GO and GO-PLL were examined and the optimal LBL Lipo-graph was found to have a particle size of 267.9 ± 13 nm, zeta potential of +43.9 ± 6.9 mV and encapsulation efficiency of 86.4 ± 4.7%. The morphology of LBL Lipo-graph was examined by cryogenic-transmission electron microscopy (Cryo-TEM), atomic force microcopy (AFM) and scanning electron microscopy (SEM). The buildup of LBL Lipo-graph was confirmed via ultraviolet-visible (UV–Vis) spectrophotometry, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis. Infra-red (IR) response suggests that four layers are sufficient to induce a gel-to-liquid phase transition in response to near infra-red (NIR) laser irradiation. Light-matter interaction of LBL Lipo-graph was studied by calculating the absorption cross section in the frequency domain by utilizing Fourier analysis. Drug release assay indicates that the LBL Lipo-graph releases much faster in an acidic environment than a liposome control. A cytotoxicity assay was conducted to prove the efficacy of LBL Lipo-graph to destroy MD-MB-231 cells in response to NIR laser emission. Also, image stream flow cytometry and two photon microcopy provide supportive data for the potential application of LBL Lipo-graph for photothermal therapy. Study results suggest the novel dual-sensitive nanoparticles allow intracellular doxorubin delivery and respond to either acidic environments or NIR excitation. Statement of Significance Stimuli sensitive hybrid nanoparticles have been synthesized using a layer-by-layer technique and demonstrated for dual chemo-photothermal destruction of breast cancer cells. The hybrid nanoparticles are composed of alternating layers of graphene oxide and graphene oxide conjugated poly-l-lysine coating the surface of a thermosensitive cationic liposome containing doxorubicin as a core. Data suggests that the hybrid nanoparticles may offer many advantages for chemo-photothermal therapy. Advantages include a decrease of the initial burst release which may result in the reduction in systemic toxicity, increase in pH responsivity around the tumor environment and improved NIR light absorption.
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      PubDate: 2017-12-12T15:12:08Z
  • Lectin-conjugated pH-responsive mesoporous silica nanoparticles for
           targeted bone cancer treatment
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Marina Martínez-Carmona, Daniel Lozano, Montserrat Colilla, María Vallet-Regí
      A novel multifunctional nanodevice based in doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs) as nanoplatforms for the assembly of different building blocks has been developed for bone cancer treatment. These building blocks consists of: i) a polyacrylic acid (PAA) capping layer grafted to MSNs via an acid-cleavable acetal linker, to minimize premature cargo release and provide the nanosystem of pH-responsive drug delivery ability; and ii) a targeting ligand, the plant lectin concanavalin A (ConA), able to selectively recognize, bind and internalize owing to certain cell-surface glycans, such as sialic acids (SA), overexpressed in given tumor cells. This multifunctional nanosystem exhibits a noticeable higher internalization degree into human osteosarcoma cells (HOS), overexpressing SA, compared to healthy preosteoblast cells (MC3T3-E1). Moreover, the results indicate that small DOX loading (2.5 µg mL−1) leads to almost 100% of osteosarcoma cell death in comparison with healthy bone cells, which significantly preserve their viability. Besides, this nanodevice has a cytotoxicity on tumor cells 8-fold higher than that caused by the free drug. These findings demonstrate that the synergistic combination of different building blocks into a unique nanoplatform increases antitumor effectiveness and decreases toxicity towards normal cells. This line of attack opens up new insights in targeted bone cancer therapy. Statement of Significance The development of highly selective and efficient tumor-targeted smart drug delivery nanodevices remains a great challenge in nanomedicine. This work reports the design and optimization of a multifunctional nanosystem based on mesoporous silica nanoparticles (MSNs) featuring selectivity towards human osteosarcoma cells and pH-responsive antitumor drug delivery capability. The novelty and originality of this manuscript relies on proving that the synergistic assembly of different building blocks into a unique nanoplatform increases antitumor effectiveness and decreases toxicity towards healthy cells, which constitutes a new paradigm in targeted bone cancer therapy.
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      PubDate: 2017-12-12T15:12:08Z
  • Overcoming multiple gastrointestinal barriers by bilayer modified hollow
           mesoporous silica nanocarriers
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Ying Wang, Yating Zhao, Yu Cui, Qinfu Zhao, Qiang Zhang, Sara Musetti, Karina A Kinghorn, Siling Wang
      Oral administration of nanocarriers remains a significant challenge in the pharmaceutical sciences. The nanocarriers must efficiently overcome multiple gastrointestinal barriers including the harsh gastrointestinal environment, the mucosal layer, and the epithelium. Neutral hydrophilic surfaces are reportedly necessary for mucus permeation, but hydrophobic and cationic surfaces are important for efficient epithelial absorption. To accommodate these conflicting surface property requirements, we developed a strategy to modify nanocarrier surfaces with cationic cell-penetrating peptides (CPP) concealed by a hydrophilic succinylated casein (SCN) layer. SCN is a mucus-inert natural material specifically degraded in the intestine, thus protecting nanocarriers from the harsh gastric environment, facilitating their mucus permeation, and inducing exposure of CPPs after degradation for further effective transepithelial transport. Quantum dots doped hollow silica nanoparticles (HSQN) with a diameter around 180 nm was used as the nanocarrier and demonstrated as high as 50% loading efficacy of paclitaxel, a model drug with poor solubility and permeability. The dual layer modification strategy prevented premature drug leakage in stomach and maintained high mucus permeation (the trajectory spanned 9-fold larger area than single CPP modification). After intestinal degradation of SCN by trypsin, these nanocarriers exhibited strong interaction with epithelial membranes and a 5-fold increase in cellular uptake. Significant transepithelial transport and intestinal distribution were also observed for this dual-modified formulation. A pharmacokinetics study on the paclitaxel-loaded nanocarrier found 40% absolute bioavailability and 7.8-fold higher AUC compared to oral Taxol®. Compared with single CPP modified nanocarriers, our formulation showed increased in vivo efficacy and tumor accumulation of the model drug with negligible intestinal toxicity. In summary, sequential modification with CPP and SCN layers on HSQN offers a potential strategy to overcome the multiple barriers of the gastrointestinal tract. Statement of Significance Oral administration of nanocarriers remains a big challenge due to the multiple gastrointestinal barriers. In order to achieve both strong mucus permeation and efficient epithelial absorption, we modified the surface of silica nanoparticles with two layers: cell penetrating peptide (CPP) layer and succinylated casein (SCN) layer. The newly developed nanoformulations are demonstrated to have the following advantages: 1) versatile carrier with easy preparation, 2) high drug loading especially for poor soluble molecules, 3) reduced drug leakage in the stomach, 4) effective mucus penetration and transepithelial transport and 5) good biocompatibility, which in all indicate a great potential of this bilayer-modification strategy to facilitate the oral delivery of therapeutic agents.
