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Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 22)
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: 26)
Acta Biotheoretica     Hybrid Journal   (Followers: 4)
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: 10)
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: 4)
Advances in Bioinformatics     Open Access   (Followers: 20)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 7)
Advances in Cell Biology     Open Access   (Followers: 25)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 13)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 6)
Advances in Ecological Research     Full-text available via subscription   (Followers: 47)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 9)
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Advances in Human Biology     Open Access   (Followers: 2)
Advances in Life Science and Technology     Open Access   (Followers: 14)
Advances in Life Sciences     Open Access   (Followers: 6)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
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Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
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Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Virus Research     Full-text available via subscription   (Followers: 6)
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: 9)
Aging Cell     Open Access   (Followers: 11)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Full-text available via subscription   (Followers: 14)
AJP Endocrinology and Metabolism     Full-text available via subscription   (Followers: 23)
AJP Lung Cellular and Molecular Physiology     Full-text available via subscription   (Followers: 3)
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: 14)
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 Human Biology     Hybrid Journal   (Followers: 13)
American Journal of Medical and Biological Research     Open Access   (Followers: 8)
American Journal of Plant Sciences     Open Access   (Followers: 18)
American Journal of Primatology     Hybrid Journal   (Followers: 14)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 74)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 11)
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: 5)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 14)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 23)
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: 37)
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: 22)
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: 9)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 4)
Apmis     Hybrid Journal   (Followers: 1)
APOPTOSIS     Hybrid Journal   (Followers: 8)
Applied Bionics and Biomechanics     Open Access   (Followers: 8)
Applied Vegetation Science     Full-text available via subscription   (Followers: 10)
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: 21)
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: 3)
Artificial Photosynthesis     Open Access   (Followers: 1)
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Journal of Biodiversity     Open Access   (Followers: 5)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 6)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 3)
Asian Journal of Nematology     Open Access   (Followers: 4)
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: 1)
Berita Biologi     Open Access   (Followers: 1)
Between the Species     Open Access   (Followers: 2)
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: 29)
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)
Biofilms     Full-text available via subscription   (Followers: 1)
Biogeosciences (BG)     Open Access   (Followers: 10)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 1)
Bioinformatics     Hybrid Journal   (Followers: 289)
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: 18)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 18)
Biological Letters     Open Access   (Followers: 5)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 45)
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: 41)
Biologija     Open Access  
Biology     Open Access   (Followers: 5)
Biology and Philosophy     Hybrid Journal   (Followers: 17)
Biology Bulletin     Hybrid Journal   (Followers: 1)

        1 2 3 4 5 6 7 8 | Last

Journal Cover Acta Biomaterialia
  [SJR: 2.02]   [H-I: 104]   [26 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7061
   Published by Elsevier Homepage  [3177 journals]
  • Extracellular matrix hydrogel therapies: In vivo applications and
    • Authors: Martin T. Spang; Karen L. Christman
      Pages: 1 - 14
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Martin T. Spang, Karen L. Christman
      Decellularized extracellular matrix (ECM) has been widely used for tissue engineering applications and is becoming increasingly versatile as it can take many forms, including patches, powders, and hydrogels. Following additional processing, decellularized ECM can form an inducible hydrogel that can be injected, providing for new minimally-invasive procedure opportunities. ECM hydrogels have been derived from numerous tissue sources and applied to treat many disease models, such as ischemic injuries and organ regeneration or replacement. This review will focus on in vivo applications of ECM hydrogels and functional outcomes in disease models, as well as discuss considerations for clinical translation. Statement of Significance Extracellular matrix (ECM) hydrogel therapies are being developed to treat diseased or damaged tissues and organs throughout the body. Many ECM hydrogels are progressing from in vitro models to in vivo biocompatibility studies and functional models. There is significant potential for clinical translation of these therapies since one ECM hydrogel therapy is already in a Phase 1 clinical trial.
      Graphical abstract image

      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.019
      Issue No: Vol. 68 (2018)
  • Preparation of decellularized biphasic hierarchical myotendinous junction
           extracellular matrix for muscle regeneration
    • Authors: Chenchen Zhao; Shengyu Wang; Gangliang Wang; Mingzhen Su; Liyang Song; Jiaxin Chen; Shunwu Fan; Xianfeng Lin
      Pages: 15 - 28
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Chenchen Zhao, Shengyu Wang, Gangliang Wang, Mingzhen Su, Liyang Song, Jiaxin Chen, Shunwu Fan, Xianfeng Lin
      Muscle injury and defect affect people's quality of life, and effective treatment is lacking. Herein, we generated a scaffold to obtain decellularized porcine Achilles tendon myotendinous junction (D-MTJ) extracellular matrix (ECM) with well-preserved native biphasic hierarchical structure, biological composition, and excellent mechanical properties for muscle regeneration. The combined use of potassium chloride, potassium iodide, Triton-X 100, and sodium-dodecyl sulfate (SDS) can completely remove the main immunogenicity, while maintaining the major biological components and microstructure. The specific biomechanics of D-MTJ is comparable to the native muscle-tendon physiological conditions. Additionally, the D-MTJ ECM scaffold induced minimal immunological reaction (histology analysis) through rat subcutaneous implantation. Moreover, in vitro, muscle satellite cells adhered, proliferated, and infiltrated into the D-MTJ scaffold, and myofiber-like cell differentiation was observed as shown by increased expression of myogenesis-related genes during culture. In vivo, newly formed myofibers were observed in a muscle defect model with D-MTJ orthotopic transplantation, while the control group presented mostly with fibrous tissue deposition. Additionally, the number of Myod and MyHC-positive cells in the ECM scaffold group was higher at day 30. We preliminary explored the mechanisms underlying D-MTJ-mediated muscle regeneration, which may be attributed to its specific biphasic hierarchical structure, bio-components, and attractiveness for myogenesis cells. In conclusion, our findings suggest the D-MTJ ECM scaffold prepared in this study is a promising choice for muscle regeneration. Statement of Significance This study is the first to use decellularization technology obtaining the specifically decellularized myotendinous junction (D-MTJ) with well-preserved biphasic hierarchical structure and constituents, excellent mechanical properties and good biocompatibility. The D-MTJ was further proved to be efficient for muscle regeneration in vitro and in vivo, and the underlying mechanisms may be attributed to its specifically structure and constituents, improved myogenesis and good preservation of repair-related factors. Our study may provide basis for the decellularization of other biphasic hierarchical tissues and a platform for further studies on muscle fiber and tendon integrations in vitro.
      Graphical abstract image

      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.035
      Issue No: Vol. 68 (2018)
  • In vivo performance of freeze-dried decellularized pulmonary heart valve
           allo- and xenografts orthotopically implanted into juvenile sheep
    • Authors: Tobias Goecke; Karolina Theodoridis; Igor Tudorache; Anatol Ciubotaru; Serghei Cebotari; Robert Ramm; Klaus Höffler; Samir Sarikouch; Andrés Vásquez Rivera; Axel Haverich; Willem F. Wolkers; Andres Hilfiker
      Pages: 41 - 52
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Tobias Goecke, Karolina Theodoridis, Igor Tudorache, Anatol Ciubotaru, Serghei Cebotari, Robert Ramm, Klaus Höffler, Samir Sarikouch, Andrés Vásquez Rivera, Axel Haverich, Willem F. Wolkers, Andres Hilfiker
      The decellularization of biological tissues decreases immunogenicity, allows repopulation with cells, and may lead to improved long-term performance after implantation. Freeze drying these tissues would ensure off-the-shelf availability, save storage costs, and facilitates easy transport. This study evaluates the in vivo performance of freeze-dried decellularized heart valves in juvenile sheep. TritonX-100 and sodium dodecylsulfate decellularized ovine and porcine pulmonary valves (PV) were freeze-dried in a lyoprotectant sucrose solution. After rehydration for 24 h, valves were implanted into the PV position in sheep as allografts (fdOPV) and xenografts (fdPPV), while fresh dezellularized ovine grafts (frOPV) were implanted as controls. Functional assessment was performed by transesophageal echocardiography at implantation and at explantation six months later. Explanted grafts were analysed histologically to assess the matrix, and immunofluorescence stains were used to identify the repopulating cells. Although the graft diameters and orifice areas increased, good function was maintained, except for one insufficient, strongly deteriorated frOPV. Cells which were positive for either endothelial or interstitial markers were found in all grafts. In fdPPV, immune-reactive cells were also found. Our findings suggest that freeze-drying does not alter the early hemodynamic performance and repopulation potential of decellularized grafts in vivo, even in the challenging xenogeneic situation. Despite evidence of an immunological reaction for the xenogenic valves, good early functionalities were achieved. Statement of Significance Decellularized allogeneic heart valves show excellent results as evident from large animal experiments and clinical trials. However, a long-term storing method is needed for an optimal use of this limited resource in the clinical setting, where an optimized matching of graft and recipient is requested. As demonstrated in this study, freeze-dried and freshly decellularized grafts reveal equally good results after implantation in the juvenile sheep concerning function and repopulation with recipients’ cells. Thus, freeze-drying arises as a promising method to extend the shelf-life of valvular grafts compared to those stored in antibiotic-solution as currently practised.
      Graphical abstract image

      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.11.041
      Issue No: Vol. 68 (2018)
  • Fracture mechanics of shear crack propagation and dissection in the
           healthy bovine descending aortic media
    • Authors: Henry W. Haslach; Ahmed Siddiqui; Amanda Weerasooriya; Ryan Nguyen; Jacob Roshgadol; Noel Monforte; Eileen McMahon
      Pages: 53 - 66
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Henry W. Haslach, Ahmed Siddiqui, Amanda Weerasooriya, Ryan Nguyen, Jacob Roshgadol, Noel Monforte, Eileen McMahon
      This experimental study adopts a fracture mechanics strategy to investigate the mechanical cause of aortic dissection. Inflation of excised healthy bovine aortic rings with a cut longitudinal notch that extends into the media from the intima suggests that an intimal tear may propagate a nearly circumferential-longitudinal rupture surface that is similar to the delamination that occurs in aortic dissection. Radial and 45°-from-radial cut notch orientations, as seen in the thickness surface, produce similar circumferential crack propagation morphologies. Partial cut notches, whose longitudinal length is half the width of the ring, measure the influence of longitudinal material on crack propagation. Such specimens also produce circumferential cracks from the notch root that are visible in the thickness circumferential-radial plane, and often propagate a secondary crack from the base of the notch, visible in the intimal circumferential-longitudinal plane. Inflation of rings with pairs of cut notches demonstrates that a second notch modifies the propagation created in a specimen with a single notch. The circumferential crack propagation is likely a consequence of the laminar medial structure. These fracture surfaces are probably due to non-uniform circumferential shear deformation in the heterogeneous media as the aortic wall expands. The qualitative deformation morphology around the root of the cut notch during inflation is evidence for such shear deformation. The shear apparently results from relative slip in the circumferential direction of collagen fibers. The slip may produce shear in the longitudinal-circumferential plane between medial layers or in the radial-circumferential plane within a medial lamina in an idealized model. Circumferential crack propagation in the media is then a shear mechanical process that might be facilitated by disease of the tissue. Statement of Significance An intimal tear of an apparently healthy aortic wall near the aortic arch is life-threatening because it may lead to full rupture or to wall dissection in which delamination of the medial layer extends around most of the aortic circumference. The mechanical events underlying dissection are not definitively established. This experimental fracture mechanics study provides evidence that shear rupture is the main mechanical process underlying aortic dissection. The commonly performed tensile strength tests of aortic tissue are not clinically useful to predict or describe aortic dissection. One implication of the study is that shear tests might produce more fruitful simple assessments of the aortic wall strength. A clinical implication is that when presented with an intimal tear, those who guide care might recommend steps to reduce the shear load on the aorta.
      Graphical abstract image

      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.027
      Issue No: Vol. 68 (2018)
  • Ultrastructural organization of elastic fibres in the partition boundaries
           of the annulus fibrosus within the intervertebral disc
    • Authors: J. Tavakoli; J.J. Costi
      Pages: 67 - 77
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): J. Tavakoli, J.J. Costi
      The relationship between elastic fibre disorders and disc degeneration, aging and progression of spine deformity have been discussed in a small number of studies. However, the clinical relevance of elastic fibres in the annulus fibrosus (AF) of the disc is poorly understood. Ultrastructural visualization of elastic fibres is an important step towards understanding their structure-function relationship. In our previous studies, a novel technique for visualization of elastic fibres across the AF was presented and their ultrastructural organization in intra- and inter-lamellar regions was compared. Using the same novel technique in the present study, the ultrastructural organization of elastic fibres in the partition boundaries (PBs), which are located between adjacent collagen bundles, is presented for the first time. Visualization of elastic fibres in the PBs in control and partially digested (digested) samples was compared, and their orientation in two different cutting planes (transverse and oblique) were discussed. The ultrastructural analysis revealed that elastic fibres in PBs were a well-organized dense and complex network having different size and shape. Adjacent collagen bundles in a cross section (CS) lamella appear to be connected to each other, where elastic fibres in the PBs were merged in parallel or penetrated into the collagen bundles. There was no significant difference in directional coherency coefficient of elastic fibres between the two different cutting planes (p = .35). The present study revealed that a continuous network of elastic fibres may provide disc integrity by connecting adjacent bundles of CS lamellae together. Compared to our previous studies, the density of the elastic fibre network in PBs was lower, and fibre orientation was similar to the intra-lamellar space and inter-lamellar matrix. Statement of Significance A detailed ultrastructural study in the partition boundaries of the annulus fibrosus within the disc revealed a well-organized elastic fibre network with a complex ultrastructure. The continuous network of elastic fibres may provide disc integrity by connecting adjacent bundles of cross section lamellae together. The density of the elastic fibre network in PBs was lower, and fibre orientation was similar to the intra-lamellar space and the inter-lamellar matrix.
      Graphical abstract image

      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.017
      Issue No: Vol. 68 (2018)
  • Comparison of in vivo and ex vivo viscoelastic behavior of the spinal cord
    • Authors: Nicole L. Ramo; Snehal S. Shetye; Femke Streijger; Jae H.T. Lee; Kevin L. Troyer; Brian K. Kwon; Peter Cripton; Christian M. Puttlitz
      Pages: 78 - 89
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Nicole L. Ramo, Snehal S. Shetye, Femke Streijger, Jae H.T. Lee, Kevin L. Troyer, Brian K. Kwon, Peter Cripton, Christian M. Puttlitz
      Despite efforts to simulate the in vivo environment, post-mortem degradation and lack of blood perfusion complicate the use of ex vivo derived material models in computational studies of spinal cord injury. In order to quantify the mechanical changes that manifest ex vivo, the viscoelastic behavior of in vivo and ex vivo porcine spinal cord samples were compared. Stress-relaxation data from each condition were fit to a non-linear viscoelastic model using a novel characterization technique called the direct fit method. To validate the presented material models, the parameters obtained for each condition were used to predict the respective dynamic cyclic response. Both ex vivo and in vivo samples displayed non-linear viscoelastic behavior with a significant increase in relaxation with applied strain. However, at all three strain magnitudes compared, ex vivo samples experienced a higher stress and greater relaxation than in vivo samples. Significant differences between model parameters also showed distinct relaxation behaviors, especially in non-linear relaxation modulus components associated with the short-term response (0.1–1 s). The results of this study underscore the necessity of utilizing material models developed from in vivo experimental data for studies of spinal cord injury, where the time-dependent properties are critical. The ability of each material model to accurately predict the dynamic cyclic response validates the presented methodology and supports the use of the in vivo model in future high-resolution finite element modeling efforts. Statement of Significance Neural tissues (such as the brain and spinal cord) display time-dependent, or viscoelastic, mechanical behavior making it difficult to model how they respond to various loading conditions, including injury. Methods that aim to characterize the behavior of the spinal cord almost exclusively use ex vivo cadaveric or animal samples, despite evidence that time after death affects the behavior compared to that in a living animal (in vivo response). Therefore, this study directly compared the mechanical response of ex vivo and in vivo samples to quantify these differences for the first time. This will allow researchers to draw more accurate conclusions about spinal cord injuries based on ex vivo data (which are easier to obtain) and emphasizes the importance of future in vivo experimental animal work.
      Graphical abstract image

