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BIOLOGY (1420 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 18)
Achievements in the Life Sciences     Open Access   (Followers: 4)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Biologica Colombiana     Open Access   (Followers: 6)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 25)
Acta Biotheoretica     Hybrid Journal   (Followers: 5)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales : The Journal of Silesian Museum in Opava     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 9)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Bioinformatics     Open Access   (Followers: 18)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biology     Open Access   (Followers: 8)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 6)
Advances in Cell Biology     Open Access   (Followers: 23)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Ecological Research     Full-text available via subscription   (Followers: 39)
Advances in Ecology     Open Access   (Followers: 13)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 20)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Genome Biology     Full-text available via subscription   (Followers: 12)
Advances in High Energy Physics     Open Access   (Followers: 20)
Advances in Human Biology     Open Access  
Advances in Life Science and Technology     Open Access   (Followers: 14)
Advances in Life Sciences     Open Access   (Followers: 4)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 21)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
Advances in Structural Biology     Full-text available via subscription   (Followers: 7)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 6)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 1)
Ageing Research Reviews     Hybrid Journal   (Followers: 7)
Aging Cell     Open Access   (Followers: 9)
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: 13)
AJP Endocrinology and Metabolism     Full-text available via subscription   (Followers: 22)
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: 12)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 10)
American Journal of Bioethics     Hybrid Journal   (Followers: 10)
American Journal of Biostatistics     Open Access   (Followers: 9)
American Journal of Human Biology     Hybrid Journal   (Followers: 12)
American Journal of Medical and Biological Research     Open Access   (Followers: 5)
American Journal of Plant Sciences     Open Access   (Followers: 19)
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: 63)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 7)
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: 8)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Human Biology     Hybrid Journal   (Followers: 4)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 17)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 25)
Annual Review of Cell and Developmental Biology     Full-text available via subscription   (Followers: 37)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 14)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 18)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 10)
Anthropological Review     Open Access   (Followers: 23)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antibiotics     Open Access   (Followers: 8)
Antioxidants     Open Access   (Followers: 4)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 8)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 4)
Apmis     Hybrid Journal   (Followers: 1)
APOPTOSIS     Hybrid Journal   (Followers: 8)
Applied Bionics and Biomechanics     Open Access   (Followers: 8)
Applied Vegetation Science     Full-text available via subscription   (Followers: 9)
Aquaculture Environment Interactions     Open Access   (Followers: 2)
Aquaculture International     Hybrid Journal   (Followers: 22)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 6)
Aquatic Biology     Open Access   (Followers: 4)
Aquatic Ecology     Hybrid Journal   (Followers: 30)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 13)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 19)
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: 7)
Archives of Oral Biology     Hybrid Journal   (Followers: 2)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 3)
Arquivos do Instituto Biológico     Open Access   (Followers: 1)
Arquivos do Museu Dinâmico Interdisciplinar     Open Access  
Arthropod Structure & Development     Hybrid Journal   (Followers: 2)
Arthropods     Open Access   (Followers: 1)
Artificial DNA: PNA & XNA     Hybrid Journal   (Followers: 2)
Artificial Photosynthesis     Open Access   (Followers: 1)
Asian Bioethics Review     Full-text available via subscription   (Followers: 1)
Asian Journal of Biodiversity     Open Access   (Followers: 5)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 2)
Asian Journal of Nematology     Open Access   (Followers: 3)
Asian Journal of Poultry Science     Open Access   (Followers: 4)
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 5)
Autophagy     Hybrid Journal   (Followers: 2)
Avian Biology Research     Full-text available via subscription   (Followers: 3)
Avian Conservation and Ecology     Open Access   (Followers: 7)