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      PubDate: 2017-12-12T15:12:08Z
  • Transcriptional profile of human macrophages stimulated by ultra-high
           molecular weight polyethylene particulate debris of orthopedic implants
           uncovers a common gene expression signature of rheumatoid arthritis
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Mohamad Alaa Terkawi, Masanari Hamasaki, Daisuke Takahashi, Masahiro Ota, Ken Kadoya, Tomoyo Yutani, Keita Uetsuki, Tsuyoshi Asano, Tohru Irie, Ryuta Arai, Tomohiro Onodera, Masahiko Takahata, Norimasa Iwasaki
      Osteolysis is a serious postoperative complication of total joint arthroplasty that leads to aseptic loosening and surgical revision. Osteolysis is a chronic destructive process that occurs when host macrophages recognize implant particles and release inflammatory mediators that increase bone-resorbing osteoclastic activity and attenuate bone-formation osteoblastic activity. Although much progress has been made in understanding the molecular responses of macrophages to implant particles, the pathways/signals that initiate osteolysis remain poorly characterized. Transcriptomics and gene-expression profiling of these macrophages may unravel key mechanisms in the pathogenesis of osteolysis and aid the identification of molecular candidates for therapeutic intervention. To this end, we analyzed the transcriptional profiling of macrophages exposed to ultra-high molecular weight polyethylene (UHMWPE) particles, the most common components used in bearing materials of orthopedic implants. Regulated genes in stimulated macrophages were involved in cytokine, chemokine, growth factor and receptor activities. Gene enrichment analysis suggested that stimulated macrophages elicited common gene expression signatures for inflammation and rheumatoid arthritis. Among the regulated genes, tumor necrosis factor superfamily member 15 (TNFSF15) and chemokine ligand 20 (CCL20) were further characterized as molecular targets involved in the pathogenesis of osteolysis. Treatment of monocyte cultures with TNFSF15 and CCL20 resulted in an increase in osteoclastogenesis and bone-resorbing osteoclastic activity, suggesting their potential contribution to loosening between implants and bone tissues. Statement of Significance Implant loosening due to osteolysis is the most common mode of arthroplasty failure and represents a great challenge to orthopedic surgeons and a significant economic burden for patients and healthcare services worldwide. Bone loss secondary to a local inflammatory response initiated by particulate debris from implants is considered the principal feature of the pathogenesis of osteolysis. In the present study, we analyzed the transcriptional profiling of human macrophages exposed to UHMWPE particles and identified a large number of inflammatory genes that were not identified previously in macrophage responses to wear particles. Our data provide a new insight into the molecular pathogenesis of osteolysis and highlights a number of molecular targets with prognostic and therapeutic implications.
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      PubDate: 2017-12-12T15:12:08Z
  • Orthopaedic implant materials drive M1 macrophage polarization in a spleen
           tyrosine kinase- and mitogen-activated protein kinase-dependent manner
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Olwyn R. Mahon, Sarah O'Hanlon, Clare C. Cunningham, Geraldine M McCarthy, Christopher Hobbs, Valeria Nicolosi, Daniel J. Kelly, Aisling Dunne
      Total joint replacements (TJR) are costly procedures required to relieve pain and restore function in patients suffering from end-stage arthritis. Despite great progress in the development and durability of TJRs, the generation of prosthesis-associated wear particles over time leads to an inflammatory cascade which culminates in periprosthetic osteolysis. Studies suggest that wear particles drive the polarization/differentiation of immature macrophages towards a pro-inflammatory M1 phenotype rather than an anti-inflammatory M2 phenotype associated with normal bone and wound healing. This, in turn, contributes to the initiation of peri-implant inflammation. As a result, modulating M1 macrophage cytokine production has been recognised as a viable therapeutic option. The aim of this study was to examine the impact of hydroxyapatite (HA) and poly(methyl methacrylate) (PMMA) particles on human macrophage polarization by comparing their effect on M1/M2-associated gene expression using real-time PCR. Furthermore, using immunoblotting to assess kinase activation, we sought to identify the intracellular signalling molecules activated by PMMA/HA particles and to determine whether pharmacological blockade of these molecules impacts on macrophage phenotype and cytokine production as measured by ELISA. We report that wear particles preferentially polarize macrophages towards an M1 phenotype, an effect that is dependent on activation of the membrane proximal kinase, Syk and members of the mitogen-activated protein kinase (MAPK) family of signalling molecules. Pre-treatment of macrophages with Syk inhibitors (R788/piceatannol) or MAPK inhibitors (SB203580 and PD98059), not only prevents M1 polarization, but also attenuates production of key pro-inflammatory mediators that have been specifically implicated in periprosthetic osteolysis and osteoclast differentiation. Statement of Significance It is now well established that wear-debris particles from implanted materials drive deleterious inflammatory responses which can eventually lead to implant loosening. In this study, we provide further insight into the specific cellular pathways activated by wear particles in primary human immune cells. We demonstrate that PMMA bone cement and hydroxyapatite, a commonly used biomaterial, drive the polarization of macrophages towards an inflammatory phenotype and identify the specific signalling molecules that are activated in this process. Pre-treatment of macrophages with pharmacological inhibitors of these molecules in turn prevents macrophage polarization and dampens inflammatory cytokine production. Hence these signalling molecules represent potential therapeutic targets to treat or possibly prevent particulate induced osteolysis.