      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.024
      Issue No: Vol. 68 (2018)
  • 3D printed structures for modeling the Young’s modulus of bamboo
    • Authors: P.G. Dixon; J.T. Muth; X. Xiao; M.A. Skylar-Scott; J.A. Lewis; L.J. Gibson
      Pages: 90 - 98
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): P.G. Dixon, J.T. Muth, X. Xiao, M.A. Skylar-Scott, J.A. Lewis, L.J. Gibson
      Bamboo is a sustainable, lightweight material that is widely used in structural applications. To fully develop micromechanical models for plants, such as bamboo, the mechanical properties of each individual type of tissue are needed. However, separating individual tissues and testing them mechanically is challenging. Here, we report an alternative approach in which micro X-ray computed tomography (µ-CT) is used to image moso bamboo (Phyllostachys pubescens). The acquired images, which correspond to the 3D structure of the parenchyma, are then transformed into physical, albeit larger scale, structures by 3D printing, and their mechanical properties are characterized. The normalized longitudinal Young’s moduli of the fabricated structures depend on relative density raised to a power between 2 and 3, suggesting that elastic deformation of the parenchyma cellular structure involves considerable cell wall bending. The mechanical behavior of other biological tissues may also be elucidated using this approach. Statement of Significance Bamboo is a lightweight, sustainable engineering material widely used in structural applications. By combining micro X-ray computed tomography and 3D printing, we have produced bamboo parenchyma mimics and characterized their stiffness. Using this approach, we gained insight into bamboo parenchyma tissue mechanics, specifically the cellular geometry’s role in longitudinal elasticity.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.036
      Issue No: Vol. 68 (2018)
  • Nanoparticle-induced inflammation can increase tumor malignancy
    • Authors: Bella B. Manshian; Jennifer Poelmans; Shweta Saini; Suman Pokhrel; Julio Jiménez Grez; Uwe Himmelreich; Lutz Mädler; Stefaan J. Soenen
      Pages: 99 - 112
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Bella B. Manshian, Jennifer Poelmans, Shweta Saini, Suman Pokhrel, Julio Jiménez Grez, Uwe Himmelreich, Lutz Mädler, Stefaan J. Soenen
      Nanomaterials, such as aluminum oxide, have been regarded with high biomedical promise as potential immune adjuvants in favor of their bulk counterparts. For pathophysiological conditions where elevated immune activity already occurs, the contribution of nanoparticle-activated immune reactions remains unclear. Here, we investigated the effect of spherical and wire-shaped aluminum oxide nanoparticles on primary splenocytes and observed a clear pro-inflammatory effect of both nanoparticles, mainly for the high aspect ratio nanowires. The nanoparticles resulted in a clear activation of NLRP3 inflammasome, and also secreted transforming growth factor β. When cancer cells were exposed to these cytokines, this resulted in an increased level of epithelial-to-mesenchymal-transition, a hallmark for cancer metastasis, which did not occur when the cancer cells were directly exposed to the nanoparticles themselves. Using a syngeneic tumor model, the level of inflammation and degree of lung metastasis were significantly increased when the animals were exposed to the nanoparticles, particularly for the nanowires. This effect could be abrogated by treating the animals with inflammatory inhibitors. Collectively, these data indicate that the interaction of nanoparticles with immune cells can have secondary effects that may aggravate pathophysiological conditions, such as cancer malignancy, and conditions must be carefully selected to finely tune the induced aspecific inflammation into cancer-specific antitumor immunity. Statement of Significance Many different types of nanoparticles have been shown to possess immunomodulatory properties, depending on their physicochemical parameters. This can potentially be harnessed as a possible antitumor therapy. However, in the current work we show that inflammation elicited by nanomaterials can have grave effects in pathophysiological conditions, where non-specific inflammation was found to increase cancer cell mobility and tumor malignancy. These data show that immunomodulatory properties of nanomaterials must be carefully controlled to avoid any undesired side-effects.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.020
      Issue No: Vol. 68 (2018)
  • Repurposing disulfiram for cancer therapy via targeted nanotechnology
           through enhanced tumor mass penetration and disassembly
    • Authors: Huacheng He; Eleni Markoutsa; Jing Li; Peisheng Xu
      Pages: 113 - 124
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Huacheng He, Eleni Markoutsa, Jing Li, Peisheng Xu
      Disulfiram (DSF), an FDA approved drug for the treatment of alcoholism, degrades to therapeutically active diethyldithiocarbamate (DDTC) in the body by reduction. Hereby, we developed a redox sensitive DDTC-polymer conjugate for targeted cancer therapy. It was found that the DDTC-polymer conjugate modified with a β-d-galactose receptor targeting ligand can self-assemble into LDNP nanoparticle and efficiently enter cancer cells by receptor-mediated endocytosis. Upon cellular uptake, the LDNP nanoparticle degrades and releases DDTC due to the cleavage of disulfide bonds, and subsequently forms copper (II) DDTC complex to kill a broad spectrum of cancer cells. 3D cell culture revealed that this nanoparticle shows much stronger tumor mass penetrating and destructive capacity. Furthermore, LDNP nanoparticles exhibited much greater potency in inhibiting tumor growth in a peritoneal metastatic ovarian tumor model. Statement of Significance The β-d-galactose receptor targeted disulfiram loaded nanoparticle (LDNP) is novel in the following aspects: 1. Lactobionic acid (LBA) targets β-d-galactose receptor, which is a surface lectin that is overexpressed in various types of cancer cells, such as liver and ovarian cancers. The introducing of LBA ligand, endows the LDNP/Cu nanoparticle with stronger penetrating and destructive capacity in a tumor spheroid model. 2. The premature release of disulfiram from the nanoparticle can be minimized through the formation of polymer-prodrug based LDNP. 3. The LDNP nanoparticle fabricated from a polymer-disulfiram derivative conjugate can selectively kill a broad spectrum of cancer cells, while sparing normal cells. 4. In vivo study carried out in a clinically relevant orthotopic ovarian tumor model revealed that LDNP/Cu exhibits stronger efficacy in inhibiting the progression of metastatic ovarian cancer than a dosage form used in clinical trial, while not inducing side effects.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.023
      Issue No: Vol. 68 (2018)
  • Microparticle-mediated sequestration of cell-secreted proteins to modulate
           chondrocytic differentiation
    • Authors: Torri E. Rinker; Brandon D. Philbrick; Marian H. Hettiaratchi; David M. Smalley; Todd C. McDevitt; Johnna S. Temenoff
      Pages: 125 - 136
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Torri E. Rinker, Brandon D. Philbrick, Marian H. Hettiaratchi, David M. Smalley, Todd C. McDevitt, Johnna S. Temenoff
      Protein delivery is often used in tissue engineering applications to control differentiation processes, but is limited by protein instability and cost. An alternative approach is to control the cellular microenvironment through biomaterial-mediated sequestration of cell-secreted proteins important to differentiation. Thus, we utilized heparin-based microparticles to modulate cellular differentiation via protein sequestration in an in vitro model system of endochondral ossification. Heparin and poly(ethylene-glycol) (PEG; a low-binding material control)-based microparticles were incorporated into ATDC5 cell spheroids or incubated with ATDC5 cells in transwell culture. Reduced differentiation was observed in the heparin microparticle group as compared to PEG and no microparticle-containing groups. To determine if observed changes were due to sequestration of cell-secreted protein, the proteins sequestered by heparin microparticles were analyzed using SDS-PAGE and mass spectrometry. It was found that heparin microparticles bound insulin-like growth factor binding proteins (IGFBP)-3 and 5. When incubated with a small-molecule inhibitor of IGFBPs, NBI 31772, a similar delay in differentiation of ATDC5 cells was observed. These results indicate that heparin microparticles modulated chondrocytic differentiation in this system via sequestration of cell-secreted protein, a technique that could be beneficial in the future as a means to control cellular differentiation processes. Statement of Significance In this work, we present a proof-of-principle set of experiments in which heparin-based microparticles are shown to modulate cellular differentiation through binding of cell-secreted protein. Unlike existing systems that rely on expensive protein with limited half-lives to elicit changes in cellular behavior, this technique focuses on temporal modulation of cell-generated proteins. This technique also provides a biomaterials-based method that can be used to further identify sequestered proteins of interest. Thus, this work indicates that glycosaminoglycan-based biomaterial approaches could be used as substitutes or additions to traditional methods for modulating and identifying the cell-secreted proteins involved in directing cellular behavior.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.038
      Issue No: Vol. 68 (2018)
  • Redox-responsive polymeric micelles formed by conjugating gambogic acid
           with bioreducible poly(amido amine)s for the co-delivery of docetaxel and
           MMP-9 shRNA
    • Authors: Yanan Kang; Lu Lu; Jinshuai Lan; Yue Ding; Jing Yang; Yong Zhang; Yuan Zhao; Tong Zhang; Rodney J.Y. Ho
      Pages: 137 - 153
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Yanan Kang, Lu Lu, Jinshuai Lan, Yue Ding, Jing Yang, Yong Zhang, Yuan Zhao, Tong Zhang, Rodney J.Y. Ho
      A novel redox-sensitive system for co-delivering hydrophobic drugs and hydrophilic siRNA or shRNA was developed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs) through amide bonds, which is called GA-conjugated PAAs (PAG). PAG can self-assemble into micelles as amphiphilic block copolymers, which exhibits an excellent loading ability for the co-delivery of docetaxel (DTX) and MMP-9 shRNA with adjustable dosing ratios. In addition, confocal microscopy, flow cytometry and in vitro transfection analyses demonstrated more efficient cellular internalization of DTX and MMP-9 shRNA after incubation with PAG/DTX- MMP-9 shRNA micelles (PAG/DTX-shRNA) than with free drugs. Unlike traditional amphiphilic copolymer micelles, GA conjugated in PAG possesses an intrinsic anticancer efficacy. The presence of disulfide bonds in PAAs enables rapid disassembly of PAG micelles in response to reducing agents, inducing the release of loaded drugs (DTX, GA and MMP-9 shRNA). In vitro cellular assays revealed that PAG/DTX-shRNA micelles inhibited MCF-7 cell proliferation more efficiently than the single drug or single drug-loaded micelles. In vivo biodistribution and anti-tumor effect studies using an MCF-7 breast cancer xenograft mouse model have indicated that PAG/DTX-shRNA micelles can enhance drug accumulation compared with the free drug, thereby sustaining the therapeutic effect on tumors. Additionally, PAG/DTX-shRNA micelles displayed a greater anti-tumor efficacy than Taxotere® and PAG-shRNA micelles. These results suggest that the redox-sensitive PAG platform is a promising co-delivery system for combining drugs and gene therapy for the treatment of cancer. Statement of Significance The PAG micelles were designed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs), which would serve dual purposes as both gene and drugs co-delivery carrier and an anti-tumor prodrug. Unlike traditional amphiphilic micelles, GA conjugated in PAG could exert its intrinsic efficacy and provide synergistic antiproliferative effects with docetaxel (DTX) on MCF-7 cells. Disulfide bonds in PAG enables a rapid disassembly of PAG micelles in response to reducing agents and to release all loaded drugs (DTX, GA and MMP-9 shRNA) at tumor sites. PAG/DTX-shRNA micelles displayed greater anti-tumor efficacy than that of Taxotere®, indicating the design concept for PAG works well. And the strategy for PAG could be used to develop a series of similar co-delivery systems through conjugations of other small-molecule drugs with PAAs, such as doxorubicin, methotrexate and other drugs with carboxy groups in their structure.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.028
      Issue No: Vol. 68 (2018)
  • Multifunctional nanoparticles as somatostatin receptor-targeting delivery
           system of polyaniline and methotrexate for combined chemo–photothermal
    • Authors: Hanh Thuy Nguyen; Cao Dai Phung; Raj Kumar Thapa; Tung Thanh Pham; Tuan Hiep Tran; Jee-Heon Jeong; Sae Kwang Ku; Han-Gon Choi; Chul Soon Yong; Jong Oh Kim
      Pages: 154 - 167
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Hanh Thuy Nguyen, Cao Dai Phung, Raj Kumar Thapa, Tung Thanh Pham, Tuan Hiep Tran, Jee-Heon Jeong, Sae Kwang Ku, Han-Gon Choi, Chul Soon Yong, Jong Oh Kim
      Lanreotide (LT), a synthetic analog of somatostatin, has been demonstrated to specifically bind to somatostatin receptors (SSTRs), which are widely overexpressed in several types of cancer cells. In this study, we incorporated a chemotherapeutic agent, methotrexate (MTX), and a photosensitizer material, polyaniline (PANI), into hybrid polymer nanoparticles (NPs), which could target cancer cells after conjugation with LT (LT-MTX/PANI NPs). The successful preparation of LT–MTX/PANI NPs was confirmed by a small particle size (187.9 ± 3.2 nm), a polydispersity index of 0.232 ± 0.011, and a negative ζ potential of −14.6 ± 1.0 mV. Notably, LT-MTX/PANI NPs showed a greater uptake into SSTR-positive cancer cells and thereby better inhibited cell viability and induced higher levels of apoptosis than MTX, PANI NP, and MTX/PANI NP treatments did. In addition, the heat associated with the burst drug release induced by near-infrared (NIR) irradiation resulted in remarkably enhanced cell apoptosis, which was confirmed by an increase in the expression levels of apoptotic marker proteins. In agreement with the in vitro results, the administration of the SSTR-targeting NPs, followed by NIR exposure, to xenograft tumor-bearing mice resulted in an improved suppression of tumor development compared to that shown by MTX, PANI NPs, and MTX/PANI NPs, as well as by LT-MTX/PANI NPs without photothermal therapy. Thus, the SSTR-targeting NPs could be a promising delivery system for the effective treatment of SSTR-positive cancers. Statement of significance Somatostatin receptors are widely overexpressed in several types of cancer cells. In this study, we designed nanoparticles for targeted delivery of chemotherapeutic agents to tumor sites by conjugating hybrid polymers with a synthetic analog of somatostatin, specifically binding to somatostatin receptors. In addition, a photosensitizer material, polyaniline, was incorporated into the nanoparticles for combined chemo–photothermal therapy. The results demonstrated clear advantages of the newly designed targeted nanoparticles over their non-targeted counterparts or a free chemotherapeutic drug in inhibiting the viability of cancer cells in vitro and targeting/suppressing the tumor growth in an animal xenograft model. The study suggests that the designed nanoparticles are a promising delivery system for the effective treatment of somatostatin receptor-positive cancers.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.033
      Issue No: Vol. 68 (2018)
  • A poly(beta-amino ester) activates macrophages independent of NF-κB
    • Authors: Neil M. Dold; Qin Zeng; Xiangbin Zeng; Christopher M. Jewell
      Pages: 168 - 177
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Neil M. Dold, Qin Zeng, Xiangbin Zeng, Christopher M. Jewell
      Nucleic acid delivery vehicles are poised to play an important role in delivering gene therapy for vaccines and immunotherapies, and in delivering nucleic acid based adjuvants. A number of common polymeric delivery vehicles used in nucleic acid delivery have recently been shown to interact with immune cells and directly stimulate immunogenic responses, particularly in particle form. Poly(beta-amino esters) were designed for nucleic acid delivery and have demonstrated promising performance in a number of vaccine and therapeutic studies. Yet, little work has characterized the mechanisms by which these polymers activate immune cells. Here we demonstrate that a poly(beta-amino ester) activates antigen presenting cells in soluble and particulate forms, and that these effects are independent of TLR signaling pathways. Moreover, we show the polymers induce activation independent of NF-κB signaling, but do activate IRF, an important innate inflammatory pathway. New knowledge linking physicochemical features of poly(beta-amino esters) or other polymeric carriers to inflammatory mechanisms could support more rational design approaches for vaccines and immunotherapies harnessing these materials. Significance Statement The last several years have brought exciting work exploring biomaterials as delivery vehicles for immunotherapies, vaccines, and gene therapies. However, a gap remains between the striking finding that many biomaterials exhibit intrinsic immunogenic features, and the specific structural properties that drive these responses. The results in the current study indicate PBAEs cause macrophage activation by pathways that are distinct from pathways activated by common vaccine and immunotherapies components, such as toll-like receptor agonists. Thus, the work reveals new mechanistic details that can be exploited in investigating other materials, and to support more rational design of future biomaterial vaccines and immunotherapy carriers.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.040
      Issue No: Vol. 68 (2018)
  • Reducible disulfide poly(beta-amino ester) hydrogels for antioxidant
    • Authors: Andrew L. Lakes; Carolyn T. Jordan; Prachi Gupta; David A. Puleo; J. Zach Hilt; Thomas D. Dziubla
      Pages: 178 - 189
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Andrew L. Lakes, Carolyn T. Jordan, Prachi Gupta, David A. Puleo, J. Zach Hilt, Thomas D. Dziubla
      Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g. glutathione/glutathione disulfide), if these biomaterials modify the cellular redox environment, they may inadvertently affect cellular compatibility and/or oxidative stress defenses. In this work, we hypothesize that the degradation products of a poly(β-amino ester) (PBAE) hydrogel formed with redox sensitive disulfide (cystamine) crosslinking could serve as a supplement to the environmental cellular antioxidant defenses. Upon introduction into a reducing environment, these disulfide-containing hydrogels cleave to present bound-thiol groups, yet remain in the bulk form at up to 66 mol% cystamine of the total amines. By controlling the molar fraction of cystamine, it was apparent that the thiol content varied human umbilical vein endothelial cell (HUVEC) viability IC50 values across an order of magnitude. Further, upon introduction of an enzymatic oxidative stress generator to the cell culture (HX/XO), pre-incubated thiolated hydrogel degradation products conferred cellular and mitochondrial protection from acute oxidative stress, whereas non-reduced disulfide-containing degradation products offered no protection. This polymer may be an advantageous implantable drug delivery system for use in acute oxidative stress prophylaxis and/or chronic oxidative stress cell therapies due to its solid/liquid reversibility in a redox environment, controlled thiolation, high loading capacity through covalent drug-addition, and simple post-synthesis modification which bound-thiols introduce. Statement of Significance In this work, we demonstrate a unique property of disulfide containing degradable biomaterials. By changing the redox state of the degradation products (from oxidized to reduced), it is possible to increase the IC50 of the material by an order of magnitude. This dramatic shift is linked directly to the oxidative stress response of the cells and suggests a possible mechanism by which one can tune the cellular response to degradable biomaterials.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.030
      Issue No: Vol. 68 (2018)
  • Simvastatin and nanofibrous poly(l-lactic acid) scaffolds to promote the
    • Authors: Diana G. Soares; Zhanpeng Zhang; Fatma Mohamed; Thomas W. Eyster; Carlos A. de Souza Costa; Peter X. Ma
      Pages: 190 - 203
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Diana G. Soares, Zhanpeng Zhang, Fatma Mohamed, Thomas W. Eyster, Carlos A. de Souza Costa, Peter X. Ma
      In this study, we investigated the anti-inflammatory, odontogenic and pro-angiogenic effects of integrating simvastatin and nanofibrous poly(l-lactic acid) (NF-PLLA) scaffolds on dental pulp cells (DPCs). Highly porous NF-PLLA scaffolds that mimic the nanofibrous architecture of extracellular matrix were first fabricated, then seeded with human DPCs and cultured with 0.1 μM simvastatin and/or 10 μg/mL pro-inflammatory stimulator lipopolysaccharide (LPS). The gene expression of pro-inflammatory mediators (TNF-α, IL-1β and MMP-9 mRNA) and odontoblastic markers (ALP activity, calcium content, DSPP, DMP-1 and BMP-2 mRNA) were quantified after long-term culture in vitro. In addition, we evaluated the scaffold’s pro-angiogenic potential after 24 h of in vitro co-culture with endothelial cells. Finally, we assessed the combined effects of simvastatin and NF-PLLA scaffolds in vivo using a subcutaneous implantation mouse model. The in vitro studies demonstrated that, compared with the DPC/NF-PLLA scaffold constructs cultured only with pro-inflammatory stimulator LPS, adding simvastatin significantly repress the expression of pro-inflammatory mediators. Treating LPS+ DPC/NF-PLLA constructs with simvastatin also reverted the negative effects of LPS on expression of odontoblastic markers in vitro and in vivo. Western blot analysis demonstrated that these effects were related to a reduction in NFkBp65 phosphorylation and up-regulation of PPARγ expression, as well as to increased phosphorylation of pERK1/2 and pSmad1, mediated by simvastatin on LPS-stimulated DPCs. The DPC/NF-PLLA constructs treated with LPS/simvastatin also led to an increase in vessel-like structures, correlated with increased VEGF expression in both DPSCs and endothelial cells. Therefore, the combination of low dosage simvastatin and NF-PLLA scaffolds appears to be a promising strategy for dentin regeneration with inflamed dental pulp tissue, by minimizing the inflammatory reaction and increasing the regenerative potential of resident stem cells. Statement of Significance The regeneration potential of stem cells is dependent on their microenvironment. In this study, we investigated the effect of the microenvironment of dental pulp stem cells (DPSCs), including 3D structure of a macroporous and nanofibrous scaffold, the inflammatory stimulus lipopolysaccharide (LPS) and a biological molecule simvastatin, on their regenerative potential of mineralized dentin tissue. The results demonstrated that LPS upregulated inflammatory mediators and suppressed the odontogenic potential of DPSCs. Known as a lipid-lowing agent, simvastatin was excitingly found to repress the expression of pro-inflammatory mediators, up-regulate odontoblastic markers, and exert a pro-angiogenic effect on endothelial cells, resulting in enhanced vascularization and mineralized dentin tissue regeneration in a biomimetic 3D tissue engineering scaffold. This novel finding is significant for the fields of stem cells, inflammation and dental tissue regeneration.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.037
      Issue No: Vol. 68 (2018)
  • Poly (ethylene-co-vinyl alcohol) is a suitable substrate for human
           olfactory neuroepithelial cell differentiation in vitro through a defined
           regulatory pathway
    • Authors: Sheng-Tien Li; Tai-Horng Young; Tsung-Wei Huang
      Pages: 204 - 213
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Sheng-Tien Li, Tai-Horng Young, Tsung-Wei Huang
      Olfactory dysfunction significantly influences patients’ life quality, but currently has no adequate treatment. Poly (ethylene-co-vinyl alcohol) (EVAL) mediates cell adhesion, growth and modulates differentiation of neural stem cells. However, whether EVAL is a suitable substrate to establish an in vitro culture system that can promote development and differentiation of human olfactory neuroepithelial cells (HONCs) remains unexplored. This study isolates and cultures HONCs on controls and EVAL films for 21 days. The effects of treatment are assessed using immunocytochemistry, microarray analysis, quantitative PCR, ELISA and western blots following culturing. Most of the cell morphology on controls is epithelial and expresses markers of sustentacular cells (SCs), cadherin-1 and cytokeratin18, whereas the main population on EVAL presents as morphology with extended thin processes and possesses markers of mature olfactory sensory neurons (OSNs), olfactory marker protein (OMP). Microarray analyses reveal neuropeptide Y (NPY) and amphiregulin (AREG) are the two important regulating factors on EVAL films. HONCs cultured on EVAL films enhance the development of mature OSNs through NPY signaling, and significantly decrease the growth of SCs by blocking epidermal growth factor receptor (EGFR) activation. EVAL is a potential biomaterial to serve as an ideal substrate for treating olfactory dysfunction in the future. Statement of Significance Olfaction not only contributes to enjoyments of food, but provides a clue to escape from dangerous environmental hazards. However, loss of smell is commonly progressive and there is no good prognostic approach for olfactory dysfunction. Here, we use poly (ethylene-co-vinyl alcohol) (EVAL) to establish an in vitro culture system that promotes development and differentiation of human olfactory neuroepithelial cells. We show that EVAL not only enhances the development of mature olfactory sensory neurons through neuronpeptide Y signaling, but significantly protects the olfactory neuroepithelium from metaplasia by inhibiting EGFR activation. Therefore, EVAL is a potential biomaterial to serve as an ideal substrate for treating olfactory dysfunction in the future.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.029
      Issue No: Vol. 68 (2018)
  • High resolution 3D microscopy study of cardiomyocytes on polymer scaffold
           nanofibers reveals formation of unusual sheathed structure
    • Authors: Victor Balashov; Anton Efimov; Olga Agapova; Alexander Pogorelov; Igor Agapov; Konstantin Agladze
      Pages: 214 - 222
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Victor Balashov, Anton Efimov, Olga Agapova, Alexander Pogorelov, Igor Agapov, Konstantin Agladze
      Building functional and robust scaffolds for engineered biological tissue requires a nanoscale mechanistic understanding of how cells use the scaffold for their growth and development. A vast majority of the scaffolds used for cardiac tissue engineering are based on polymer materials, the matrices of nanofibers. Attempts to load the polymer fibers of the scaffold with additional sophisticated features, such as electrical conductivity and controlled release of the growth factors or other biologically active molecules, as well as trying to match the mechanical features of the scaffold to those of the extracellular matrix, cannot be efficient without a detailed knowledge of how the cells are attached and strategically positioned with respect to the scaffold nanofibers at micro and nanolevel. Studying single cell – single fiber interactions with the aid of confocal laser scanning microscopy (CLSM), scanning probe nanotomography (SPNT), and transmission electron microscopy (TEM), we found that cardiac cells actively interact with substrate nanofibers, but in different ways. While cardiomyocytes often create a remarkable “sheath” structure, enveloping fiber and, thus, substantially increasing contact zone, fibroblasts interact with nanofibers in the locations of focal adhesion clusters mainly without wrapping the fiber. Statements of Significance We found that cardiomyocytes grown on electrospun polymer nanofibers often create a striking “sheath” structure, enveloping fiber with the formation of a very narrow (∼22 nm) membrane gap leading from the fiber to the extracellular space. This wrapping makes the entire fiber surface available for cell attachment. This finding gives a new prospective view on how scaffold nanofibers may interact with growing cells. It may play a significant role in effective design of novel nanofiber scaffolds for tissue engineering concerning mechanical and electrical properties of scaffolds as well as controlled drug release from “smart” biomaterials.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.031
      Issue No: Vol. 68 (2018)
  • A compound scaffold with uniform longitudinally oriented guidance cues and
           a porous sheath promotes peripheral nerve regeneration in vivo
    • Authors: Liangliang Huang; Lei Zhu; Xiaowei Shi; Bing Xia; Zhongyang Liu; Shu Zhu; Yafeng Yang; Teng Ma; Pengzhen Cheng; Kai Luo; Jinghui Huang; Zhuojing Luo
      Pages: 223 - 236
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Liangliang Huang, Lei Zhu, Xiaowei Shi, Bing Xia, Zhongyang Liu, Shu Zhu, Yafeng Yang, Teng Ma, Pengzhen Cheng, Kai Luo, Jinghui Huang, Zhuojing Luo
      Scaffolds with inner fillers that convey directional guidance cues represent promising candidates for nerve repair. However, incorrect positioning or non-uniform distribution of intraluminal fillers might result in regeneration failure. In addition, proper porosity (to enhance nutrient and oxygen exchange but prevent fibroblast infiltration) and mechanical properties (to ensure fixation and to protect regenerating axons from compression) of the outer sheath are also highly important for constructing advanced nerve scaffolds. In this study, we constructed a compound scaffold using a stage-wise strategy, including directionally freezing orientated collagen-chitosan (O-CCH) filler, electrospinning poly(ε-caprolactone) (PCL) sheaths and assembling O-CCH/PCL scaffolds. Based on scanning electron microscopy (SEM) and mechanical tests, a blend of collagen/chitosan (1:1) was selected for filler fabrication, and a wall thickness of 400 μm was selected for PCL sheath production. SEM and three-dimensional (3D) reconstruction further revealed that the O-CCH filler exhibited a uniform, longitudinally oriented microstructure (over 85% of pores were 20–50 μm in diameter). The electrospun PCL porous sheath with pore sizes of 6.5 ± 3.3 μm prevented fibroblast invasion. The PCL sheath exhibited comparable mechanical properties to commercially available nerve conduits, and the O-CCH filler showed a physiologically relevant substrate stiffness of 2.0 ± 0.4 kPa. The differential degradation time of the filler and sheath allows the O-CCH/PCL scaffold to protect regenerating axons from compression stress while providing enough space for regenerating nerves. In vitro and in vivo studies indicated that the O-CCH/PCL scaffolds could promote axonal regeneration and Schwann cell migration. More importantly, functional results indicated that the CCH/PCL compound scaffold induced comparable functional recovery to that of the autograft group at the end of the study. Our findings demonstrated that the O-CCH/PCL scaffold with uniform longitudinal guidance filler and a porous sheath exhibits favorable properties for clinical use and promotes nerve regeneration and functional recovery. The O-CCH/PCL scaffold provides a promising new path for developing an optimal therapeutic alternative for peripheral nerve reconstruction. Statement of Significance Scaffolds with inner fillers displaying directional guidance cues represent a promising candidate for nerve repair. However, further clinical translation should pay attention to the problem of non-uniform distribution of inner fillers, the porosity and mechanical properties of the outer sheath and the morphological design facilitating operation. In this study, a stage-wise fabrication strategy was used, which made it possible to develop an O-CCH/PCL compound scaffold with a uniform longitudinally oriented inner filler and a porous outer sheath. The uniform distribution of the pores in the O-CCH/PCL scaffold provides a solution to resolve the problem of non-uniform distribution of inner fillers, which impede the clinical translation of scaffolds with longitudinal microstructured fillers, especially for aligned-fiber-based scaffolds. In vitro and in vivo studies indicated that the O-CCH/PCL scaffolds could provide topographical cues for axonal regeneration and SC migration, which were not found for random scaffolds (with random microstructure resemble sponge-based scaffolds). The electrospun porous PCL sheath of the O-CCH/PCL scaffold not only prevented fibroblast infiltration, but also satisfied the mechanical requirements for clinical use, paving the way for clinical translation. The differential degradation time of the O-CCH filler and the PCL sheath makes O-CCH/PCL scaffold able to provide long protection for regenerating axons from compression stress, but enough space for regenerating nerve. These findings highlight the possibility of developing an optimal therapeutic alternative for nerve defects using the O-CCH/PCL scaffold.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.010
      Issue No: Vol. 68 (2018)
  • CO2-expanded nanofiber scaffolds maintain activity of encapsulated
           bioactive materials and promote cellular infiltration and positive host
    • Authors: Jiang Jiang; Shixuan Chen; Hongjun Wang; Mark A. Carlson; Adrian F. Gombart; Jingwei Xie
      Pages: 237 - 248
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Jiang Jiang, Shixuan Chen, Hongjun Wang, Mark A. Carlson, Adrian F. Gombart, Jingwei Xie
      Traditional electrospun nanofiber membranes were incapable of promoting cellular infiltration due to its intrinsic property (e.g., dense structure and small pore size) limiting their use in tissue regeneration. Herein, we report a simple and novel approach for expanding traditional nanofiber membranes from two-dimensional to three-dimensional (3D) with controlled thickness and porosity via depressurization of subcritical CO2 fluid. The expanded 3D nanofiber scaffolds formed layered structures and simultaneously maintained the aligned nanotopographic cues. The 3D scaffolds also retained the fluorescent intensity of encapsulated coumarin 6 and the antibacterial activity of encapsulated antimicrobial peptide LL-37. In addition, the expanded 3D nanofiber scaffolds with arrayed holes can significantly promote cellular infiltration and neotissue formation after subcutaneous implantation compared to traditional nanofiber membranes. Such scaffolds also significantly increased the blood vessel formation and the ratio of M2/M1 macrophages after subcutaneous implantation for 2 and 4 weeks compared to traditional nanofiber membranes. Together, the presented method holds great potential in the fabrication of functional 3D nanofiber scaffolds for various applications including engineering 3D in vitro tissue models, antimicrobial wound dressing, and repairing/regenerating tissues in vivo. Statement of Significance Electrospun nanofibers have been widely used in regenerative medicine due to its biomimicry property. However, most of studies are limited to the use of 2D electrospun nanofiber membranes. To the best of our knowledge, this article is the first instance of the transformation of traditional electrospun nanofiber membranes from 2D to 3D via depressurization of subcritical CO2 fluid. This method eliminates many issues associated with previous approaches such as necessitating the use of aqueous solutions and chemical reactions, multiple-step process, loss of the activity of encapsulated biological molecules, and unable to expand electrospun nanofiber mats made of hydrophilic polymers. Results indicate that these CO2 expanded nanofiber scaffolds can maintain the activity of encapsulated biological molecules. Further, the CO2 expanded nanofiber scaffolds with arrayed holes can greatly promote cellular infiltration, neovascularization, and positive host response after subcutaneous implantation in rats. The current work is the first study elucidating such a simple and novel strategy for fabrication of 3D nanofiber scaffolds.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.018
      Issue No: Vol. 68 (2018)
  • Microchannel system for rate-controlled, sequential, and pH-responsive
           drug delivery
    • Authors: Dasom Yang; Jung Seung Lee; Chang-Kuk Choi; Hong-Pyo Lee; Seung-Woo Cho; WonHyoung Ryu
      Pages: 249 - 260
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Dasom Yang, Jung Seung Lee, Chang-Kuk Choi, Hong-Pyo Lee, Seung-Woo Cho, WonHyoung Ryu
      Controlled delivery of drug at a constant rate, in a sequential order, or responsive to environment conditions has been pursued for a long time to enhance the efficacy of therapeutic molecules and to minimize side effects of highly potent drugs. However, achieving such delicately-controlled delivery of a drug molecule is non-trivial and still remains a challenge. We propose the use of microchannels to control the rate, sequence, and pH-responsiveness of drug delivery for high precision and predictability. In this study, we introduce elementary drug delivery units consisting of micro-reservoirs and microchannels that have variations in their lengths, widths, numbers, and straightness. The release study demonstrates that the release rates of model drugs can be modulated by the design of microchannels. Finite element modeling of drug release predicts the performance of the drug delivery units with high accuracy. The possibility of sequential drug delivery is also demonstrated using biodegradable polymer plug in microchannels. Finally, pH-responsive delivery of drugs in microfluidic units is also discussed and demonstrated via cell viability tests. Statement of Significance In this work, we developed microchannel-based drug delivery devices whose release rate could be accurately calculated and controlled by design of microchannel geometry. Although there have been many advances in microfabricated drug delivery systems, in particular, reservoir-based systems, no systematic investigation has been made to utilize the release channels. In our work, an equivalent electrical circuit concept was applied to the microfluidic systems for more detailed design and analysis. A microfluidic channel was regarded as an electrical resistor; their diffusion/electrical flux could be tuned with geometric factors such as length, width, a number of channel/resistor and their connections. Furthermore, from delivery rate control using channel geometry, multifunctional channel-based release systems for sequential and pH-responsive were demonstrated.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.013
      Issue No: Vol. 68 (2018)
  • Copper-containing mesoporous bioactive glass promotes angiogenesis in an
           in vivo zebrafish model
    • Authors: Lilian B. Romero-Sánchez; Manuel Marí-Beffa; Paloma Carrillo; Miguel Ángel Medina; Aránzazu Díaz-Cuenca
      Pages: 272 - 285
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Lilian B. Romero-Sánchez, Manuel Marí-Beffa, Paloma Carrillo, Miguel Ángel Medina, Aránzazu Díaz-Cuenca
      The osteogenic and angiogenic responses of organisms to the ionic products of degradation of bioactive glasses (BGs) are being intensively investigated. The promotion of angiogenesis by copper (Cu) has been known for more than three decades. This element can be incorporated to delivery carriers, such as BGs, and the materials used in biological assays. In this work, Cu-containing mesoporous bioactive glass (MBG) in the SiO2-CaO-P2O5 compositional system was prepared incorporating 5% mol Cu (MBG-5Cu) by replacement of the corresponding amount of Ca. The biological effects of the ionic products of MBG biodegradation were evaluated on a well-known endothelial cell line, the bovine aorta endothelial cells (BAEC), as well as in an in vivo zebrafish (Danio rerio) embryo assay. The results suggest that ionic products of both MBG (Cu free) and MBG-5Cu materials promote angiogenesis. In vitro cell cultures show that the ionic dissolution products of these materials are not toxic and promote BAEC viability and migration. In addition, the in vivo assay indicates that both exposition and microinjection of zebrafish embryos with Cu free MBG material increase vessel number and thickness of the subintestinal venous plexus (SIVP), whereas assays using MBG-5Cu enhance this effect. Statement of Significance Mesoporous bioactive glasses (MBGs) with high specific surface area, well-ordered pores, large pore volumes and controllable amount of ions are interesting to develop controlled drug delivery systems for bone tissue regeneration. Copper (Cu) incorporation to the basic SiO2-CaO-P2O5 composition has attracted high interest due to its multifunctional biological properties. Promotion of angiogenesis is one of these properties, which can be integrated to the biomaterial with lower cost and higher stability when compared with growth factors. This work reports the synthesis and characterization of Cu-containing MBG evaluating its angiogenic properties in the subintestinal vessel zebrafish assay. This transgenic in vivo assay is merging as an alternative model providing short-time consuming protocols and facilities during pro-angiogenic drug screenings. The report shows that the ionic products of this MBG material delivered to the zebrafish incubation media significantly enhance angiogenesis in comparison with control groups. Besides, results indicate Cu ions may exhibit a synergic effect with Si, Ca, and P ions in angiogenesis stimulation both in vitro and in vivo. To our knowledge, this is the first time that zebrafish in vivo assays are used to evaluate angiogenic activity of ionic dissolution products from MBG materials.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.032
      Issue No: Vol. 68 (2018)
  • Sub-surface assessment of hydrothermal ageing in zirconia-containing
           femoral heads for hip joint applications
    • Authors: L. Gremillard; J. Chevalier; L. Martin; T. Douillard; S. Begand; K. Hans; T. Oberbach
      Pages: 286 - 295
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): L. Gremillard, J. Chevalier, L. Martin, T. Douillard, S. Begand, K. Hans, T. Oberbach
      Zirconia-based materials have been used in orthopaedics since the 1980s, with large success, mainly thanks to transformation toughening. On the other hand, their main drawback is their potential sensitivity to hydrothermal ageing, i.e. tetragonal to monoclinic phase transformation on their surface in the presence of water. Hydrothermal ageing may result in roughness increase and microcracking of the surface. In this article the hydrothermal ageing behaviour of three medical-grade zirconia-based materials is assessed at high temperature and extrapolated to room or body temperature. The degradation is also characterized by FIB/SEM nano-tomography to better assess sub-surface evolutions. In both zirconia and alumina-toughened zirconia (ATZ), ageing results in the presence of a homogenous transformed layer of constant thickness whose growth rate is about 8 times slower in ATZ than in zirconia. Microcracking occurs in the entire transformed layer in zirconia, but was much less relevant in ATZ. Zirconia-toughened alumina (ZTA) is much less prone to ageing. In ZTA ageing results in a thin transformed layer in which the monoclinic fraction decreases with depth. No microcracking was observed in ZTA. Statement of Significance This article details the microstructural evolution of the surface of three zirconia-based ceramics when exposed to water (hydrothermal ageing), and establishes a time-temperature equivalences of these evolutions. It shows that different zirconia-alumina composites do not degrade the same way: zirconia and alumina-toughened zirconia present a homogeneous degraded zone of constant thickness, whereas zirconia-toughened-alumina presents a gradient of transformation. These new findings will help understanding better the hydrothermal degradation of zirconia based materials, and in particular will facilitate a better prediction of the durability of zirconia-based devices such as orthopaedic implants and dental devices (implants, crowns, abutments…).
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.021
      Issue No: Vol. 68 (2018)
  • Regulation of osteoclasts by osteoblast lineage cells depends on titanium
           implant surface properties
    • Authors: Ethan M. Lotz; Michael B. Berger; Zvi Schwartz; Barbara D. Boyan
      Pages: 296 - 307
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Ethan M. Lotz, Michael B. Berger, Zvi Schwartz, Barbara D. Boyan
      A critical stage during osseointegration of a titanium (Ti) implant is primary bone remodeling, which involves cross talk among osteoclast precursors, osteoclasts, mesenchymal stem cells (MSCs), and osteoblasts. This phase couples the processes of bone formation and resorption. During remodeling, osteoclasts produce factors capable of regulating MSC migration and osteogenesis. Furthermore, they degrade primary bone, creating a foundation with a specific chemistry, stiffness, and morphology for osteoblasts to synthesize and calcify their matrix. MSCs and osteoblasts receiving cues from the implant surface produce factors capable of regulating osteoclasts in order to promote net new bone formation. The purpose of this study was to determine the effects Ti implant surfaces have on bone remodeling. Human MSCs and normal human osteoblasts (NHOsts) were cultured separately on 15 mm grade 2 smooth PT, hydrophobic-microrough SLA, hydrophilic-microrough Ti (mSLA) (Institut Straumann AG, Basel, Switzerland), or tissue culture polystyrene (TCPS). After 7d, conditioned media from surface cultures were used to treat human osteoclasts for 2d. Activity was measured by fluorescence of released collagen followed by mRNA quantification. This study demonstrates that MSC and NHOst cultures are able to suppress osteoclast activity in a surface dependent manner and osteoclast mRNA levels are selectively regulated by surface treatments. The substrate-dependent regulatory effect was mitigated when MSCs were silenced for integrin subunits and when conditioned media were denatured. These results indicate that MSCs and NHOsts regulate at least two aspects of remodeling: reduced fusion of new osteoclasts and reduced activity of existing osteoclasts. Statement of Significance In this study, we developed a novel in vitro model to study how microstructured and hydrophilic titanium implants impact bone remodeling for dental and orthopaedic applications. Our approach intersects biomaterials and systems physiology, revealing for the first time that implant surface properties are capable of regulating the communication among the cells involved in remodeling of primary bone during osseointegration. We believe that the basic research presented in our manuscript will provide important knowledge in our understanding of factors that impact implant success. Furthermore, it provides a solid foundation for the development of materials that enable rapid osseointegration and earlier loading times for implants in bone that has been compromised by trauma or disease.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.039
      Issue No: Vol. 68 (2018)
  • pH-responsive gold nanoclusters-based nanoprobes for lung cancer targeted
           near-infrared fluorescence imaging and chemo-photodynamic therapy
    • Authors: Fangfang Xia; Wenxiu Hou; Chunlei Zhang; Xiao Zhi; Jin Cheng; Jesús M. de la Fuente; Jie Song; Daxiang Cui
      Pages: 308 - 319
      Abstract: Publication date: 1 March 2018
      Source:Acta Biomaterialia, Volume 68
      Author(s): Fangfang Xia, Wenxiu Hou, Chunlei Zhang, Xiao Zhi, Jin Cheng, Jesús M. de la Fuente, Jie Song, Daxiang Cui
      Nanoparticle-based drug delivery systems have drawn a great deal of attention for their opportunities to improve cancer treatments over intrinsic limits of conventional cancer therapies. Herein, we developed the polypeptide-modified gold nanoclusters (GNCs)-based nanoprobes for tumor-targeted near-infrared fluorescence imaging and chemo-photodynamic therapy. The nanoprobes comprise of tetra-functional components: i) polyethylene glycol (PEG) shell for long blood circulation and better biocompatibility; ii) MMP2 polypeptide (CPLGVRGRGDS) for tumor targeting; iii) cis-aconitic anhydride-modified doxorubicin (CAD) for pH-sensitive drug release; iv) photosensitizer chlorin e6 (Ce6) for photodynamic therapy and fluorescence imaging. The in vitro results demonstrated that the as-synthesized nanoprobes could be efficiently internalized into A549 cells and then significantly enhance the mortality of cancer cells compared with free Ce6 and doxorubicin. For in vivo tests, the nanoprobes showed excellent tumor targeting ability, long blood circulation time, and could remarkably inhibit the growth of tumor. Our results will help to advance the design of combination strategies to enhance the efficacy of imaging-guided cancer therapy. Statement of Significance The as-prepared CDGM NPs could accumulate into the tumor tissue with the enhanced permeability and retention (EPR) effect as well as the active tumor targeting ability from the MMP2 polypeptides. With the acid-sensitive linker, the doxorubicin (DOX) would be released from the synthesized nanoparticles after exposing to the acid tumor microenvironment. The CDGM NPs exhibit excellent tumor targeting ability and could remarkably suppress the growth of tumor compared with free Ce6 and DOX.
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      PubDate: 2018-02-05T09:14:40Z
      DOI: 10.1016/j.actbio.2017.12.034
      Issue No: Vol. 68 (2018)
  • Erratum to “Overcoming multiple gastrointestinal barriers by bilayer
           modified hollow mesoporous silica nanocarriers” [Acta Biomater. 65
           (2017) 405–416]
    • Authors: Ying Wang; Yating Zhao; Yu Cui; Qinfu Zhao; Qiang Zhang; Sara Musetti; Karina A. Kinghorn; Siling Wang
      Abstract: Publication date: Available online 21 February 2018
      Source:Acta Biomaterialia
      Author(s): Ying Wang, Yating Zhao, Yu Cui, Qinfu Zhao, Qiang Zhang, Sara Musetti, Karina A. Kinghorn, Siling Wang