Bacteriology Journal     Open Access   (Followers: 2)
Bacteriophage     Full-text available via subscription   (Followers: 3)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Plant Taxonomy     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Berita Biologi     Open Access   (Followers: 1)
Between the Species     Open Access   (Followers: 1)
Bio Tribune Magazine     Hybrid Journal  
BIO Web of Conferences     Open Access  
BIO-Complexity     Open Access  
Bio-Grafía. Escritos sobre la Biología y su enseñanza     Open Access  
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
Biochemistry and Cell Biology     Full-text available via subscription   (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)
Biodiversidad Colombia     Open Access  
Biodiversity : Research and Conservation     Open Access   (Followers: 26)
Biodiversity and Natural History     Open Access   (Followers: 5)
Biodiversity Data Journal     Open Access   (Followers: 3)
Biodiversity Informatics     Open Access  
Bioedukasi : Jurnal Pendidikan Biologi FKIP UM Metro     Open Access  
Bioeksperimen : Jurnal Penelitian Biologi     Open Access  
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 1)
Bioenergy Research     Hybrid Journal   (Followers: 2)
Bioengineering and Bioscience     Open Access   (Followers: 1)
BioEssays     Hybrid Journal   (Followers: 10)
Bioethics     Hybrid Journal   (Followers: 14)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 3)
Biogeosciences (BG)     Open Access   (Followers: 9)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 1)
Bioinformatics     Hybrid Journal   (Followers: 231)
Bioinformatics and Biology Insights     Open Access   (Followers: 14)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 6)
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: 4)
Biological Control     Hybrid Journal   (Followers: 5)
Biological Invasions     Hybrid Journal   (Followers: 16)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 14)
Biological Letters     Open Access   (Followers: 4)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 41)
Biological Psychology     Hybrid Journal   (Followers: 6)
Biological Research     Open Access  
Biological Rhythm Research     Hybrid Journal   (Followers: 2)
Biological Theory     Hybrid Journal   (Followers: 1)
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: 44)
Biologija     Open Access  
Biology     Open Access   (Followers: 5)
Biology and Philosophy     Hybrid Journal   (Followers: 16)
Biology Bulletin     Hybrid Journal   (Followers: 1)
Biology Bulletin Reviews     Hybrid Journal  
Biology Direct     Open Access   (Followers: 7)
Biology Letters     Full-text available via subscription   (Followers: 35)
Biology Methods and Protocols     Hybrid Journal  

        1 2 3 4 5 6 7 8 | Last

Journal Cover Acta Biomaterialia
  [SJR: 2.02]   [H-I: 104]   [25 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7061
   Published by Elsevier Homepage  [3031 journals]
  • Scaffolds for 3D in vitro culture of neural lineage cells
    • Authors: Ashley R. Murphy; Andrew Laslett; Carmel M. O'Brien; Neil R. Cameron
      Pages: 1 - 20
      Abstract: Publication date: May 2017
      Source:Acta Biomaterialia, Volume 54
      Author(s): Ashley R. Murphy, Andrew Laslett, Carmel M. O'Brien, Neil R. Cameron
      Understanding how neurodegenerative disorders develop is not only a key challenge for researchers but also for the wider society, given the rapidly aging populations in developed countries. Advances in this field require new tools with which to recreate neural tissue in vitro and produce realistic disease models. This in turn requires robust and reliable systems for performing 3D in vitro culture of neural lineage cells. This review provides a state of the art update on three-dimensional culture systems for in vitro development of neural tissue, employing a wide range of scaffold types including hydrogels, solid porous polymers, fibrous materials and decellularised tissues as well as microfluidic devices and lab-on-a-chip systems. To provide some context with in vivo development of the central nervous system (CNS), we also provide a brief overview of the neural stem cell niche, neural development and neural differentiation in vitro. We conclude with a discussion of future directions for this exciting and important field of biomaterials research. Statement of Significance Neurodegenerative diseases, including dementia, Parkinson’s and Alzheimer’s diseases and motor neuron diseases, are a major societal challenge for aging populations. Understanding these conditions and developing therapies against them will require the development of new physical models of healthy and diseased neural tissue. Cellular models resembling neural tissue can be cultured in the laboratory with the help of 3D scaffolds – materials that allow the organization of neural cells into tissue-like structures. This review presents recent work on the development of different types of scaffolds for the 3D culture of neural lineage cells and the generation of functioning neural-like tissue. These in vitro culture systems are enabling the development of new approaches for modelling and tackling diseases of the brain and CNS.