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      PubDate: 2017-12-12T15:12:08Z
  • Understanding the structural drivers governing glass–water interactions
           in borosilicate based model bioactive glasses
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Nicholas Stone-Weiss, Eric M. Pierce, Randall E. Youngman, Ozgur Gulbiten, Nicholas J. Smith, Jincheng Du, Ashutosh Goel
      The past decade has witnessed a significant upsurge in the development of borate and borosilicate based resorbable bioactive glasses owing to their faster degradation rate in comparison to their silicate counterparts. However, due to our lack of understanding about the fundamental science governing the aqueous corrosion of these glasses, most of the borate/borosilicate based bioactive glasses reported in the literature have been designed by “trial–and–error” approach. With an ever-increasing demand for their application in treating a broad spectrum of non-skeletal health problems, it is becoming increasingly difficult to design advanced glass formulations using the same conventional approach. Therefore, a paradigm shift from the “trial–and–error” approach to “materials–by–design” approach is required to develop new-generations of bioactive glasses with controlled release of functional ions tailored for specific patients and disease states, whereby material functions and properties can be predicted from first principles. Realizing this goal, however, requires a thorough understanding of the complex sequence of reactions that control the dissolution kinetics of bioactive glasses and the structural drivers that govern them. While there is a considerable amount of literature published on chemical dissolution behavior and apatite-forming ability of potentially bioactive glasses, the majority of this literature has been produced on silicate glass chemistries using different experimental and measurement protocols. It follows that inter-comparison of different datasets reveals inconsistencies between experimental groups. There are also some major experimental challenges or choices that need to be carefully navigated to unearth the mechanisms governing the chemical degradation behavior and kinetics of boron-containing bioactive glasses, and to accurately determine the composition–structure–property relationships. In order to address these challenges, a simplified borosilicate based model melt-quenched bioactive glass system has been studied to depict the impact of thermal history on its molecular structure and dissolution behavior in water. It has been shown that the methodology of quenching of the glass melt impacts the dissolution rate of the studied glasses by 1.5×–3× depending on the changes induced in their molecular structure due to variation in thermal history. Further, a recommendation has been made to study dissolution behavior of bioactive glasses using surface area of the sample – to – volume of solution (SA/V) approach instead of the currently followed mass of sample – to – volume of solution approach. The structural and chemical dissolution data obtained from bioactive glasses following the approach presented in this paper can be used to develop the structural descriptors and potential energy functions over a broad range of bioactive glass compositions. Statement of Significance Realizing the goal of designing third generation bioactive glasses requires a thorough understanding of the complex sequence of reactions that control their rate of degradation (in physiological fluids) and the structural drivers that control them. In this article, we have highlighted some major experimental challenges and choices that need to be carefully navigated in order to unearth the mechanisms governing the chemical dissolution behavior of borosilicate based bioactive glasses. The proposed experimental approach allows us to gain a new level of conceptual understanding about the composition–structure–property relationships in these glass systems, which can be applied to attain a significant leap in designing borosilicate based bioactive glasses with controlled dissolution rates tailored for specific patient and disease states.
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      PubDate: 2017-12-12T15:12:08Z
  • Multifunctional pH sensitive 3D scaffolds for treatment and prevention of
           bone infection
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Mónica Cicuéndez, Juan C. Doadrio, Ana Hernández, M. Teresa Portolés, Isabel Izquierdo-Barba, María Vallet-Regí
      Multifunctional-therapeutic three-dimensional (3D) scaffolds have been prepared. These biomaterials are able to destroy the S. aureus bacterial biofilm and to allow bone regeneration at the same time. The present study is focused on the design of pH sensitive 3D hierarchical meso-macroporous 3D scaffolds based on MGHA nanocomposite formed by a mesostructured glassy network with embedded hydroxyapatite nanoparticles, whose mesopores have been loaded with levofloxacin (Levo) as antibacterial agent. These 3D platforms exhibit controlled and pH-dependent Levo release, sustained over time at physiological pH (7.4) and notably increased at infection pH (6.7 and 5.5), which is due to the different interaction rate between diverse Levo species and the silica matrix. These 3D systems are able to inhibit the S. aureus growth and to destroy the bacterial biofilm without cytotoxic effects on human osteoblasts and allowing an adequate colonization and differentiation of preosteoblastic cells on their surface. These findings suggest promising applications of these hierarchical MGHA nanocomposite 3D scaffolds for the treatment and prevention of bone infection. Statement of Significance Multifunctional 3D nanocomposite scaffolds with the ability for loading and sustained delivery of an antimicrobial agent, to eliminate and prevent bone infection and at the same time to contribute to bone regeneration process without cytotoxic effects on the surrounding tissue has been proposed. These 3D scaffolds exhibit a sustained levofloxacin delivery at physiological pH (pH 7.4), which increasing notably when pH decreases to characteristic values of bone infection process (pH 6.7 and pH 5.5). In vitro competitive assays between preosteoblastic and bacteria onto the 3D scaffold surface demonstrated an adequate osteoblast colonization in entire scaffold surface together with the ability to eliminate bacteria contamination.
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      PubDate: 2017-12-12T15:12:08Z
  • Cu-doping of calcium phosphate bioceramics: From mechanism to the control
           of cytotoxicity
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Sandrine Gomes, Charlotte Vichery, Stéphane Descamps, Hervé Martinez, Amandeep Kaur, Aurélie Jacobs, Jean-Marie Nedelec, Guillaume Renaudin
      In this study, the Cu-doping mechanism of Biphasic Calcium Phosphate (BCP) was thoroughly investigated, as was its ionic release behavior, in order to elucidate cytotoxicity features of these bioceramics. BCP are composed of hydroxyapatite (Ca10(PO4)6(OH)2) and β-TCP (Ca3(PO4)2). The two phases present two different doping mechanisms. Incorporation into the β-TCP structure is achieved at around 700 °C thanks to a substitution mechanism leading to the Cu-doped Ca3− x Cu x (PO4)2 compound. Incorporation into the HAp structure is achieved thanks to an interstitial mechanism that is limited to a Cu-poor HAp phase for temperatures below 1100 °C (Ca10Cu x (PO4)6(OH)2−2 x O2 x with x < 0.1). Above 1100 °C, the same interstitial mechanism leads to the formation of a Cu-rich HAp mixed-valence phase (Ca10Cu2+ x Cu+ y (PO4)6(OH)2−2 x-y O2 x+y with x + y ∼ 0.5). The formation of both high-temperature Cu-doped α-TCP and Cu3(PO4)2 phases above 1100 °C induces a transformation into the Cu-rich HAp phase on cooling. The linear OCuO oxocuprate entity was confirmed by EXAFS spectroscopy, and the mixed Cu+/Cu2+ valence was evidenced by XPS analyses. Ionic releases (Cu+/Cu2+, Ca2+, PO4 2− and OH−) in water and in simulated body media were investigated on as-synthesized ceramics to establish a pretreatment before biological applications. Finally the cytotoxicity of pretreated disks was evaluated, and results confirm that Cu-doped BCP samples are promising bioceramics for bone substitutes and/or prosthesis coatings. Statement of Significance Biphasic Calcium Phosphates (BCP) are bioceramics composed of hydroxyapatite (HAp, Ca10(PO4)6(OH)2) and beta-Tricalium Phosphate (β-TCP, Ca3(PO4)2). Because their chemical and mineral composition closely resembles that of the mineral component of bone, they are potentially interesting candidates for bone repair surgery. Doping can advantageously be used to improve their biological behaviors; however, it is important to describe the doping mechanism of BCP thoroughly in order to fully appraise the benefit of the doping process. The present paper scrutinizes in detail the incorporation of copper cation in order to correctly interpret the behavior of the Cu-doped bioceramic in biological fluid. The understanding of the copper doping mechanism, related to doping mechanism of others 3d-metal cations, makes it possible to explain the rates and kinetic of release of the dopant in biological medium. Finally, the knowledge of the behavior of the copper doped ceramic in biological environment allowed the tuning of its cytotoxicity properties. The present study resulted on pre-treated ceramic disks which have been evaluated as promising biocompatible ceramic for bone substitute and/or prosthesis coating: good adherence of bone marrow cells with good cell viability.