      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.046
  • Macrophage involvement affects matrix stiffness-related influences on cell
           osteogenesis under three-dimensional culture conditions
    • Authors: Xiao-Tao He; Rui-Xin Wu; Xin-Yue Xu; Jia Wang; Yuan Yin; Fa-Ming Chen
      Abstract: Publication date: Available online 17 February 2018
      Source:Acta Biomaterialia
      Author(s): Xiao-Tao He, Rui-Xin Wu, Xin-Yue Xu, Jia Wang, Yuan Yin, Fa-Ming Chen
      Accumulating evidence indicates that the physicochemical properties of biomaterials exert profound influences on stem cell fate decisions. However, matrix-based regulation selected through in vitro analyses based on a given cell population do not genuinely reflect the in vivo conditions, in which multiple cell types are involved and interact dynamically. This study constitutes the first investigation of how macrophages (Mφs) in stiffness-tunable transglutaminase cross-linked gelatin (TG-gel) affect the osteogenesis of bone marrow-derived mesenchymal stem cells (BMMSCs). When a single cell type was cultured, low-stiffness TG-gels promoted BMMSC proliferation, whereas high-stiffness TG-gels supported cell osteogenic differentiation. However, Mφs in high-stiffness TG-gels were more likely to polarize toward the pro-inflammatory M1 phenotype. Using either conditioned medium (CM)-based incubation or Transwell-based co-culture, we found that Mφs encapsulated in the low-stiffness matrix exerted a positive effect on the osteogenesis of co-cultured BMMSCs. Conversely, Mφs in high-stiffness TG-gels negatively affected cell osteogenic differentiation. When both cell types were cultured in the same TG-gel type and placed into the Transwell system, the stiffness-related influences of Mφs on BMMSCs were significantly altered; both the low- and high-stiffness matrices induced similar levels of BMMSC osteogenesis. Although the best material parameter for synergistically affecting Mφs and BMMSCs remains unknown, our data suggest that Mφ involvement in the co-culture system alters previously identified material-related influences on BMMSCs, such as matrix stiffness-related effects, which were identified based on a culture system involving a single cell type. Such Mφ-stem cell interactions should be considered when establishing proper matrix parameter-associated cell regulation in the development of biomimetic biomaterials for regenerative applications. Statement of significance The substrate stiffness of a scaffold plays critical roles in modulating both reparative cells, such as mesenchymal stem cells (MSCs), and immune cells, such as macrophages (Mφs). Although the influences of material stiffness on either Mφs or MSCs, have been extensively described, how the two cell types respond to matrix cues to dynamically affect each other in a three-dimensional (3D) biosystem remains largely unknown. Here, we report our findings that, in a platform wherein Mφs and bone marrow-derived MSCs coexist, matrix stiffness can influence stem cell fate through both direct matrix-associated regulation and indirect Mφ-based modulation. Our data support future studies of the MSC-Mφ-matrix interplay in the 3D context to optimize matrix parameters for the development of the next biomaterial.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.015
  • Exogenous mineralization of hard tissues using photo-absorptive minerals
           and femto-second lasers; the case of dental enamel
    • Authors: A.D. Anastasiou; S. Strafford; C.L. Thomson; J. Gardy; T.J. Edwards; M. Malinowski; S.A. Hussain; N.K. Metzger; A. Hassanpour; C.T.A. Brown; A.P. Brown; M.S. Duggal; A. Jha
      Abstract: Publication date: Available online 17 February 2018
      Source:Acta Biomaterialia
      Author(s): A.D. Anastasiou, S. Strafford, C.L. Thomson, J. Gardy, T.J. Edwards, M. Malinowski, S.A. Hussain, N.K. Metzger, A. Hassanpour, C.T.A. Brown, A.P. Brown, M.S. Duggal, A. Jha
      A radical new methodology for the exogenous mineralization of hard tissues is demonstrated in the context of laser-biomaterials interaction. The proposed approach is based on the use of femtosecond pulsed lasers (fs) and Fe3+-doped calcium phosphate minerals (specifically in this work fluorapatite powder containing Fe2O3 nanoparticles (NP)). A layer of the synthetic powder is applied to the surface of eroded bovine enamel and is irradiated with a fs laser (1040 nm wavelength, 1 GHz repetition rate, 150 fs pulse duration and 0.4 W average power). The Fe2O3 NPs absorb the light and may act as thermal antennae, dissipating energy to the vicinal mineral phase. Such a photothermal process triggers the sintering and densification of the surrounding calcium phosphate crystals thereby forming a new, dense layer of typically 20 μm in thickness, which is bonded to the underlying surface of the natural enamel. The dispersed iron oxide NPs, ensure the localization of temperature excursion, minimizing collateral thermal damage to the surrounding natural tissue during laser irradiation. Simulated brushing trials (pH cycle and mechanical force) on the synthetic layer show that the sintered material is more acid resistant than the natural mineral of enamel. Furthermore, nano-indentation confirms that the hardness and Young’s modulus of the new layers are significantly more closely matched to enamel than current restorative materials used in clinical dentistry. Although the results presented herein are exemplified in the context of bovine enamel restoration, the methodology may be more widely applicable to human enamel and other hard-tissue regenerative engineering. Statement of Significance In this work we provide a new methodology for the mineralisation of dental hard tissues using femtosecond lasers and iron doped biomaterials. In particular, we demonstrate selective laser sintering of an iron doped fluorapatite on the surface of eroded enamel under low average power and mid-IR wavelength and the formation of a new layer to substitute the removed material. The new layer is evaluated through simulated brushing trials and nano-indentation. From the results we can conclude that is more acid resistant than natural enamel while, its mechanical properties are superior to that of current restorative materials. To the best of our knowledge this is the first time that someone demonstrated, laser sintering and bonding of calcium phosphate biomaterials on hard tissues. Although we here we discuss the case of dental enamel, similar approach can be adopted for other hard tissues, leading to new strategies for the fixation of bone/tooth defects.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.012
  • Fibrin glue mesh fixation combined with mesenchymal stem cells or exosomes
           modulates the inflammatory reaction in a murine model of incisional hernia
    • Authors: Rebeca Blázquez; Francisco Miguel Sánchez-Margallo; Verónica Álvarez; Alejandra Usón; Federica Marinaro; Javier G. Casado
      Abstract: Publication date: Available online 17 February 2018
      Source:Acta Biomaterialia
      Author(s): Rebeca Blázquez, Francisco Miguel Sánchez-Margallo, Verónica Álvarez, Alejandra Usón, Federica Marinaro, Javier G. Casado
      Surgical meshes are effective and frequently used to reinforce soft tissues. Fibrin glue (FG) has been widely used for mesh fixation and is also considered an optimal vehicle for stem cell delivery. The aim of this preclinical study was to evaluate the therapeutic effect of MSCs and their exosomes combined with FG for the treatment of incisional hernia. A murine incisional hernia model was used to implant surgical meshes and different treatments with FG, MSCs and exo-MSCs were applied. The implanted meshes were evaluated at day 7 by anatomopathology, cellular analysis of infiltrating leukocytes and gene expression analysis of TH1/TH2 cytokines, MMPs, TIMPs and collagens. Our results demonstrated a significant increase of anti-inflammatory M2 macrophages and TH2 cytokines when MSCs or exo-MSCs were used. Moreover, the analysis of MMPs, TIMPs and collagen exerted significant differences in the extracellular matrix and in the remodeling process. Our in vivo study suggests that the fixation of surgical meshes with FG and MSCs or exo-MSCs will have a beneficial effect for the treatment of incisional hernia in terms of improved outcomes of damaged tissue, and especially, in the modulation of inflammatory responses towards a less aggressive and pro-regenerative profile. Statement of significance The implantation of surgical meshes is the standard procedure to reinforce tissue defects such as hernias. However, an exacerbated and persistent inflammatory response secondary to this implantation is frequently observed, leading to a strong discomfort and chronic pain in the patients. In many cases, an additional surgical intervention is needed to remove the mesh. This study shows that mesenchymal stem cells and their exosomes, combined with a fibrin sealant, can be used for the successful fixation of these meshes. This new therapeutic approach, assayed in a murine model of incisional hernia, favors the modulation of the inflammatory response towards a less aggressive and pro-regenerative profile.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.014
  • Investigation of Adhesive Interactions in the Specific Targeting of
           Triptorelin-conjugated PEG-coated Magnetite Nanoparticles to Breast Cancer
    • Authors: Jingjie Hu; Sina Youssefian; John Obayemi; Karen Malatesta; Nima Rahbar; Winston Soboyejo
      Abstract: Publication date: Available online 16 February 2018
      Source:Acta Biomaterialia
      Author(s): Jingjie Hu, Sina Youssefian, John Obayemi, Karen Malatesta, Nima Rahbar, Winston Soboyejo
      The understanding of adhesive interaction at the nanoscale between functionalized nanoparticles and biological cells is of great importance to develop effective theranostic nanocarriers for targeted cancer therapy. Here, we report a combination of experimental and computational approaches to evaluate the adhesion between Triptorelin (a Luteinizing Hormone-Releasing Hormone (LHRH) agonist)-conjugated poly-(ethylene glycol) (PEG)-coated magnetite nanoparticles (Triptorelin-MNPs) and breast cells. The adhesion forces between Triptorelin-MNPs and normal/cancerous breast cells are obtained using atomic force microscopy. The corresponding work of adhesion is then estimated using Johnson-Kendall-Roberts model. Our results demonstrate that Triptorelin-MNPs have a fourteen-fold greater work of adhesion to breast cancer cells than to normal breast cells. In addition, the work of adhesion between Triptorelin-MNPs and breast cancer cells is found to be three times more than that between unmodified MNPs and breast cancer cells. Hence, the experimental observation indicates that Triptorelin ligands facilitate the specific targeting of breast cancer cells. Furthermore, molecular dynamics simulations are performed to investigate the molecular origins of the adhesive interactions. The simulations reveal that the interactions between molecules (e.g. Triptorelin and PEG) and LHRH receptors are dominated by van der Waals energies, while the interactions of these molecules with cell membrane are dominated by electrostatic interactions. Moreover, both experimental and computational results reveal that PEG serves as an effective coating that enhances adhesive interactions to breast cancer cells that over-express LHRH receptors, while reduces the adhesion to normal breast cells. Our results highlight the potential to develop Triptorelin-MNPs into tumor-specific MRI contrast agents and drug carriers. Statement of Significance Systematic investigation of adhesive interactions between functionalized nanoparticles and cancer cells is of great importance in developing effective theranostic nanocarriers for targeted cancer therapy. Herein, we use a combination of atomic force microscopy technique and molecular dynamics simulations approach to explore the adhesive interactions at the nanoscale between Triptorelin-conjugated polyethylene glycol (PEG)-coated magnetite nanoparticles and normal/cancerous breast cells. This study characterizes and quantifies the work of adhesion, as well as adhesion forces, at the nanocarrier/cell interfaces, unravels the molecular origins of adhesive interactions and highlights the effectiveness of PEG coatings and Triptorelin ligands in the specific targeting of breast cancer cells. Our findings expand the fundamental understanding of nanoparticle/cell adhesion and provide guidelines for the design of more rational nanocarriers.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.011
  • An aligned porous electrospun fibrous membrane with controlled drug
           delivery- an efficient strategy to accelerate diabetic wound healing with
           improved angiogenesis
    • Authors: Xiaozhi Ren; Yiming Han; Jie Wang; Yuqi Jiang; Zhengfang Yi; He Xu; Qinfei Ke
      Abstract: Publication date: Available online 15 February 2018
      Source:Acta Biomaterialia
      Author(s): Xiaozhi Ren, Yiming Han, Jie Wang, Yuqi Jiang, Zhengfang Yi, He Xu, Qinfei Ke
      A chronic wound in diabetic patients is usually characterized by poor angiogenesis and delayed wound closure. The exploration of efficient strategy to significantly improve angiogenesis in the diabetic wound bed and thereby accelerate wound healing is still a significant challenge. Herein, we reported a kind of aligned porous poly (L-lactic acid) (PLLA) electrospun fibrous membranes containing dimethyloxalylglycine (DMOG)-loaded mesoporous silica nanoparticles (DS) for diabetic wound healing. The PLLA electrospun fibers aligned in a single direction and there were ellipse-shaped nano-pores in situ generated onto the surface of fibers, while the DS were well distributed in the fibers and the DMOG as well as Si ion could be controlled released from the nanopores on the fibers. The in vitro results revealed that the aligned porous composite membranes (DS-PL) could stimulate the proliferation, migration and angiogenesis-related gene expression of human umbilical vein endothelial cells (HUVECs) compared with the pure PLLA membranes. The in vivo study further demonstrated that the prepared DS-PL membranes significantly improved neo-vascularization, re-epithelialization and collagen formation as well as inhibited inflammatory reaction in the diabetic wound bed, which eventually stimulated the healing of the diabetic wound. Collectively, these results suggest that the combination of hierarchical structures (nanopores on the aligned fibers) with the controllable released DMOG drugs as well as Si ions from the membranes, which could create a synergetic effect on the rapid stimulation of angiogenesis in the diabetic wound bed, is a potential novel therapeutic strategy for highly efficient diabetic wound healing.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.010
  • Nanofibrous PLGA Electrospun Scaffolds Modified with Type I Collagen
           Influence Hepatocyte Function and Support Viability In Vitro
    • Authors: Jessica H. Brown; Prativa Das; Michael D. DiVito; David Ivancic; Lay Poh Tan; Jason A. Wertheim
      Abstract: Publication date: Available online 15 February 2018
      Source:Acta Biomaterialia
      Author(s): Jessica H. Brown, Prativa Das, Michael D. DiVito, David Ivancic, Lay Poh Tan, Jason A. Wertheim
      A major challenge of maintaining primary hepatocytes in vitro is progressive loss of hepatocyte-specific functions, such as protein synthesis and cytochrome P450 (CYP450) catalytic activity. We developed a three-dimensional (3D) nanofibrous scaffold made from poly(L-lactide-co-glycolide) (PLGA) polymer using a newlyoptimizedwet electrospinning techniquethat resulted in a highly porous structure that accommodated inclusion of primary human hepatocytes. Extracellular matrix (ECM) proteins (type I collagen or fibronectin) at varying concentrations were chemically linked to electrospun PLGA using amine coupling to develop an in vitro culture system containing the minimal essential ECM components of the liver micro-environment that preserve hepatocyte function in vitro. Cell-laden nanofiber scaffolds were tested in vitro to maintain hepatocyte function over a two-week period. Incorporation of type I collagen onto PLGA scaffolds (PLGA-Chigh: 100 µg/mL) led to 10-fold greater albumin secretion, 4-fold higher urea synthesis, and elevated transcription of hepatocyte-specific CYP450 genes (CYP3A4, 3.5-fold increase and CYP2C9, 3-fold increase) in primary human hepatocytes compared to the same cells grown within unmodified PLGA scaffolds over two weeks. These indices, measured using collagen-bonded scaffolds, were also higher than scaffolds coupled to fibronectin or an ECM control sandwich culture composed of type I collagen and Matrigel. Induction of CYP2C9 activity was also higher in these same type I collagen PLGA scaffolds compared to other ECM-modified or unmodified PLGA constructs and was equivalent to the ECM control at 7 days. Together, we demonstrate a minimalist ECM-based 3D synthetic scaffold that accommodates primary human hepatocyte inclusion into the matrix, maintains long-term in vitro survival and stimulates function, which can be attributed to coupling of type I collagen. Statement of Significance Culturing primary hepatocytes within a three-dimensional (3D) structure that mimics the natural liver environment is a promising strategy for extending the function and viability of hepatocytes in vitro. In the present study we generate porous PLGA nanofibers, that are chemically modified with extracellular matrix proteins, to serve as 3D scaffolds for the in vitro culture of primary human hepatocytes. Our findings demonstrate that the use of ECM proteins, especially type I collagen, in a porous 3D environment helps to improve the synthetic function of primary hepatocytes over time. We believe the work presented within will provide insights to readers for drug toxicity and tissue engineering applications.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.009
  • Polyisocyanopeptide hydrogels: a novel thermo-responsive hydrogel
           supporting pre-vascularization and the development of organotypic
    • Authors: Jakub Zimoch; Joan Simó Padial; Agnes S. Klar; Queralt Vallmajo-Martin; Martin Meuli; Thomas Biedermann; Christopher J. Wilson; Alan Rowan; Ernst Reichmann
      Abstract: Publication date: Available online 15 February 2018
      Source:Acta Biomaterialia
      Author(s): Jakub Zimoch, Joan Simó Padial, Agnes S. Klar, Queralt Vallmajo-Martin, Martin Meuli, Thomas Biedermann, Christopher J. Wilson, Alan Rowan, Ernst Reichmann
      Molecular and mechanical interactions with the 3D extracellular matrix are essential for cell functions such as survival, proliferation, migration, and differentiation. Thermo-responsive biomimetic polyisocyanopeptide (PIC) hydrogels are promising new candidates for 3D cell, tissue, and organ cultures. This is a synthetic, thermo-responsive and stress-stiffening material synthesized via polymerization of the corresponding monomers using a nickel perchlorate as a catalyst. It can be tailored to meet various demands of cells by modulating its stiffness and through the decoration of the polymer with short GRGDS peptides using copper free click chemistry. These peptides make the hydrogels biocompatible by mimicking the binding sites of certain integrins. This study focuses on the optimization of the PIC polymer properties for efficient cell, tissue and organ development. Screening for the optimal stiffness of the hydrogel and the ideal concentration of the GRGDS ligand conjugated with the polymer, enabled cell proliferation, migration and differentiation of various primary cell types of human origin. We demonstrate that fibroblasts, endothelial cells, adipose-derived stem cells and melanoma cells, do survive, thrive and differentiate in optimized PIC hydrogels. Importantly, these hydrogels support the spontaneous formation of complex structures like blood capillaries in vitro. Additionally, we utilized the thermo-responsive properties of the hydrogels for a rapid and gentle recovery of viable cells. Finally, we show that organotypic structures of human origin grown in PIC hydrogels can be successfully transplanted subcutaneously onto immune-compromised rats, on which they survive and integrate into the surrounding tissue. Statement of Significance Molecular and mechanical interactions with the surrounding environment are essential for cell functions. Although 2D culture systems greatly contributed to our understanding of complex biological phenomena, they cannot substitute for crucial interaction that take place in 3D. 3D culture systems aim to overcome limitations of the 2D cultures and answer new questions about cell functions. Thermo-responsive biomimetic polyisocyanopeptide (PIC) hydrogels are promising new candidates for 3D cell, tissue, and organ cultures. They are synthetic and can be tailor to meet certain experimental demands. Additionally, they are characterized by strain-stiffening, a feature crucial for cell behaviour, but rare in hydrogels. Their thermos-responsive properties enable quick recovery of the cells by a simple procedure of lowering the temperature.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.042
  • Lung cancer specific and reduction-responsive chimaeric polymersomes for
           highly efficient loading of pemetrexed and targeted suppression of lung
           tumor in vivo
    • Authors: Weijing Yang; Liang Yang; Yifeng Xia; Liang Cheng; Jian Zhang; Fenghua Meng; Jiandong Yuan; Zhiyuan Zhong
      Abstract: Publication date: Available online 14 February 2018
      Source:Acta Biomaterialia
      Author(s): Weijing Yang, Liang Yang, Yifeng Xia, Liang Cheng, Jian Zhang, Fenghua Meng, Jiandong Yuan, Zhiyuan Zhong
      Lung cancer is one of the worldwide leading and fast-growing malignancies. Pemetrexed disodium (PEM, Alimta®), a small hydrophilic drug, is currently used for treating lung cancer patients. However, PEM suffers from issues like fast elimination, low bioavailability, poor tumor cell selectivity and penetration. Here, we report on lung cancer specific CSNIDARAC (CC9) peptide-functionalized reduction-responsive chimaeric polymersomes (CC9-RCPs) for efficient encapsulation and targeted delivery of PEM to H460 human lung cancer cells in vitro and in vivo. PEM-loaded CC9-RCPs (PEM-CC9-RCPs) was obtained from co-self-assembly of poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) and CC9-functionalized PEG-P(TMC-DTC) in the presence of PEM followed by self-crosslinking. PEM-CC9-RCPs displayed an optimal CC9 density of 9.0% in targeting H460 cells, a high PEM loading content of 14.2 wt%, a small hydrodynamic size of ca. 60 nm and glutathione-triggered PEM release. MTT assays showed that PEM-CC9-RCPs was 2.6- and 10- fold more potent to H460 cells than the non-targeting PEM-RCPs and free PEM controls, respectively. Interestingly, PEM-CC9-RCPs exhibited 22-fold longer circulation time and 9.1-fold higher accumulation in H460 tumor than clinical formulation Alimta®. Moreover, CC9-RCPs showed obviously better tumor penetration than RCPs. Remarkably, PEM-CC9-RCPs at 12.5 mg PEM equiv./kg effectively suppressed growth of H460 xenografts and significantly prolonged mouse survival time as compared to PEM-RCPs and Alimta® controls. These lung cancer specific and reduction-responsive chimaeric polymersomes provide a unique pemetrexed nanoformulation for targeted lung cancer therapy. Statement of Significance Multitargeted antifolate agent pemetrexed (PEM, Alimta®) is currently used for treating lung cancer patients and has low side-effects. However, PEM suffers from issues like fast elimination, low bioavailability, poor tumor cell selectivity and penetration. Scarce work on targeted delivery of PEM has been reported, partly because most conventional nanocarriers show a low and instable loading for hydrophilic, negatively charged drugs like PEM. Herewith, we report on lung cancer specific CSNIDARAC (CC9) peptide-functionalized reduction-responsive chimaeric polymersomes (CC9-RCPs) which showed efficient PEM encapsulation (14.2 wt%, 60 nm) and targeted delivery of PEM to H460 human lung cancer cells, leading to effective suppression of H460 tumor xenografts and significantly prolonged survival rates of mice than Alimta®. To the best of our knowledge, this represents a first report on targeted nanosystems that are capable of efficient loading and targeted delivery of PEM to lung tumors.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.015
  • Corrigendum to “Tailoring surface nanoroughness of electrospun scaffolds
           for skeletal tissue engineering” Acta Biomater. 59 (2017) 82–93
    • Authors: Honglin Chen; Xiaobin Huang; Minmin Zhang; Febriyani Damanik; Matthew B. Baker; Anne Leferink; Huipin Yuan; Roman Truckenmüller; Clemens van Blitterswijk; Lorenzo Moroni
      Abstract: Publication date: Available online 14 February 2018
      Source:Acta Biomaterialia
      Author(s): Honglin Chen, Xiaobin Huang, Minmin Zhang, Febriyani Damanik, Matthew B. Baker, Anne Leferink, Huipin Yuan, Roman Truckenmüller, Clemens van Blitterswijk, Lorenzo Moroni