      Graphical abstract image

      PubDate: 2017-05-04T12:57:27Z
      DOI: 10.1016/j.actbio.2017.02.046
      Issue No: Vol. 54 (2017)
  • Design strategies and applications of nacre-based biomaterials
    • Authors: Ethan Michael Gerhard; Wei Wang; Caiyan Li; Jinshan Guo; Ibrahim Tarik Ozbolat; Kevin Michael Rahn; April Dawn Armstrong; Jingfen Xia; Guoying Qian; Jian Yang
      Pages: 21 - 34
      Abstract: Publication date: May 2017
      Source:Acta Biomaterialia, Volume 54
      Author(s): Ethan Michael Gerhard, Wei Wang, Caiyan Li, Jinshan Guo, Ibrahim Tarik Ozbolat, Kevin Michael Rahn, April Dawn Armstrong, Jingfen Xia, Guoying Qian, Jian Yang
      The field of tissue engineering and regenerative medicine relies heavily on materials capable of implantation without significant foreign body reactions and with the ability to promote tissue differentiation and regeneration. The field of bone tissue engineering in particular requires materials capable of providing enhanced mechanical properties and promoting osteogenic cell lineage commitment. While bone repair has long relied almost exclusively on inorganic, calcium phosphate ceramics such as hydroxyapatite and their composites or on non-degradable metals, the organically derived shell and pearl nacre generated by mollusks has emerged as a promising alternative. Nacre is a naturally occurring composite material composed of inorganic, calcium carbonate plates connected by a framework of organic molecules. Similar to mammalian bone, the highly organized microstructure of nacre endows the composite with superior mechanical properties while the organic phase contributes to significant bioactivity. Studies, both in vitro and in vivo, have demonstrated nacre’s biocompatibility, biodegradability, and osteogenic potential, which are superior to pure inorganic minerals such as hydroxyapatite or non-degradable metals. Nacre can be used directly as a bulk implant or as part of a composite material when combined with polymers or other ceramics. While nacre has demonstrated its effectiveness in multiple cell culture and animal models, it remains a relatively underexplored biomaterial. This review introduces the formation, structure, and characteristics of nacre, and discusses the present and future uses of this biologically-derived material as a novel biomaterial for orthopedic and other tissue engineering applications. Statement of Significance Mussel derived nacre, a biological composite composed of mineralized calcium carbonate platelets and interplatelet protein components, has recently gained interest as a potential alternative ceramic material in orthopedic biomaterials, combining the integration and mechanical capabilities of calcium phosphates with increased bioactivity derived from proteins and biomolecules; however, there is limited awareness of this material’s potential. Herein, we present, to our knowledge, the first comprehensive review of nacre as a biomaterial. Nacre is a highly promising yet overlooked biomaterial for orthopedic tissue engineering with great potential in a wide variety of material systems. It is our hope that publication of this article will lead to increased community awareness of the potential of nacre as a versatile, bioactive ceramic capable of improving bone tissue regeneration and will elicit increased research effort and innovation utilizing nacre.
      Graphical abstract image

      PubDate: 2017-05-04T12:57:27Z
      DOI: 10.1016/j.actbio.2017.03.003
      Issue No: Vol. 54 (2017)
  • Nanodiamond-based injectable hydrogel for sustained growth factor release:
           preparation, characterization and in vitro analysis
    • Authors: Settimio Pacelli; Francisca Acosta; Aparna R. Chakravarti; Saheli G. Samanta; Jonathan Whitlow; Saman Modaresi; Rafeeq P.H. Ahmed; Johnson Rajasingh; Arghya Paul
      Abstract: Publication date: Available online 19 May 2017
      Source:Acta Biomaterialia
      Author(s): Settimio Pacelli, Francisca Acosta, Aparna R. Chakravarti, Saheli G. Samanta, Jonathan Whitlow, Saman Modaresi, Rafeeq P.H. Ahmed, Johnson Rajasingh, Arghya Paul
      Nanodiamonds (NDs) represent an emerging class of carbon nanomaterials that possess favorable physical and chemical properties to be used as multifunctional carriers for a variety of bioactive molecules. Here we report the synthesis and characterization of a new injectable ND-based nanocomposite hydrogel which facilitates a controlled release of therapeutic molecules for regenerative applications. In particular, we have formulated a thermosensitive hydrogel using gelatin, chitosan and NDs that provides a sustained release of exogenous human vascular endothelial growth factor (VEGF) for wound healing applications. Addition of NDs improved the mechanical properties of the injectable hydrogels without affecting its thermosensitive gelation properties. Biocompatibility of the generated hydrogel was verified by in vitro assessment of apoptotic gene expressions and anti-inflammatory interleukin productions. NDs were complexed with VEGF and the inclusion of this complex in the hydrogel network enabled the sustained release of the angiogenic growth factor. These results suggest for the first time that NDs can be used to formulate a biocompatible, thermosensitive and multifunctional hydrogel platform that can function both as a filling agent to modulate hydrogel properties, as well as a delivery platform for the controlled release of bioactive molecules and growth factors. Statement of significance One of the major drawbacks associated with the use of conventional hydrogels as carriers of growth factors is their inability to control the release kinetics of the loaded molecules. In fact, in most cases, a burst release is inevitable leading to diminished therapeutic effects and unsuccessful therapies. As a potential solution to this issue, we hereby propose a strategy of incorporating ND complexes within an injectable hydrogel matrix. The functional groups on the surface of the NDs can establish interactions with the model growth factor VEGF and promote a prolonged release from the polymer network, therefore, providing a longer therapeutic effect. Our strategy demonstrates the efficacy of using NDs as an essential component for the design of a novel injectable nanocomposite system with improved release capabilities.