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      PubDate: 2017-12-12T15:12:08Z
  • Strontium-modified premixed calcium phosphate cements for the therapy of
           osteoporotic bone defects
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): A. Lode, C. Heiss, G. Knapp, J. Thomas, B. Nies, M. Gelinsky, M. Schumacher
      In this study a premixed strontium-containing calcium phosphate bone cement for the application in osteoporotic bone defects has been developed and characterised regarding its material and in vitro properties as well as minimally invasive applicability in balloon kyphoplasty. Strontium was introduced into the cement by substitution of one precursor component, CaCO3, with its strontium analogue, SrCO3. Using a biocompatible oil phase as carrier liquid, a cement paste that only set upon contact with aqueous environment was obtained. Strontium modification resulted in an increased strength of set cements and radiographic contrast; and the cements released biologically relevant doses of Sr2+-ions that were shown to enhance osteoprogenitor cell proliferation and osteogenic differentiation. Finally, applicability of strontium-containing cement pastes in balloon kyphoplasty was demonstrated in a human cadaver spine procedure. The cement developed in this study may therefore be well suited for minimally invasive, osteoporosis-related bone defect treatment. Statement of Significance Strontium-releasing calcium phosphate bone cements are promising materials for the clinical regeneration of osteoporosis-related bone defects since they have been shown to stimulate bone formation and at the same time limit osteoclastic bone resorption. Today clinical practice favours minimally invasive surgical techniques, e.g. for vertebral fracture treatment, posing special demands on such cements. We have therefore developed a premixed, strontium-releasing bone cement with enhanced mechanical properties and high radiographic visibility that releases biologically relevant strontium concentrations and thus stimulates cells of the osteogenic lineage. In a pilot experiment we also exemplify its excellent suitability for minimally invasive balloon kyphoplasty procedures.
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      PubDate: 2017-12-12T15:12:08Z
  • Dual modulation of bone formation and resorption with zoledronic
           acid-loaded biodegradable magnesium alloy implants improves osteoporotic
           fracture healing: An in vitro and in vivo study
    • Abstract: Publication date: January 2018
      Source:Acta Biomaterialia, Volume 65
      Author(s): Guoyuan Li, Lei Zhang, Lei Wang, Guangyin Yuan, Kerong Dai, Jia Pei, Yongqiang Hao
      Osteoporotic fracture (OPF) remains a major clinical challenge for skeletal regeneration. Impaired osteogenesis and excessive remodeling result in prolonged and poor quality of fracture healing. To augment bone formation and inhibit excessive resorption simultaneously, we constructed a biodegradable magnesium-based implant integrated with the anti-catabolic drug zoledronic acid (ZA); this implant exhibits controllable, sustained release of magnesium degradation products and ZA in vitro. The extracts greatly stimulate the osteogenic differentiation of rat-bone marrow-derived mesenchymal stem cells (rBMSCs), while osteoclastogenesis is inhibited by ZA. Implantation of intramedullary nails to fix femur fracture in ovariectomy-induced osteoporotic rats for up to 12 weeks demonstrates magnesium implants alone can enhance OPF repair through promoting callus formation compared to conventional stainless steel, while the combinatory treatment with local ZA release from implant coating further increases bone regeneration rate and callus size, remarkably improves bone quality and mechanical strength and suppresses osteoclasts and bone remodeling, due to the synergistic effect of both agents. The slow and uniform degradation of the implant ensures a steady decrease in bending force, which meets clinical requirements. In summary, biodegradable magnesium-based implants can locally co-deliver magnesium degradation products and zoledronic acid in a controlled manner, and can be superior alternatives for the reconstruction of osteoporosis-related fracture. Statement of Significance Management of osteoporotic fracture has posed a major challenge in orthopedics, as the imbalance between diminished osteogenesis and excessive bone remodeling often leads to delayed and compromised fracture repair. Among various efforts expended on augmenting osteoporotic fracture healing, herein we reported a new strategy by engineering and utilizing a biodegradable magnesium-based implant integrated with local drug delivery, specifically, zoledronic acid (ZA)-loaded polylactic acid/brushite bilayer coating on a biodegradable Mg−Nd−Zn−Zr alloy (denoted as Mg/ZA/CaP), aiming to combine the favorable properties of Mg and zoledronic acid for simultaneous modulation of bone formation and bone resorption. In vitro and in vivo studies demonstrated its superior treatment efficacy along with adequate degradation. It stimulated new bone formation while suppressing remodeling, ascribed to the local release of magnesium degradation products and zoledronic acid. To our knowledge, the enhanced fracture repair capability of Mg-based implants was for the first time demonstrated in an osteoporotic fracture animal model. This innovative biodegradable Mg-based orthopedic implant presents great potential as a superior alternative to current internal fixation devices for treating osteoporotic fracture.
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      PubDate: 2017-12-12T15:12:08Z
  • An implantable depot capable of in situ generation of micelles to achieve
           controlled and targeted tumor chemotherapy
    • Abstract: Publication date: Available online 12 December 2017
      Source:Acta Biomaterialia
      Author(s): Xiaoming Luo, Maohua Chen, Zhoujiang Chen, Songzhi Xie, Nan He, Tao Wang, Xiaohong Li
      Camptothecin (CPT)-containing promicelle polymers (PMCPT) based on 4-armed poly(ethylene glycol) (PEG) were developed previously to self-assemble into folate-targeted and glutathione (GSH)-sensitive micelles (MCPT). To address severe systemic toxicity and lack of tumor specificity implicated in the intravenous administration of MCPT, a micelle-generating depot has been developed by blend electrospinning of PEG-poly(lactide) (PELA) copolymers, PMCPT and polyethylene oxide (PEO). Upon implantation of the depot onto the tumor, PMCPT are sustainably released to spontaneously form MCPT on the tumor site. The release of PMCPT is adjusted by varying PEO/PELA ratios and reach in the range of 23−92% after 30 days of incubation in PBS. By making use of the aggregation-induced emission (AIE) features of tetraphenylethylene (TPE) derivatives, the release process of TPE-containing promicelle polymers (PMTPE) from the depot and the formation of micelles (MTPE) have been monitored from the self-assembly-induced fluorescence light-up both in vitro and in vivo. Compared with intravenous injection of MCPT, the micelle-generating depot has significantly enhanced micelle accumulation at tumor sites for an extended period of time and resulted in stronger tumor inhibitory efficacy, reduced systemic toxicity and more effective inhibition of tumor metastasis, demonstrating great potential for targeted cancer therapy with sustained efficacy. Statement of Significance The promicelle polymer-co-electrospun fibers are developed to form a micelle-generating depot after implantation onto the tumor. The promicelle polymers are continuously released and simultaneously self-assemble into folate-targeted and glutathione-sensitive micelles, ensuring sustained micelle delivery for more than 30 days. The process of micelle formation at tumor site is visualized in vivo for the first time based on the mechanism of aggregation-induced emission. This in situ micelle formation also prevents premature drug release and rapid clearance from the bloodstream. In addition, these fibers deliver anti-cancer agents directly within tumor cells via dual selectivity (i.e. spatially selective accumulation in tumor tissues via implantation and selective internalization into tumor cells via folate receptor-mediated endocytosis) and on-demand drug release in response to cytosol GSH. They exhibit superior tumor inhibitory efficacy with minimal systemic toxicity, and prevent from malignant metastasis of cancer cells.