      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.030
  • 3D Bioprinted Functional and Contractile Cardiac Tissue Constructs
    • Authors: Zhan Wang; Sang Jin Lee; Heng-Jie Cheng; James J. Yoo; Anthony Atala
      Abstract: Publication date: Available online 13 February 2018
      Source:Acta Biomaterialia
      Author(s): Zhan Wang, Sang Jin Lee, Heng-Jie Cheng, James J. Yoo, Anthony Atala
      Bioengineering of a functional cardiac tissue composed of primary cardiomyocytes has great potential for myocardial regeneration and in vitro tissue modeling. However, its applications remain limited because the cardiac tissue is a highly organized structure with unique physiologic, biomechanical, and electrical properties. In this study, we undertook a proof-of-concept study to develop a contractile cardiac tissue with cellular organization, uniformity, and scalability by using three-dimensional (3D) bioprinting strategy. Primary cardiomyocytes were isolated from infant rat hearts and suspended in a fibrin-based bioink to determine the priting capability for cardiac tissue engineering. This cell-laden hydrogel was sequentially printed with a sacrificial hydrogel and a supporting polymeric frame through a 300-µm nozzle by pressured air. Bioprinted cardiac tissue constructs had a spontaneous synchronous contraction in culture, implying in vitro cardiac tissue development and maturation. Progressive cardiac tissue development was confirmed by immunostaining for α-actinin and connexin 43, indicating that cardiac tissues were formed with uniformly aligned, dense, and electromechanically coupled cardiac cells. These constructs exhibited physiologic responses to known cardiac drugs regarding beating frequency and contraction forces. In addition, Notch signaling blockade significantly accelerated development and maturation of bioprinted cardiac tissues. Our results demonstrated the feasibility of bioprinting functional cardiac tissues that could be used for tissue engineering applications and pharmaceutical purposes. Statement of Significance Cardiovascular disease remains a leading cause of death in the United States and a major health-care burden. Myocardial infarction (MI) is a main cause of death in cardiovascular diseases. MI occurs as a consequence of sudden blocking of blood vessels supplying the heart. When occlusions in the coronary arteries occur, an immediate decrease in nutrient and oxygen supply to the cardiac muscle, resulting in permanent cardiac cell death. Eventually, scar tissue formed in the damaged cardiac muscle that cannot conduct electrical or mechanical stimuli thus leading to a reduction in the pumping efficiency of the heart. The therapeutic options available for end-stage heart failure is to undergo heart transplantation or the use of mechanical ventricular assist devices (VADs). However, many patients die while being on a waiting list, due to the organ shortage and limitation of VADs, such as surgical complications, infection, thrombogenesis, and failure of the electrical motor and hemolysis. Ultimately, 3D bioprinting strategy aims to create clinically applicable tissue constructs that can be immediately implanted in the body. To date, the focus on replicating complex and heterogeneous tissue constructs continues to increase as 3D bioprinting technologies advance. In this study, we demonstrated the feasibility of 3D bioprinting strategy to bioengineer the functional cardiac tissue that possesses a highly organized structure with unique physiological and biomechanical properties similar to native cardiac tissue. This bioprinting strategy has great potential to precisely generate functional cardiac tissues for use in pharmaceutical and regenerative medicine applications.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.007
  • Control of Thiol-Maleimide Reaction Kinetics in PEG Hydrogel Networks
    • Authors: Lauren E. Jansen; Lenny J. Negrón-Piñeiro; Sualyneth Galarza; Shelly R. Peyton
      Abstract: Publication date: Available online 13 February 2018
      Source:Acta Biomaterialia
      Author(s): Lauren E. Jansen, Lenny J. Negrón-Piñeiro, Sualyneth Galarza, Shelly R. Peyton
      Michael-type addition reactions are widely used to polymerize biocompatible hydrogels. The thiol-maleimide modality achieves the highest macromer coupling efficiency of the reported Michael-type pairs, but the resulting hydrogel networks are heterogeneous, because polymerization is faster than the individual components can be manually mixed. The reactivity of the thiol dictates the overall reaction speed, which can be slowed in organic solvents and acidic buffers. Since these modifications also reduce the biocompatibility of resulting hydrogels, we investigated a series of biocompatible buffers and crosslinkers to decelerate gelation while maintaining high cell viability. We found that lowering the polymer weight percentage (wt%), buffer concentration, and pH slowed gelation kinetics, but crosslinking with an electronegative peptide was optimal for both kinetics and cell viability. Including a high glucose medium supplement in the polymer solvent buffer improved the viability of the cells being encapsulated without impacting gelation time. Slowing the speed of polymerization resulted in more uniform hydrogels, both in terms of visual inspection and the diffusion of small molecules through the network. However, reactions that were too slow resulted in non-uniform particle dispersion due to settling, thus there is a trade-off in hydrogel network uniformity versus cell distribution in the hydrogels when using these networks in cell applications.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.043
  • Synergistic interplay between the two major bone minerals, hydroxyapatite
           and whitlockite nanoparticles, for osteogenic differentiation of
           mesenchymal stem cells
    • Authors: Hao Cheng; Rosa Chabok; Xiaofei Guan; Aditya Chawla; Yuxiao Li; Ali Khademhosseini; Hae Lin Jang
      Abstract: Publication date: Available online 13 February 2018
      Source:Acta Biomaterialia
      Author(s): Hao Cheng, Rosa Chabok, Xiaofei Guan, Aditya Chawla, Yuxiao Li, Ali Khademhosseini, Hae Lin Jang
      The inorganic part of human bone is mainly composed of hydroxyapatite (HAP: Ca10(PO4)6(OH)2) and whitlockite (WH: Ca18Mg2(HPO4)2(PO4)12) minerals, where the WH phase occupies up to 20–35% of total weight. These two bone minerals have different crystal structures and physicochemical properties, implying their distinguished role in bone physiology. However, until now, the biological significance of the presence of a certain ratio between HAP and WH in bone is unclear. To address this fundamental question, bone mimetic scaffolds are designed to encapsulate human mesenchymal stem cells (MSCs) for assessing their osteogenic activity depending on different ratios of HAP and WH. Interestingly, cellular growth and osteogenic differentiation are significantly promoted when MSCs are grown with a 3–1 ratio of HAP and WH nanoparticles, which is similar to bone. One of the reasons for this synergism between HAP and WH in hydrogel scaffolds is that, while WH nanoparticles can enhance osteogenic differentiation of MSCs compared to HAP, WH counterintuitively decreases the mechanical stiffness of nanocomposite hydrogels and hinders the osteogenic activity of cells. Taken together, these findings identify the optimal ratio between two major minerals in bone mimetic scaffolds to maximize the osteogenic differentiation of MSCs. Statement of significance Human bone minerals are composed of HAP and WH inorganic nanoparticles which have different material properties. However, the reason for the coexistence of HAP and WH in human bone is not fully identified, and HAP and WH composite biomaterial has not been utilized in the clinic. In this study, we have developed bone mimetic HAP and WH nanocomposite hydrogel scaffolds with various ratios. Importantly, we found out that HAP can promote the mechanical stiffness of the composite hydrogel scaffolds while WH can enhance the osteogenic activity of stem cells, which together induced synergism to maximize osteogenic differentiation of stem cells when mixed into 3–1 ratio that is similar to human bone.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.016
  • Carrier-free nanodrug by co-assembly of chemotherapeutic agent and
           photosensitizer for cancer imaging and chemo-photo combination therapy
    • Authors: Ruirui Zhao; Guirong Zheng; Lulu Fan; Zhichun Shen; Kai Jiang; Yan Guo; Jing-Wei Shao
      Abstract: Publication date: Available online 13 February 2018
      Source:Acta Biomaterialia
      Author(s): Ruirui Zhao, Guirong Zheng, Lulu Fan, Zhichun Shen, Kai Jiang, Yan Guo, Jing-Wei Shao
      Nanosized drug delivery systems (NDDS) with photothermal therapy (PTT) and photodynamic therapy (PDT) have been extensively exploited to improve the therapeutic performance and bio-safety of chemotherapeutic drugs in cancer. In this work, a carrier-free nanodrug was developed by co-assembly of the anti-cancer agent ursolic acid (UA), an asialoglycoprotein receptor (ASGPR), which can recognize the target molecule lactobionic acid (LA), and the near-infrared (NIR) probe dye indocyanine green (ICG) to form UA-LA-ICG NPs by a simple and green self-assembly approach. The UA-LA-ICG NPs had suitable stability, showed controlled release profile of UA drugs, and exhibited preferable temperature response (∼59.4 °C) under laser irradiation (808 nm, 1 W/cm2). Compared with free ICG, the UA-LA-ICG NPs significantly enhanced the intracellular ICG uptake. Upon irradiation of the NIR laser, co-assembled nanodrugs demonstrated great performance as a reactive oxygen species (ROS) producer and exhibited more anti-proliferative activities on ASGPR-overexpressing HepG2 cells than ASGPR low-expressing HeLa cells. Meanwhile, in vivo NIR fluorescence imaging exhibited that the co-assembled nanodrugs were specifically targeted to the tumor by the active targeting property of LA, and its circulation time was much longer than that of free ICG. In addition, UA-LA-ICG NPs + NIR irradiation treatment displayed enhanced inhibitory effect on tumor growth in H22 tumor-bearing mice. Overall, the co-assembly of chemotherapeutic agent and photosensitizer by the self-assembly approach might open an alternative avenue and give inspiration to fabricate new carrier-free nanodrugs for cancer imaging and chemo-photo combination therapy. Statement of Significance The present study for the first time reported carrier-free nanoparticles (NPs) by co-assembly of a natural product ursolic acid (UA), an asialoglycoprotein receptor (ASGPR)-recognized sugar molecule lactobionic acid (LA), and the near-infrared dye indocyanine green (ICG) through a simple and green approach. The preparation process of nanodrugs is simple, rapid, effective, and labor-saving. The co-assembled nanodrugs were capable of stabilizing the ICG molecules and specifically targeting to the tumor, which could increase the tumor accumulation in cancer imaging and also enhance the efficacy of chemo-phototherapy.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.028
  • Effects of maturation and advanced glycation on tensile mechanics of
           collagen fibrils from rat tail and Achilles tendons
    • Authors: Rene B. Svensson; Stuart T. Smith; Patrick J. Moyer; S. Peter Magnusson
      Abstract: Publication date: Available online 13 February 2018
      Source:Acta Biomaterialia
      Author(s): Rene B. Svensson, Stuart T. Smith, Patrick J. Moyer, S. Peter Magnusson
      Connective tissues are ubiquitous throughout the body and consequently affect the function of many organs. In load bearing connective tissues like tendon, the mechanical functionality is provided almost exclusively by collagen fibrils that in turn are stabilized by covalent cross-links. Functionally distinct tendons display different cross-link patterns, which also change with maturation, but these differences have not been studied in detail at the fibril level. In the present study, a custom built nanomechanical test platform was designed and fabricated to measure tensile mechanics of individual fibrils from rat tendons. The influence of animal maturity (4 vs. 16 week old rats) and functionally different tendons (tail vs. Achilles tendons) were examined. Additionally the effect of methylglyoxal (MG) treatment in vitro to form advanced glycation end products (AGEs) was investigated. Age and tissue type had no significant effect on fibril mechanics, but MG treatment increased strength and stiffness without inducing brittleness and gave rise to a distinct three-phase mechanical response corroborating that previously reported in human patellar tendon fibrils. That age and tissue had little mechanical effect, tentatively suggest that variations in enzymatic cross-links may play a minor role after initial tissue formation. Statement of significance Tendons are connective tissues that connect muscle to bone and carry some of the greatest mechanical loads in the body, which makes them common sites of injury. A tendon is essentially a biological rope formed by thin strands called fibrils made of the protein collagen. Tendon function relies on the strength of these fibrils, which in turn depends on naturally occurring cross-links between collagen molecules, but the mechanical influence of these cross-links have not been measured before. It is believed that beneficial cross-linking occurs with maturation while additional cross-linking with aging may lead to brittleness, but this study provides evidence that maturation has little effect on mechanical function and that age-related cross-linking does not result in brittle collagen fibrils.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.005
  • Predicting patient exposure to nickel released from cardiovascular devices
           using multi-scale modeling
    • Authors: David M. Saylor; Brent A. Craven; Vaishnavi Chandrasekar; David D. Simon; Ronald P. Brown; Eric M. Sussman
      Abstract: Publication date: Available online 13 February 2018
      Source:Acta Biomaterialia
      Author(s): David M. Saylor, Brent A. Craven, Vaishnavi Chandrasekar, David D. Simon, Ronald P. Brown, Eric M. Sussman
      Many cardiovascular device alloys contain nickel, which if released in sufficient quantities, can lead to adverse health effects. However, in-vivo nickel release from implanted devices and subsequent biodistribution of nickel ions to local tissues and systemic circulation are not well understood. To address this uncertainty, we have developed a multi-scale (material, tissue, and system) biokinetic model. The model links nickel release from an implanted cardiovascular device to concentrations in peri-implant tissue, as well as in serum and urine, which can be readily monitored. The model was parameterized for a specific cardiovascular implant, nitinol septal occluders, using in-vitro nickel release test results, studies of ex-vivo uptake into heart tissue, and in-vivo and clinical measurements from the literature. Our results show that the model accurately predicts nickel concentrations in peri-implant tissue in an animal model and in serum and urine of septal occluder patients. The congruity of the model with these data suggests it may provide useful insight to establish nickel exposure limits and interpret biomonitoring data. Finally, we use the model to predict local and systemic nickel exposure due to passive release from nitinol devices produced using a wide range of manufacturing processes, as well as general relationships between release rate and exposure. These relationships suggest that peri-implant tissue and serum levels of nickel will remain below 5 μg/g and 10 μg/l, respectively, in patients who have received implanted nitinol cardiovascular devices provided the rate of nickel release per device surface area does not exceed 0.074 μg/(cm2 d) and is less than 32 μg/d in total. Statement of significance The uncertainty in whether in-vitro tests used to evaluate metal ion release from medical products are representative of clinical environments is one of the largest roadblocks to establishing the associated patient risk. We have developed and validated a multi-scale biokinetic model linking nickel release from cardiovascular devices in-vivo to both peri-implant and systemic levels. By providing clinically relevant exposure estimates, the model vastly improves the evaluation of risk posed to patients by the nickel contained within these devices. Our model is the first to address the potential for local and systemic metal ion exposure due to a medical device and can serve as a basis for future efforts aimed at other metal ions and biomedical products.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.024
  • A laser-activated multifunctional targeted nanoagent for imaging and gene
           therapy in a mouse xenograft model with retinoblastoma Y79 cells
    • Authors: Mingxing Wu; Haibo Xiong; Hongmi Zou; Meng Li; Pan Li; Yu Zhou; Yan Xu; Jia Jian; Fengqiu Liu; Hongyun Zhao; Zhigang Wang; Xiyuan Zhou
      Abstract: Publication date: Available online 13 February 2018
      Source:Acta Biomaterialia
      Author(s): Mingxing Wu, Haibo Xiong, Hongmi Zou, Meng Li, Pan Li, Yu Zhou, Yan Xu, Jia Jian, Fengqiu Liu, Hongyun Zhao, Zhigang Wang, Xiyuan Zhou
      Retinoblastoma (RB) is the most common intraocular malignancy of childhood that urgently needs early detection and effective therapy methods. The use of nanosized gene delivery systems is appealing because of their highly adjustable structure to carry both therapeutic and imaging agents. Herein, we report a folic acid (FA)-modified phase-changeable cationic nanoparticle encapsulating liquid perfluoropentane (PFP) and indocyanine green (ICG) (FA-CN-PFP-ICG, FCNPI) with good plasmid DNA (pDNA) carrying capacity, favorable biocompatibility, excellent photoacoustic (PA) and ultrasound (US) contrast, enhanced gene transfection efficiency and therapeutic effect. The liquid-gas phase transition of the FCNPI upon laser irradiation has provided splendid contrasts for US/PA dual-modality imaging in vitro as well as in vivo. More importantly, laser-mediated gene transfection with targeted cationic FCNPI nanoparticles demonstrated the best therapeutic effect compared with untargeted cationic nanoparticle (CN-PFP-ICG, CNPI) and neutral nanoparticle (NN-PFP-ICG, NNPI), both in vitro and in vivo. Such a multifunctional nanoagent is expected to combine dual-mode guided imaging with fewer side effects and proper therapeutic efficacy. These results establish an experimental foundation for the clinical detection of and therapy for RB. Statement of significance We successfully constructed a multifunctional targeted cationic nanoparticle (FCNPI) and meticulously compared the variations in the plasmid loading capacity and binding to Y79 cells with NNPI, CNPI, and FCNPI. FCNPI exhibited favorable plasmid loading capability, splendid ability for targeting and only it could provide optimal US and PA contrast to background during a considerable long time. The FCNPI/pDNA + Laser system also exhibited the best therapeutic effect in vivo; this finding proposes a potential strategy for the evaluation of an efficient gene delivery nanocarrier for gene targeting therapy of RB tumor. Our study showed that there are great advantages of targeting FCNPI to provide PA/US imaging and to enlighten laser-mediated gene transfection. FCNPI is a very helpful multifunctional agent with potential.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.006
  • pH-sensitive doxorubicin-conjugated prodrug micelles with
           charge-conversion for cancer therapy
    • Authors: Boxuan Ma; Weihua Zhuang; Yanan Wang; Rifang Luo; Yunbing Wang
      Abstract: Publication date: Available online 13 February 2018
      Source:Acta Biomaterialia
      Author(s): Boxuan Ma, Weihua Zhuang, Yanan Wang, Rifang Luo, Yunbing Wang
      Intelligent drug delivery systems with prolonged circulation time, reduced drug leakage in blood, target site-triggered drug release and endosomal escape are attractive and ideal for malignant tumor therapy. Herein, doxorubicin (DOX)-conjugated smart polymeric micelles based on 4-carboxy benzaldehyde-grafted poly (L-lysine)-block-poly (methacryloyloxyethyl phosphorylcholine) (PLL(CB/DOX)-b-PMPC) copolymer are prepared. DOX and electronegative 4-carboxy benzaldehyde are conjugated to the PLL block via an imine linkage and as a result, the drug loaded micelles exhibited the pH-triggered charge-conversion property and accelerated drug release at tumor pH. In vitro cytotoxicity studies of these DOX-loaded micelles exhibited great tumor inhibition against HeLa and 4T1 cells. Moreover, in mice models of breast cancer, these DOX-loaded micelles showed better anti-tumor efficacy and less organ toxicity than free drug. In summary, these polymeric micelles could be applied as potential nanocarriers for cancer therapy. Statement of Significance As a typical anti-cancer drug, Doxorubicin (DOX) exhibited remarkable tumor inhibition but was limited by its low drug utilization and strong toxicity to organs. To overcome these challenges, we developed a DOX-conjugated polymeric micelle as a nano drug carrier which was endowed with pH-sensitivity and charge-conversion function. The structure of micelles would quickly disintegrate with surface charge-conversion in acidic environment, which would contribute to the endosomal escape and accelerated drug release. These DOX-conjugated micelles would provide a promising platform for the efficient DOX delivery and better anti-cancer efficiency.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.008
  • Mechanically Enhanced Nested-Network Hydrogels as a Coating Material for
           Biomedical Devices
    • Authors: Zhengmu Wang; Hongbin Zhang; Axel J. Chu; John Jackson; Karen Lin; Chinten James Lim; Dirk Lange; Mu Chiao
      Abstract: Publication date: Available online 12 February 2018
      Source:Acta Biomaterialia
      Author(s): Zhengmu Wang, Hongbin Zhang, Axel J. Chu, John Jackson, Karen Lin, Chinten James Lim, Dirk Lange, Mu Chiao
      Well-organized composite formations such as hierarchical nested-network (NN) structure in bone tissue and reticular connective tissue present remarkable mechanical strength and play a crucial role in achieving physical and biological functions for living organisms. Inspired by these delicate microstructures in nature, an analogous scaffold of double network hydrogel was fabricated by creating a poly(2-hydroxyethyl methacrylate) (pHEMA) network in the porous structure of alginate hydrogels. The resulting hydrogel possessed hierarchical NN structure and showed significantly improved mechanical strength but still maintained high elasticity comparable to soft tissues due to a mutual strengthening effect between the two networks. The tough hydrogel is also self-lubricated, exhibiting a surface friction coefficient comparable with polydimethylsiloxane (PDMS) substrates lubricated by a commercial aqueous lubricant (K-Y Jelly) and other low surface friction hydrogels. Additional properties of this hydrogel include high hydrophilicity, good biocompatibility, tunable cell adhesion and bacterial resistance after incorporation of silver nanoparticles. Firm bonding of the hydrogel on silicone substrates could be achieved through facile chemical modification, thus enabling the use of this hydrogel as a versatile coating material for biomedical applications. Statement of Significance In this study, we generated a tough hydrogel by crosslinking HEMA monomers in alginate hydrogels and forming a well-organized structure of hierarchical nested network (NN) which is rarely observed before. Different from most reported stretchable alginate-based hydrogels, the NN hydrogel showed higher compressive strength but retained comparable softness to alginate counterparts. This work further demonstrated the good integration of the tough hydrogel with silicone substrates through chemical modification and micropillar structures. Moreover, other functions such as low surface friction, biocompatibility, tunable cell adhesion abilities, and antibacterial properties could be achieved in the hydrogel, indicating great promise of the hydrogel as a versatile coating material for biomedical applications.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.003
  • A physiologically relevant 3D collagen-based scaffold–neuroblastoma cell
           system exhibits chemosensitivity similar to orthotopic xenograft models
    • Authors: C. Curtin; J.C. Nolan; R. Conlon; L. Deneweth; C. Gallagher; Y.J. Tan; B.L. Cavanagh; A.Z. Asraf; H. Harvey; S. Miller-Delaney; J. Shohet; I. Bray; F.J. O'Brien; R.L. Stallings; O. Piskareva
      Abstract: Publication date: Available online 12 February 2018
      Source:Acta Biomaterialia
      Author(s): C. Curtin, J.C. Nolan, R. Conlon, L. Deneweth, C. Gallagher, Y.J. Tan, B.L. Cavanagh, A.Z. Asraf, H. Harvey, S. Miller-Delaney, J. Shohet, I. Bray, F.J. O'Brien, R.L. Stallings, O. Piskareva
      3D scaffold-based in vitro cell culturing is a recent technological advancement in cancer research bridging the gap between conventional 2D culture and in vivo tumours. The main challenge in treating neuroblastoma, a paediatric cancer of the sympathetic nervous system, is to combat tumour metastasis and resistance to multiple chemotherapeutic drugs. The aim of this study was to establish a physiologically relevant 3D neuroblastoma tissue-engineered system and explore its therapeutic relevance. Two neuroblastoma cell lines, chemotherapeutic sensitive Kelly and chemotherapeutic resistant KellyCis83 were cultured in a 3D in vitro model on two collagen-based scaffolds containing either glycosaminoglycan (Coll-GAG) or nanohydroxyapatite (Coll-nHA) and compared to 2D cell culture and an orthotopic murine model. Both neuroblastoma cell lines actively infiltrated the scaffolds and proliferated displaying >100-fold increased resistance to cisplatin treatment when compared to 2D cultures, exhibiting chemosensitivity similar to orthotopic xenograft in vivo models. This model demonstrated its applicability to validate miRNA-based gene delivery. The efficacy of liposomes bearing miRNA mimics uptake and gene knockdown was similar in both 2D and 3D in vitro culturing models highlighting the proof-of-principle for the applicability of 3D collagen-based scaffolds cell system for validation of miRNA function. Collectively, this data shows the successful development and characterisation of a physiologically relevant, scaffold-based 3D tissue-engineered neuroblastoma cell model, strongly supporting its value in the evaluation of chemotherapeutics, targeted therapies and investigation of neuroblastoma pathogenesis. While neuroblastoma is the specific disease being focused upon, the platform may have multi-functionality beyond this tumour type. Statement of Significance Traditional 2D cell cultures do not completely capture the 3D architecture of cells and extracellular matrix contributing to a gap in our understanding of mammalian biology at the tissue level and may explain some of the discrepancies between in vitro and in vivo results. Here, we demonstrated the successful development and characterisation of a physiologically relevant, scaffold-based 3D tissue-engineered neuroblastoma cell model, strongly supporting its value in the evaluation of chemotherapeutics, targeted therapies and investigation of neuroblastoma pathogenesis. The ability to test drugs in this reproducible and controllable tissue-engineered model system will help reduce the attrition rate of the drug development process and lead to more effective and tailored therapies. Importantly, such 3D cell models help to reduce and replace animals for pre-clinical research addressing the principles of the 3Rs.
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      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.004
  • In vitro methods for the evaluation of antimicrobial surface designs
    • Authors: Jelmer Sjollema; Sebastian A.J. Zaat; Veronique Fontaine; Madeleine Ramstedt; Reto Luginbuehl; Karin Thevissen; Jiuyi Li; Henny C. van der Mei; Henk J. Busscher
      Abstract: Publication date: Available online 10 February 2018
      Source:Acta Biomaterialia
      Author(s): Jelmer Sjollema, Sebastian A.J. Zaat, Veronique Fontaine, Madeleine Ramstedt, Reto Luginbuehl, Karin Thevissen, Jiuyi Li, Henny C. van der Mei, Henk J. Busscher
      Bacterial adhesion and subsequent biofilm formation on biomedical implants and devices are a major cause of their failure. As systemic antibiotic treatment is often ineffective, there is an urgent need for antimicrobial biomaterials and coatings. The term “antimicrobial” can encompass different mechanisms of action (here termed “antimicrobial surface designs”), such as antimicrobial-releasing, contact-killing or non-adhesivity. Biomaterials equipped with antimicrobial surface designs based on different mechanisms of action require different in vitro evaluation methods. Available industrial standard evaluation tests do not address the specific mechanisms of different antimicrobial surface designs and have therefore been modified over the past years, adding to the myriad of methods available in the literature to evaluate antimicrobial surface designs. The aim of this review is to categorize fourteen presently available methods including industrial standard tests for the in vitro evaluation of antimicrobial surface designs according to their suitability with respect to their antimicrobial mechanism of action. There is no single method or industrial test that allows to distinguish antimicrobial designs according to all three mechanisms identified here. However, critical consideration of each method clearly relates the different methods to a specific mechanism of antimicrobial action. It is anticipated that use of the provided table with the fourteen methods will avoid the use of wrong methods for evaluating new antimicrobial designs and therewith facilitate translation of novel antimicrobial biomaterials and coatings to clinical use. The need for more and better updated industrial standard tests is emphasized. Statement of Significance European COST-action TD1305, IPROMEDAI aims to provide better understanding of mechanisms of antimicrobial surface designs of biomaterial implants and devices. Current industrial evaluation standard tests do not sufficiently account for different, advanced antimicrobial surface designs, yet are urgently needed to obtain convincing in vitro data for approval of animal experiments and clinical trials. This review aims to provide an innovative and clear guide to choose appropriate evaluation methods for three distinctly different mechanisms of antimicrobial design: (1) antimicrobial-releasing, (2) contact-killing and (3) non-adhesivity. Use of antimicrobial evaluation methods and definition of industrial standard tests, tailored toward the antimicrobial mechanism of the design, as identified here, fulfill a missing link in the translation of novel antimicrobial surface designs to clinical use.
      Graphical abstract image