      Graphical abstract image

      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.026
  • Long-term surveillance of zinc implant in murine artery: surprisingly
           steady biocorrosion rate
    • Authors: Adam Drelich; Shan Zhao; Roger J. Guillory; Jaroslaw W. Drelich; Jeremy Goldman
      Abstract: Publication date: Available online 19 May 2017
      Source:Acta Biomaterialia
      Author(s): Adam Drelich, Shan Zhao, Roger J. Guillory, Jaroslaw W. Drelich, Jeremy Goldman
      Metallic zinc implanted into the abdominal aorta of rats out to 6 months has been demonstrated to degrade while avoiding responses commonly associated with the restenosis of vascular implants. However, major questions remain regarding whether a zinc implant would ultimately passivate through the production of stable corrosion products or via a cell mediated fibrous encapsulation process that prevents the diffusion of critical reactants and products at the metal surface. Here, we have conducted clinically relevant long term in vivo studies in order to characterize late stage zinc implant biocorrosion behavior and products to address these critical questions. We found that zinc wires implanted in the murine artery exhibit steady corrosion without local toxicity for up to at least 20 months post-implantation, despite a steady buildup of passivating corrosion products and intense fibrous encapsulation of the wire. Although fibrous encapsulation was not able to prevent continued implant corrosion, it may be related to the reduced chronic inflammation observed between 10 and 20 months post-implantation. X-ray elemental and infrared spectroscopy analyses confirmed zinc oxide, zinc carbonate, and zinc phosphate as the main components of corrosion products surrounding the Zn implant. These products coincide with stable phases concluded from Pourbaix diagrams of a physiological solution and in vitro electrochemical impedance tests. The results support earlier predictions that zinc stents could become successfully bio-integrated into the arterial environment and safely degrade within a time frame of approximately 1 – 2 years. Staement of Significance Previous studies have shown zinc to be a promising candidate material for bioresorbable endovascular stenting applications. An outstanding question, however, is whether a zinc implant would ultimately passivate through the production of stable corrosion products or via a cell mediated tissue encapsulation process that prevented the diffusion of critical reactants and products at the metal surface. We found that zinc wires implanted in the murine artery exhibit steady corrosion for up to at least 20 months post-implantation. The results confirm earlier predictions that zinc stents could safely degrade within a time frame of approximately 1 – 2 years.