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      PubDate: 2017-12-12T15:12:08Z
  • Additively manufactured biodegradable porous magnesium
    • Abstract: Publication date: Available online 12 December 2017
      Source:Acta Biomaterialia
      Author(s): Y. Li, J. Zhou, P. Pavanram, M.A. Leeflang, L.I.Fockaert, B. Pouran, N.Tümer, K.-U. Schröder, J.M.C. Mol, H. Weinans, H. Jahr, A.A. Zadpoor
      An ideal bone substituting material should be bone-mimicking in terms of mechanical properties, present a precisely controlled and fully interconnected porous structure, and degrade in the human body to allow for full regeneration of large bony defects. However, simultaneously satisfying all these three requirements has so far been highly challenging. Here we present topologically ordered porous magnesium (WE43) scaffolds based on the diamond unit cell that were fabricated by selective laser melting (SLM) and satisfy all the requirements. We studied the in vitro biodegradation behavior (up to 4 weeks), mechanical properties and biocompatibility of the developed scaffolds. The mechanical properties of the AM porous WE43 (E = 700-800 MPa) scaffolds were found to fall into the range of the values reported for trabecular bone even after 4 weeks of biodegradation. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), electrochemical tests and µCT revealed a unique biodegradation mechanism that started with uniform corrosion, followed by localized corrosion, particularly in the center of the scaffolds. Biocompatibility tests performed up to 72 h showed level 0 cytotoxicity (according to ISO 10993-5 and -12), except for one time point (i.e., 24 h). Intimate contact between cells (MG-63) and the scaffolds was also observed in SEM images. The study shows for the first time that AM of porous Mg may provide distinct possibilities to adjust biodegradation profile through topological design and open up unprecedented opportunities to develop multifunctional bone substituting materials that mimic bone properties and enable full regeneration of critical-size load-bearing bony defects. Statement of significance The ideal biomaterials for bone tissue regeneration should be bone-mimicking in terms of mechanical properties, present a fully interconnected porous structure, and exhibit a specific biodegradation behavior to enable full regeneration of bony defects. Recent advances in additive manufacturing have resulted in biomaterials that satisfy the first two requirements but simultaneously satisfying the third requirement has proven challenging so far. Here we present additively manufactured porous magnesium structures that have the potential to satisfy all above-mentioned requirements. Even after 4 weeks of biodegradation, the mechanical properties of the porous structures were found to be within those reported for native bone. Moreover, our comprehensive electrochemical, mechanical, topological, and biological study revealed a unique biodegradation behavior and the limited cytotoxicity of the developed biomaterials.
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      PubDate: 2017-12-12T15:12:08Z
  • Preparation of dexamethasone-loaded biphasic calcium phosphate
           nanoparticles/collagen porous composite scaffolds for bone tissue
    • Abstract: Publication date: Available online 12 December 2017
      Source:Acta Biomaterialia
      Author(s): Ying Chen, Naoki Kawazoe, Guoping Chen
      Although bone is regenerative, its regeneration capacity is limited. For bone defects beyond a critical size, further intervention is required. As an attractive strategy, bone tissue engineering (bone TE) has been widely investigated to repair bone defects. However, the rapid and effective bone regeneration of large non-healing defects is still a great challenge. Multifunctional scaffolds having osteoinductivity and osteoconductivity are desirable to fasten functional bone tissue regeneration. In the present study, biomimetic composite scaffolds of collagen and biphasic calcium phosphate nanoparticles (BCP NPs) with a controlled release of dexamethasone (DEX) and the controlled pore structures were prepared for bone TE. DEX was introduced in the BCP NPs during preparation of the BCP NPs and hybridized with collagen scaffolds, which pore structures were controlled by using pre-prepared ice particulates as a porogen material. The composite scaffolds had well controlled and interconnected pore structures, high mechanical strength and a sustained release of DEX. The composite scaffolds showed good biocompatibility and promoted osteogenic differentiation of hMSCs when used for three-dimensional culture of human bone marrow-derived mesenchymal stem cells. Subcutaneous implantation of the composite scaffolds at the dorsa of athymic nude mice demonstrated that they facilitated the ectopic bone tissue regeneration. The results indicated the DEX-loaded BCP NPs/collagen composite scaffolds had high potential for bone TE. Statement of significance Scaffolds play a crucial role for regeneration of large bone defects. Biomimetic scaffolds having the same composition of natural bone and a controlled release of osteoinductive factors are desirable for promotion of bone regeneration. In this study, composite scaffolds of collagen and biphasic CaP nanoparticles (BCP NPs) with a controlled release nature of dexamethasone (DEX) were prepared and their porous structures were controlled by using ice particulates. In vitro cell culture and in vivo implantation experiments demonstrated the composite scaffolds exerted synergistic effects on the osteogenic differentiation of hMSCs and bone regeneration. The composite scaffolds also showed promotive effect on the formation of capillary blood vessels in the regenerated bone. This study is the first research to prepare DEX-loaded BCP NPs/collagen porous composite scaffolds. The superior performance of the composite scaffolds indicates the composite scaffolds should be useful for bone tissue engineering.