      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.02.001
  • A Continuum of Mineralization from Human Renal Pyramid to Stones on Stems
    • Authors: Benjamin A Sherer; Ling Chen; Misun Kang; Alex R. Shimotake; Scott V Wiener; Tom Chi; Marshall L Stoller; Sunita P. Ho
      Abstract: Publication date: Available online 9 February 2018
      Source:Acta Biomaterialia
      Author(s): Benjamin A Sherer, Ling Chen, Misun Kang, Alex R. Shimotake, Scott V Wiener, Tom Chi, Marshall L Stoller, Sunita P. Ho
      The development of new modalities for kidney stone prevention rests upon understanding the progression of mineralization within the renal pyramid. The progression from small foci of mineralization within the renal pyramid to larger interstitial plaques that ultimately lead to the formation of clinically detectable calcium-based stones on calcium phosphate stems will be presented through correlative microscopy approach. High resolution X-ray computed tomography (micro-XCT), electron microscopy, and energy dispersive X-ray (EDX) compositional analyses of interstitial plaques, stems, and attached stones were performed.Increase in mineral density progressed with mineralization severity, with the highest mineral densities detected within mature Randall’s plaque and stems to which kidney stones were attached. EDX analyses revealed variable elemental composition within interstitial plaque, stems, and stones. Micro-XCT reconstructions of stones with stems enabled visualization of unoccluded tubules within stems, with average tubule diameters corresponding to thin limbs of Henle, blood vessels, and collecting ducts. Correlative microscopy confirmed that the progression of mineralization leading to calcium-based nephrolithiasis occurs through a continuum involving four anatomically and structurally distinct biomineralization regions: 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall’s plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones. Statement of Significance Nephrolithiasis is a common condition affecting nearly 1 in 11 Americans. The most common type of stone, calcium oxalate is known to form on a calcium phosphate deposit on the renal papilla known as Randall's plaque. Novel imaging techniques have identified distinct regions of biomineralization not just at the tip, but throughout the renal papilla. The classic understanding of Randall’s plaque formation is reformulated using correlative imaging techniques. This study establishes a stepwise progression of anatomically-specific biomineralization events including, 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall’s plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones, and provides insights into the need for plausible site-specific therapeutic intervention.
      Graphical abstract image