      Graphical abstract image

      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.045
  • Combinatorial screening of 3D biomaterial properties that promote
           myofibrogenesis for mesenchymal stromal cell-based heart valve tissue
    • Authors: Jenna Usprech; David A. Romero; Cristina H. Amon; Craig A. Simmons
      Abstract: Publication date: Available online 19 May 2017
      Source:Acta Biomaterialia
      Author(s): Jenna Usprech, David A. Romero, Cristina H. Amon, Craig A. Simmons
      The physical and chemical properties of a biomaterial integrate with soluble cues in the cell microenvironment to direct cell fate and function. Predictable biomaterial-based control of integrated cell responses has been investigated with two-dimensional (2D) screening platforms, but integrated responses in 3D have largely not been explored systematically. To address this need, we developed a screening platform using polyethylene glycol norbornene (PEG-NB) as a model biomaterial with which the polymer wt% (to control elastic modulus) and adhesion peptide types (RGD, DGEA, YIGSR) and densities could be controlled independently and combinatorially in arrays of 3D hydrogels. We applied this platform and regression modeling to identify combinations of biomaterial and soluble biochemical (TGF-β1) factors that best promoted myofibrogenesis of human mesenchymal stromal cells (hMSCs) in order to inform our understanding of regenerative processes for heart valve tissue engineering. In contrast to 2D culture, our screens revealed that soft hydrogels (low PEG-NB wt%) best promoted spread myofibroblastic cells that expressed high levels of α-smooth muscle actin (α-SMA) and collagen type I. High concentrations of RGD enhanced α-SMA expression in the presence of TGF-β1 and cell spreading regardless of whether TGF-β1 was in the culture medium. Strikingly, combinations of peptides that maximized collagen expression depended on the presence or absence of TGF-β1, indicating that biomaterial properties can modulate MSC response to soluble signals. This combination of a 3D biomaterial array screening platform with statistical modeling is broadly applicable to systematically identify combinations of biomaterial and microenvironmental conditions that optimally guide cell responses. Statement of Significance We present a novel screening platform and methodology to model and identify how combinations of biomaterial and microenvironmental conditions guide cell phenotypes in 3D. Our approach to systematically identify complex relationships between microenvironmental cues and cell responses enables greater predictive power over cell fate in conditions with interacting material design factors. We demonstrate that this approach not only predicts that mesenchymal stromal cell (MSC) myofibrogenesis is promoted by soft, porous 3D biomaterials, but also generated new insights which demonstrate how biomaterial properties can differentially modulate MSC response to soluble signals. An additional benefit of the process includes utilizing both parametric and non parametric analyses which can demonstrate dominant significant trends as well as subtle interactions between biochemical and biomaterial cues.
      Graphical abstract image

      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.044
  • Toughening of fibrous scaffolds by mobile mineral deposits
    • Authors: Justin Lipner; John J. Boyle; Younan Xia; Victor Birman; Guy M. Genin; Stavros Thomopoulos
      Abstract: Publication date: Available online 19 May 2017
      Source:Acta Biomaterialia
      Author(s): Justin Lipner, John J. Boyle, Younan Xia, Victor Birman, Guy M. Genin, Stavros Thomopoulos
      Partially mineralized fibrous tissue situated between tendon and bone is believed to be tougher than either tendon or bone, possibly serving as a compliant, energy absorptive, protective barrier between the two. This tissue does not reform following surgical repair (e.g., rotator cuff tendon-to-bone re-attachment) and might be a factor in the poor outcomes following such surgeries. Towards our long-term goal of tissue engineered solutions to functional tendon-to-bone re-attachment, we tested the hypotheses that partially mineralized fibrous matrices can derive toughness from mobility of mineral along their fibers, and that in such cases toughness is maximized at levels of mineralization sufficiently low to allow substantial mobility. Nanofibrous electrospun poly(lactic-co-glycolic acid) (PLGA) scaffolds mineralized for prescribed times were fabricated as model systems to test these hypotheses. Tensile tests performed at varying angles relative to the dominant fiber direction confirmed that mineral cross-linked PLGA nanofibers without adhering to them. Peel tests revealed that fracture toughness increased with mineralization time up to a peak value, then subsequently decreased with increasing mineralization time back to the baseline toughness of unmineralized scaffolds. These experimental results were predicted by a theoretical model combining mineral growth kinetics with fracture energetics, suggesting that toughness increased with mineralization time until mineral mobility was attenuated by steric hindrance, then returned to baseline levels following the rigid percolation threshold. Results supported our hypotheses, and motivate further study of the roles of mobile mineral particles in toughening the tendon-to-bone attachment. Statement of significance There remains an unmet clinical need to repair connections between compliant unmineralized tissues such as tendon and stiff mineralized tissues such as bone. The current work revealed a novel mechanism by which engineered scaffolds can be fabricated to address this need. Typical material systems that combine a compliant fibrous component with stiff brittle inclusions must compromise toughness for increased strength. However, mobile mineral in the current study was able to both toughen and strengthen a fibrous polymer scaffold at intermediate levels of mineralization. This mechanism was consistent with a multiscale model that combined nucleation kinetics with the energetics of fracture. These results reveal a significant opportunity for fabrication of tough and strong fibrous scaffolds for tissue engineering applications.