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      PubDate: 2017-12-12T15:12:08Z
  • Determination of Green’s Function for Three-dimensional Traction Force
           Reconstruction Based on Geometry and Boundary Conditions of Cell Culture
    • Abstract: Publication date: Available online 12 December 2017
      Source:Acta Biomaterialia
      Author(s): Y. Du, S.C.B. Herath, Q.G. Wang, H. Asada, P.C.Y. Chen
      Cell migration plays a particular important role in the initiation and progression of many physical processes and pathological conditions such as tumor invasion and metastasis. Three-dimensional traction force microscopy (TFM) of high resolution and high accuracy is being developed in an effort to unveil the underlying mechanical process of cell migration in a vivo-like environment. Linear elasticity-based TFM (LETM) as a mainstream approach relies on the Green’s function (that relates traction forces to matrix deformation), of which the inherent boundary conditions and geometry of the matrix could remarkably affect the result as suggested by previous 2D studies. In this study, we investigated this close linkage in 3D environment, via modeling of a cell sensing a close-by fixed boundary of a 3D matrix surrounding it, and comparing the reconstructed traction forces from three different solutions of the Green’s function, including a fully matching solution derived using the adapted Mindlin’s approach. To increase fidelity in the estimate of traction forces for extreme conditions such as a sparse sampling of deformation field or targeting small focal adhesions, we numerically solved the singularity problem of the Green’s function in a non-conventional way to avoid exclusion of singular point regions that could contain representative deformation indicators for such extreme conditions. A single case experimental study was conducted for a multi-cellular structure of endothelial cells that just penetrated into the gel at the early stage of angiogenesis. Statement of Significance This study focused on the fundamental issue regarding extension of linear elasticity-based TFM to deal with physically realistic matrices (where cells are encapsulated), which concerns determination of the Green’s function matching their geometry and boundary conditions. To increase fidelity in the estimate of traction forces for extreme conditions such as a sparse sampling of deformation field or targeting small focal adhesions, we numerically solved the singularity problem of the Green’s function to avoid exclusion of singular point regions that could contain representative deformation indicators for such extreme conditions. The proposed approach to adapting the Green’s function for the specific 3D cell culture situation was examined in a single case experimental study of endothelial cells in sprouting angiogenesis.
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      PubDate: 2017-12-12T15:12:08Z
  • The impact of functional groups of poly(ethylene glycol) macromers on the
           physical properties of photo-polymerized hydrogels and the local
           inflammatory response in the host
    • Abstract: Publication date: Available online 12 December 2017
      Source:Acta Biomaterialia
      Author(s): James R. Day, Anu David, Jiwon Kim, Evan A. Farkash, Marilia Cascalho, Nikola Milašinović, Ariella Shikanov
      Poly(ethylene glycol) (PEG) can be functionalized and modified with various moieties allowing for a multitude of cross-linking chemistries. Here, we investigate how vinyl sulfone, acrylate, and maleimide functional end groups affect hydrogel formation, physical properties, viability of encapsulated cells, post-polymerization modification, and inflammatory response of the host. We have shown that PEG-VS hydrogels, in the presence of a co-monomer, N-vinyl-2-pyrrolidone (NVP), form more efficiently than PEG-Ac and PEG-Mal hydrogels, resulting in superior physical properties after 6 minutes of ultraviolet light exposure. PEG-VS hydrogels exhibited hydrolytic stability and non-fouling characteristics, as well as the ability to be modified with biological motifs, such as RGD, after polymerization. Additionally, unmodified PEG-VS hydrogels resulted in lesser inflammatory response, cellular infiltration, and macrophage recruitment after implantation for 28 days in mice. These findings show that altering the end group chemistry of PEG macromer impacts characteristics of the photo-polymerized network. We have developed a tunable non-degradable PEG system that is conducive for cell or tissue encapsulation and evokes a minimal inflammatory response, which could be utilized for future immunoisolation applications. Statement of Significance The objective of this study was to develop a tunable non-degradable PEG system that is conducive for encapsulation and evokes a minimal inflammatory response, which could be utilized for immunoisolation applications. This study has demonstrated that reactive functional groups of the PEG macromers impact free radical mediated network formation. Here, we show PEG-VS hydrogels meet the design criteria for an immunoisolating device as PEG-VS hydrogels form efficiently via photo-polymerization, impacting bulk properties, was stable in physiological conditions, and elicited a minimal inflammatory response. Further, NVP can be added to the precursor solution to expedite the cross-linking process without impacting cellular response upon encapsulation. These findings present an additional approach/chemistry to encapsulate cells or tissue for immunoisolation applications.
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      PubDate: 2017-12-12T15:12:08Z
  • NF-κB signaling is key in the wound healing processes of silk fibroin
    • Abstract: Publication date: Available online 11 December 2017
      Source:Acta Biomaterialia
      Author(s): Ye Ri Park, Md. Tipu Sultan, Hyun Jung Park, Jung Min Lee, Hyung Woo Ju, Ok Joo Lee, Dong Jin Lee, David L. Kaplan, Chan Hum Park
      Silk fibroin (SF) is a well-studied biomaterial for tissue engineering applications including wound healing. However, the signaling mechanisms underlying the impact of SF on this phenomenon have not been determined. In this study, through microarray analysis, regulatory genes of NF-ĸB signaling were activated in SF-treated NIH3T3 cells along with other genes. Immunoblot analysis confirmed the activation of the NF-ĸB signaling pathway as SF induced protein expression levels of IKKα, IKKβ, p65, and the degradation of IκBα. The treatment of NIH3T3 cells with SF also increased the expression of cyclin D1, vimentin, fibronectin, and vascular endothelial growth factor (VEGF). The expression of these factors by SF treatment was abrogated when NF-ĸB was inhibited by a pharmacological inhibitor Bay 11-7082. Knockdown of NF-ĸB using siRNA of IKKα and IKKβ also inhibited the SF-induced wound healing response of the NIH3T3 cells in a wound scratch assay. Collectively, these results indicated that SF-induced wound healing through the canonical NF-κB signaling pathway via regulation of the expression of cyclin D1, vimentin, fibronectin, and VEGF by NIH3T3 cells. Using an in vivo study with a partial-thickness excision wound in rats we demonstrated that SF-induced wound healing via NF-κB regulated proteins including cyclin D1, fibronectin, and VEGF. The in vitro and in vivo data suggested that SF induced wound healing via modulation of NF-ĸB signaling regulated proteins. Statement of Significance Silk fibroin has been effectively used as a dressing for wound treatment for more than a century. However, mechanistic insight into the basis for wound healing via silk fibroin has not been elucidated. Here we report a key mechanism involved in silk fibroin induced wound healing both in vitro and in vivo. Using genetic- and protein-level analyses, NF-κB signaling was found to regulate silk fibroin-induced wound healing by modulating target proteins. Thus, the NF-κB signaling pathway may be utilized as a therapeutic target during the formulation of silk fibroin-based biomaterials for wound healing and tissue engineering.