      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.040
  • Cyclic RGD functionalized liposomes encapsulating urokinase for
    • Authors: Nengpan Zhang; Chunlin Li; Dayong Zhou; Chen Ding; Yaqing Jin; Qingmei Tian; Xiangzhou Meng; Kefeng Pu; Yimin Zhu
      Abstract: Publication date: Available online 9 February 2018
      Source:Acta Biomaterialia
      Author(s): Nengpan Zhang, Chunlin Li, Dayong Zhou, Chen Ding, Yaqing Jin, Qingmei Tian, Xiangzhou Meng, Kefeng Pu, Yimin Zhu
      Thrombosis, a critical event in blood vessels, not only is associated with myocardial infarction and stroke, but also accounts for considerable morbidity and mortality. Thrombolytic drugs are usually applied to the treatment of acute myocardial infarction, acute cerebral infarction and pulmonary embolism. However, thrombolytic drugs show limited efficacy in clinical practice because of the short half-life in plasma and systemic side effects. In this study, the cyclic RGD (cRGD) functionalized liposomes were prepared to encapsulate urokinase, a cheap and widely used thrombolytic drug in clinic and better thrombolysis efficacy was achieved. The flow cytometry analysis showed that the cRGD liposomes could bind to the activated platelets while not to the resting platelets. In vitro release study revealed that the release percentage reached plateau in about 5 h with 60% urokinase being released from liposomes. Results from the in vitro thrombolysis experiments demonstrated a good thrombolysis potential of the cRGD urokinase liposomes. The in vivo thrombolysis study demonstrated that the cRGD liposomes could significantly reduce the dose of urokinase by 75% while achieving the equivalent thrombolysis effect as the free urokinase in mouse mesenteric thrombosis model. In conclusion, the cRGD liposomes encapsulating urokinase hold great promise in clinic for better thrombolytic efficacy. Statement of Significance In this paper, the cRGD liposomes were prepared to encapsulate urokinase for targeted thrombolysis therapy. The cRGD liposomes could specifically bind to the activated platelets and could stably and continuously release its loaded urokinase. The mouse mesenteric thrombosis model was established to evaluate the thrombolysis effect of the cRGD urokinase liposomes. The results demonstrated that the cRGD liposomes could improve the thrombolytic efficacy by almost 4-fold over free urokinase. In conclusion, the cRGD liposomes encapsulating urokinase had great potential for the clinical treatment of thrombosis.
      Graphical abstract image