      Graphical abstract image

      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.033
  • Adipose Derived Delivery Vehicle for Encapsulated Adipogenic Factors
    • Authors: Christopher M. Mahoney; Arta Kelmindi-Doko; Malik J. Snowden; J. Peter Rubin; Kacey G. Marra
      Abstract: Publication date: Available online 19 May 2017
      Source:Acta Biomaterialia
      Author(s): Christopher M. Mahoney, Arta Kelmindi-Doko, Malik J. Snowden, J. Peter Rubin, Kacey G. Marra
      Hydrogels derived from adipose tissue extracellular matrix (AdECM) have shown potential in the ability to generate new adipose tissue in vivo. To further enhance adipogenesis, a composite adipose derived delivery system (CADDS) containing single- and double-walled dexamethasone encapsulated microspheres (SW and DW Dex MS) has been developed. Previously, our laboratory has published the use of Dex MS as an additive to enhance adipogenesis and angiogenesis in adipose tissue grafts. In the current work, AdECM and CADDS are extensively characterized, in addition to conducting in vitro cell culture analysis. Study results indicate the AdECM used for the CADDS has minimal cellular and lipid content allowing for gelation of its collagen structure under physiological conditions. Adipose-derived stem cell (ASC) culture studies confirmed biocompatibility with the CADDS, and adipogenesis was increased in experimental groups containing the hydrogel scaffold. In vitro studies of AdECM hydrogel containing microspheres demonstrated a controlled release of dexamethasone from SW and DW formulations. The delivery of Dex MS via an injectable hydrogel scaffold combines two biologically responsive components to develop a minimally, invasive, off-the-shelf biomaterial for adipose tissue engineering. Statement of Significance Scientists and doctors have yet to develop an off-the-shelf product for patients with soft tissue defects. Recently, the use of adipose derived extracellular matrix (adECM) to generate new adipose tissue in vivo has shown great promise but individually, adECM still has limitations in terms of volume and consistency. The current work introduces a novel composite off-the-shelf construct comprised of an adECM-based hydrogel and dexamethasone encapsulated microspheres (Dex MS). The hydrogel construct serves not only as an injectable protein-rich scaffold but also a delivery system for the Dex MS for non-invasive application to the defect site. The methods and results presented are a progressive step forward in the field of adipose tissue engineering.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.046
  • Effects of collagen microstructure and material properties on the
           deformation of the neural tissues of the lamina cribrosa
    • Authors: A.P. Voorhees; N.-J. Jan; I.A. Sigal
      Abstract: Publication date: Available online 18 May 2017
      Source:Acta Biomaterialia
      Author(s): A.P. Voorhees, N.-J. Jan, I.A. Sigal
      It is widely considered that intraocular pressure (IOP)-induced deformation within the neural tissue pores of the lamina cribrosa (LC) contributes to neurodegeneration and glaucoma. Our goal was to study how the LC microstructure and mechanical properties determine the mechanical insult to the neural tissues within the pores of the LC. Polarized light microscopy was used to measure the collagen density and orientation in histology sections of three sheep optic nerve heads (ONH) at both mesoscale (4.4 μm) and microscale (0.73 μm) resolutions. Mesoscale fiber-aware FE models were first used to calculate ONH deformations at an IOP of 30 mmHg. The results were then used as boundary conditions for microscale models of LC regions. Models predicted large insult to the LC neural tissues, with 95th percentile 1st principal strains ranging from 7-12%. Pores near the scleral boundary suffered significantly higher stretch compared to pores in more central regions (10.0 ± 1.4% vs. 7.2 ± 0.4%; p=0.014; mean ± SD). Variations in material properties altered the minimum, median, and maximum levels of neural tissue insult but largely did not alter the patterns of pore-to-pore variation, suggesting these patterns are determined by the underlying structure and geometry of the LC beams and pores. To the best of our knowledge, this is the first computational model that reproduces the highly heterogeneous neural tissue strain fields observed experimentally. Statement of Significance The loss of visual function associated with glaucoma has been attributed to sustained mechanical insult to the neural tissues of the lamina cribrosa due to elevated intraocular pressure. Our study is the first computational model built from specimen-specific tissue microstructure to consider the mechanics of the neural tissues of the lamina separately from the connective tissue. We found that the deformation of the neural tissue was much larger than that predicted by any recent microstructure-aware models of the lamina. These results are consistent with recent experimental data and the highest deformations were found in the region of the lamina where glaucomatous damage first occurs. This study provides new insight into the complex biomechanical environment within the lamina.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.042