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      PubDate: 2017-12-12T15:12:08Z
  • Fibrin hydrogels as a xenofree and rapidly degradable support for
           transplantation of retinal pigment epithelium monolayers
    • Abstract: Publication date: Available online 9 December 2017
      Source:Acta Biomaterialia
      Author(s): Jarel K. Gandhi, Zahid Manzar, Lori A Bachman, Cynthia Andrews-Pfannkoch, Travis Knudsen, Matthew Hill, Hannah Schmidt, Raymond Iezzi, Jose S. Pulido, Alan D. Marmorstein
      Recent phase 1 trials of embryonic stem cell and induced pluripotent stem cell (iPSCs) derived RPE transplants for the treatment of macular degeneration have demonstrated the relative safety of this process. However, there is concern over clumping, thickening, folding, and wrinkling of the transplanted RPE. To deliver a flat RPE monolayer, current phase 1 trials are testing synthetic substrates for RPE transplantation. These substrates, however, cause localized inflammation and fibrosis in animal models due to long degradation times. Here we describe the use of thin fibrin hydrogels as a support material for the transplantation of RPE. Fibrin was formed into a mechanically rigid support that allow for easy manipulation with standard surgical instruments. Using fibrinolytic enzymes, fibrin hydrogels were degraded on the scale of hours. The rate of degradation could be controlled by varying the fibrinolytic enzyme concentration used. RPE cells degraded fibrin spontaneously. To preserve the fibrin support during differentiation of iPSCs to RPE, media was supplemented with the protease inhibitor aprotinin. iPSC-RPE on fibrin gels remained viable, generated monolayers with characteristic cobblestone appearance and dark pigmentation, and expressed mRNA and protein markers characteristic of RPE in the eye. Following differentiation of the cells, addition of fibrinolytic enzymes fully and rapidly degraded the fibrin support leaving behind an intact, viable iPSC-RPE monolayer. In conclusion, human fibrin hydrogels provide a xeno-free support on which iPSCs can be differentiated to RPE cells for transplant which can be rapidly degraded under controlled conditions using fibrinolytic enzymes without adverse effects to the cells. Statement of Significance Stem cell-derived retinal pigment epithelial (RPE) cell transplantation is currently in phase 1 clinical trials for macular degeneration (MD). A major obstacle in these studies is delivering the RPE as a living, flat sheets without leaving behind foreign materials in the retina. Here we investigate the suitability of using hydrogels made from human blood-derived proteins for RPE transplant. Our data shows that these fibrin hydrogels are rigid enough for use in surgery, support growth of stem cell-derived RPE, and are easily degraded within hours without damage to the RPE sheet. These fibrin hydrogels offer a promising solution to transplant RPE for patients with MD.
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      PubDate: 2017-12-12T15:12:08Z
  • Fatigue performance of additively manufactured meta-biomaterials: the
           effects of topology and material type
    • Authors: S.M. Ahmadi; R. Hedayati; Y. Li; K. Lietaert; N. Tümer; A. Fatemi; C.D. Rans; B. Pouran; H. Weinans; A.A. Zadpoor
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): S.M. Ahmadi, R. Hedayati, Y. Li, K. Lietaert, N. Tümer, A. Fatemi, C.D. Rans, B. Pouran, H. Weinans, A.A. Zadpoor
      Additive manufacturing (AM) techniques enable fabrication of bone-mimicking meta-biomaterials with unprecedented combinations of topological, mechanical, and mass transport properties. The mechanical performance of AM meta-biomaterials is a direct function of their topological design. It is, however, not clear to what extent the material type is important in determining the fatigue behavior of such biomaterials. We therefore aimed to determine the isolated and modulated effects of topological design and material type on the fatigue response of metallic meta-biomaterials fabricated with selective laser melting. Towards that end, we designed and additively manufactured Co-Cr meta-biomaterials with three types of repeating unit cells and three to four porosities per type of repeating unit cell. The AM meta-biomaterials were then mechanically tested to obtain their normalized S-N curves. The obtained S-N curves of Co-Cr meta-biomaterials were compared to those of meta-biomaterials with same topological designs but made from other materials, i.e. Ti-6Al-4V, tantalum, and pure titanium, available from our previous studies. We found the material type to be far more important than the topological design in determining the normalized fatigue strength of our AM metallic meta-biomaterials. This is the opposite of what we have found for the quasi-static mechanical properties of the same meta-biomaterials. The effects of material type, manufacturing imperfections, and topological design were different in the high and low cycle fatigue regions. That is likely because the cyclic response of meta-biomaterials depends not only on the static and fatigue strengths of the bulk material but also on other factors that may include strut roughness, distribution of the micro-pores created inside the struts during the AM process, and plasticity. Statement of Significance Meta-biomaterials are a special class of metamaterials with unusual or unprecedented combinations of mechanical, physical (e.g. mass transport), and biological properties. Topologically complex and additively manufactured meta-biomaterials have been shown to improve bone regeneration and osseointegration. The mechanical properties of such biomaterials are directly related to their topological design and material type. However, previous studies of such biomaterials have largely neglected the effects of material type, instead focusing on topological design. We show here that neglecting the effects of material type is unjustified. We studied the isolated and combined effects of topological design and material type on the normalized S-N curves of metallic bone-mimicking biomaterials and found them to be more strongly dependent on the material type than topological design.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.014
  • Laponite nanoparticle-associated silated hydroxypropylmethyl cellulose as
           an injectable reinforced interpenetrating network hydrogel for cartilage
           tissue engineering
    • Authors: Cécile Boyer; Lara Figueiredo; Richard Pace; Julie Lesoeur; Thierry Rouillon; Catherine Le Visage; Jean-François Tassin; Pierre Weiss; Jérôme Guicheux; Gildas Rethore
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): Cécile Boyer, Lara Figueiredo, Richard Pace, Julie Lesoeur, Thierry Rouillon, Catherine Le Visage, Jean-François Tassin, Pierre Weiss, Jérôme Guicheux, Gildas Rethore