      PubDate: 2018-02-26T00:38:39Z
      DOI: 10.1016/j.actbio.2018.01.038
  • The effects of platelet lysate patches on the activity of tendon-derived
    • Authors: Raquel Costa-Almeida; Albina R. Franco; Tamagno Pesqueira; Mariana B. Oliveira; Pedro S. Babo; Isabel B. Leonor; João F. Mano; Rui L. Reis; Manuela E. Gomes
      Abstract: Publication date: Available online 16 January 2018
      Source:Acta Biomaterialia
      Author(s): Raquel Costa-Almeida, Albina R. Franco, Tamagno Pesqueira, Mariana B. Oliveira, Pedro S. Babo, Isabel B. Leonor, João F. Mano, Rui L. Reis, Manuela E. Gomes
      Platelet-derived biomaterials are widely explored as cost-effective sources of therapeutic factors, holding a strong potential for endogenous regenerative medicine. Particularly for tendon repair, treatment approaches that shift the injury environment are explored to accelerate tendon regeneration. Herein, genipin-crosslinked platelet lysate (PL) patches are proposed for the delivery of human-derived therapeutic factors in patch augmentation strategies aiming at tendon repair. Developed PL patches exhibited a controlled release profile of PL proteins, including bFGF and PDGF-BB. Additionally, PL patches exhibited an antibacterial effect by preventing the adhesion, proliferation and biofilm formation by S. aureus, a common pathogen in orthopaedic surgical site infections. Furthermore, these patches supported the activity of human tendon-derived cells (hTDCs). Cells were able to proliferate over time and an up-regulation of tenogenic genes (SCX, COL1A1 and TNC) was observed, suggesting that PL patches may modify the behavior of hTDCs. Accordingly, hTDCs deposited tendon-related extracellular matrix proteins, namely collagen type I and tenascin C. In summary, PL patches can act as a reservoir of biomolecules derived from PL and support the activity of native tendon cells, being proposed as bioinstructive patches for tendon regeneration. Statement of significance Platelet-derived biomaterials hold great interest for the delivery of therapeutic factors for applications in endogenous regenerative medicine. In the particular case of tendon repair, patch augmentation strategies aiming at shifting the injury environment are explored to improve tendon regeneration. In this study, PL patches were developed with remarkable features, including the controlled release of growth factors and antibacterial efficacy. Remarkably, PL patches supported the activity of native tendon cells by up-regulating tenogenic genes and enabling the deposition of ECM proteins. This patch holds great potential towards simultaneously reducing post-implantation surgical site infections and promoting tendon regeneration for prospective in vivo applications.
      Graphical abstract image

      PubDate: 2018-01-26T08:54:47Z
      DOI: 10.1016/j.actbio.2018.01.006
  • Mesoporous silica nanoparticles decorated with polycationic dendrimers for
           infection treatment
    • Authors: Blanca González; Montserrat Colilla; Jaime Díez; Daniel Pedraza; Marta Guembe; Isabel Izquierdo-Barba; María Vallet-Regí
      Abstract: Publication date: Available online 5 January 2018
      Source:Acta Biomaterialia
      Author(s): Blanca González, Montserrat Colilla, Jaime Díez, Daniel Pedraza, Marta Guembe, Isabel Izquierdo-Barba, María Vallet-Regí
      This work aims to provide an effective and novel solution for the treatment of infection by using nanovehicles loaded with antibiotics capable of penetrating the bacterial wall, thus increasing the antimicrobial effectiveness. These nanosystems, named “nanoantibiotics”, are composed of mesoporous silica nanoparticles (MSNs), which act as nanocarriers of an antimicrobial agent (levofloxacin, LEVO) localized inside the mesopores. To provide the nanosystem of bacterial membrane interaction capability, a polycationic dendrimer, concretely the poly(propyleneimine) dendrimer of third generation (G3), was covalently grafted to the external surface of the LEVO-loaded MSNs. After physicochemical characterization of this nanoantibiotic, the release kinetics of LEVO and the antimicrobial efficacy of each released dosage were evaluated. Besides, internalization studies of the MSNs functionalized with the G3 dendrimer were carried out, showing a high penetrability throughout Gram-negative bacterial membranes. This work evidences that the synergistic combination of polycationic dendrimers as bacterial membrane permeabilization agents with LEVO-loaded MSNs triggers an efficient antimicrobial effect on Gram-negative bacterial biofilm. These positive results open up very promising expectations for their potential application in new infection therapies. Statement of Significance Seeking new alternatives to current available treatments of bacterial infections represents a great challenge in nanomedicine. This work reports the design and optimization of a new class of antimicrobial agent, named “nanoantibiotic”, based on mesoporous silica nanoparticles (MSNs) decorated with polypropyleneimine dendrimers of third generation (G3) and loaded with levofloxacin (LEVO) antibiotic. The covalently grafting of these G3 dendrimers to MSNs allows an effective internalization in Gram-negative bacteria. Furthermore, the LEVO loaded into the mesoporous cavities is released in a sustained manner at effective antimicrobial dosages. The novelty and originality of this manuscript relies on proving that the synergistic combination of bacteria-targeting and antimicrobial agents into a unique nanosystem provokes a remarkable antimicrobial effect against bacterial biofilm.
      Graphical abstract image

      PubDate: 2018-01-26T08:54:47Z
      DOI: 10.1016/j.actbio.2017.12.041
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