      Articular cartilage is a connective tissue which does not spontaneously heal. To address this issue, biomaterial-assisted cell therapy has been researched with promising advances. The lack of strong mechanical properties is still a concern despite significant progress in three-dimensional scaffolds. This article’s objective was to develop a composite hydrogel using a small amount of nano-reinforcement clay known as laponites. These laponites were capable of self-setting within the gel structure of the silated hydroxylpropylmethyl cellulose (Si-HPMC) hydrogel. Laponites (XLG) were mixed with Si-HPMC to prepare composite hydrogels leading to the development of a hybrid interpenetrating network. This interpenetrating network increases the mechanical properties of the hydrogel. The in vitro investigations showed no side effects from the XLG regarding cytocompatibility or oxygen diffusion within the composite after cross-linking. The ability of the hybrid scaffold containing the composite hydrogel and chondrogenic cells to form a cartilaginous tissue in vivo was investigated during a 6-week implantation in subcutaneous pockets of nude mice. Histological analysis of the composite constructs revealed the formation of a cartilage-like tissue with an extracellular matrix containing glycosaminoglycans and collagens. Overall, this new hybrid construct demonstrates an interpenetrating network which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, oxygen diffusion, or the ability of chondrogenic cells to self-organize in the cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects in a large animal model of articular cartilage defects. Significance Articular Cartilage is a tissue that fails to heal spontaneously. To address this clinically relevant issue, biomaterial-assisted cell therapy is considered promising but they are often lacking in mechanical properties. Our objective was to develop a composite hydrogel using a small amount of nano reinforcement (laponite) capable of gelling within polysaccharide based self-crosslinking hydrogel. This new hybrid construct demonstrates an interpenetrating network (IPN) which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, O2 diffusion and the ability of chondrogenic cells to self-organize in cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects will now be considered in a large animal model of articular cartilage defects.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.027
  • The Hierarchical Response of Human Corneal Collagen to Load
    • Authors: J.S. Bell; S. Hayes; C. Whitford; J. Sanchez-Weatherby; O. Shebanova; C. Vergari; C.P. Winlove; N Terrill; T. Sorensen; A. Elsheikh; K.M. Meek
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): J.S. Bell, S. Hayes, C. Whitford, J. Sanchez-Weatherby, O. Shebanova, C. Vergari, C.P. Winlove, N Terrill, T. Sorensen, A. Elsheikh, K.M. Meek
      Fibrillar collagen in the human cornea is integral to its function as a transparent lens of precise curvature, and its arrangement is now well-characterised in the literature. While there has been considerable effort to incorporate fibrillar architecture into mechanical models of the cornea, the mechanical response of corneal collagen to small applied loads is not well understood. In this study the fibrillar and molecular response to tensile load was quantified using small and wide angle X-ray scattering (SAXS/WAXS), and digital image correlation (DIC) photography was used to calculate the local strain field that gave rise to the hierarchical changes. A molecular scattering model was used to calculate the tropocollagen tilt relative to the fibril axis and changes associated with applied strain. Changes were measured in the D-period, molecular tilt and the orientation and spacing of the fibrillar and molecular networks. These measurements were summarised into hierarchical deformation mechanisms, which were found to contribute at varying strains. The change in molecular tilt is indicative of a sub-fibrillar “spring-like” deformation mechanism, which was found to account for most of the applied strain under physiological and near-physiological loads. This deformation mechanism may play an important functional role in tissues rich in fibrils of high helical tilt, such as skin and cartilage. Statement of Significance Collagen is the primary mediator of soft tissue biomechanics, and variations in its hierarchical structure convey the varying amounts of structural support necessary for organs to function normally. Here we have examined the structural response of corneal collagen to tensile load using X-rays to probe hierarchies ranging from molecular to fibrillar. We found a previously unreported deformation mechanism whereby molecules, which are helically arranged relative to the axis of their fibril, change in tilt akin to the manner in which a spring stretches. This “spring-like” mechanism accounts for a significant portion of the applied deformation at low strains (<3%). These findings will inform the future design of collagen-based artificial corneas being developed to address world-wide shortages of corneal donor tissue.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.015
  • Development of gelatin/ascorbic acid cryogels for potential use in corneal
           stromal tissue engineering
    • Authors: Li-Jyuan Luo; Jui-Yang Lai; Shih-Feng Chou; Yi-Jen Hsueh; David Hui-Kang Ma
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): Li-Jyuan Luo, Jui-Yang Lai, Shih-Feng Chou, Yi-Jen Hsueh, David Hui-Kang Ma
      To offer an ideal hospitable environment for corneal keratocyte growth, the carrier materials can be functionalized with incorporation of signaling molecules to regulate cell biological events. This study reports, for the first time, the development of gelatin/ascorbic acid (AA) cryogels for keratocyte carriers in vitro and in vivo. The cryogel samples were fabricated by blending of gelatin with varying amounts of AA (0-300 mg) and carbodiimide cross-linking via cryogelation technique. Hydrophilic AA content in the carriers was found to significantly affect cross-linking degree and pore dimension of cryogels, thereby dictating their mechanical and biological stability and AA release profile. The cryogel carriers with low-to-moderate AA loadings were well tolerated by rabbit keratocyte cultures and anterior segment eye tissues, demonstrating good ocular biocompatibility. Although higher incorporated AA level contributed to enhanced metabolic activity and biosynthetic capacity of keratocytes grown on cryogel matrices, the presence of excessive amounts of AA molecules could lead to toxic effect and limit cell proliferation and matrix production. The cytoprotective activity against oxidative stress was shown to be strongly dependent on AA release, which further determined cell culture performance and tissue reconstruction efficiency. With the optimum AA content in carrier materials, intrastromally implanted cell/cryogel constructs exhibited better capability to enhance tissue matrix regeneration and transparency maintenance as well as to mitigate corneal damage in an alkali burn-induced animal model. It is concluded that understanding of antioxidant molecule-mediated structure-property-function interrelationships in gelatin/AA cryogels is critical to designing carrier materials for potential use in corneal stromal tissue engineering. Statement of significance Multifunctional cryogel material can offer an ideal hospitable environment for cell-mediated tissue reconstruction. To our knowledge, this is the first report describing the use of gelatin/ascorbic acid (AA) cryogels as keratocyte carriers for corneal stromal tissue engineering. The AA loading during cryogel fabrication is found to have a significant effect on cross-linking degree and pore dimension, mechanical and biological stability, ocular biocompatibility, cell culture performance, and cytoprotective activity, giving comprehensive insight into fine-tuning the structure-property-function interrelationships of keratocyte carrier material. Using an alkali burn-induced animal model, we present evidence that with the optimum AA loading into cryogel materials, intrastromally implanted cell/carrier constructs exhibited better capability to enhance tissue matrix regeneration and transparency maintenance as well as to mitigate corneal damage.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.018
  • Injectable nanocomposite cryogels for versatile protein drug delivery
    • Authors: Sandeep T. Koshy; David K.Y. Zhang; Joshua M. Grolman; Alexander G. Stafford; David J. Mooney
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): Sandeep T. Koshy, David K.Y. Zhang, Joshua M. Grolman, Alexander G. Stafford, David J. Mooney
      Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems. Statement of Significance Here we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein’s activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.024
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