  • Cross-linking of a Biopolymer-Peptide Co-Assembling System
    • Authors: Karla E. Inostroza-Brito; Estelle C. Collin; Anna Poliniewicz; Sherif Elsharkawy; Alistair Rice; Armando E. del Río Hernández; Xin Xiao; José Rodríguez-Cabello; Alvaro Mata
      Abstract: Publication date: Available online 18 May 2017
      Source:Acta Biomaterialia
      Author(s): Karla E. Inostroza-Brito, Estelle C. Collin, Anna Poliniewicz, Sherif Elsharkawy, Alistair Rice, Armando E. del Río Hernández, Xin Xiao, José Rodríguez-Cabello, Alvaro Mata
      The ability to guide molecular self-assembly at the nanoscale into complex macroscopic structures could enable the development of functional synthetic materials that exhibit properties of natural tissues such as hierarchy, adaptability, and self-healing. However, the stability and structural integrity of these kinds of materials remains a challenge for many practical applications. We have recently developed a dynamic biopolymer-peptide co-assembly system with the capacity to grow and undergo morphogenesis into complex shapes. Here we explored the potential of different synthetic (succinimidyl carboxymethyl ester [SCM-PEG-SCM], poly (ethylene glycol) ether tetrasuccinimidyl glutarate [4S-StarPEG] and glutaraldehyde) and natural (genipin) cross-linking agents to stabilize membranes made from these biopolymer-peptide co-assemblies. We investigated the cross-linking efficiency, resistance to enzymatic degradation, and mechanical properties of the different cross-linked membranes. We also compared their biocompatibility by assessing the metabolic activity and morphology of adipose-derived stem cells (ADSC) cultured on the different membranes. While all cross-linkers successfully stabilized the system under physiological conditions, membranes cross-linked with genipin exhibited better resistance in physiological environments, improved stability under enzymatic degradation, and a higher degree of in vitro cytocompatibility compared to the other cross-linking agents. The results demonstrated that genipin is an attractive candidate to provide functional structural stability to complex self-assembling structures for potential tissue engineering or in vitro model applications. Statement of significance Molecular self-assembly is widely used for the fabrication of complex functional biomaterials to replace and/or repair any tissue or organ in the body. However, maintaining the stability and corresponding functionality of these kinds of materials in physiological conditions remains a challenge. Chemical cross-linking strategies (natural or synthetic) have been used in an effort to improve their structural integrity. Here we investigate key performance parameters of different cross-linking strategies for stabilising self-assembled materials with potential biomedical applications using a novel protein-peptide co-assembling membrane as proof-of-concept. From the different cross-linkers tested, the natural cross-linker genipin exhibited the best performance. This cross-linker successfully enhanced the mechanical properties of the system enabling the maintenance of the structure in physiological conditions without compromising its bioactivity and biocompatibility. Altogether, we provide a systematic characterization of cross-linking alternatives for self-assembling materials focused on biocompatibility and stability and demonstrate that genipin is a promising alternative for the cross-linking of such materials with a wide variety of potential applications such as in tissue engineering and drug delivery.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.043
  • The ultra-structural organization of the elastic network in the intra- and
           inter-lamellar matrix of the intervertebral disc
    • Authors: J. Tavakoli; D.M. Elliott; J.J. Costi
      Abstract: Publication date: Available online 17 May 2017
      Source:Acta Biomaterialia
      Author(s): J. Tavakoli, D.M. Elliott, J.J. Costi
      The inter-lamellar matrix (ILM) —located between adjacent lamellae of the annulus fibrosus— consists of a complex structure of elastic fibres, while elastic fibers of the intra-lamellar region are aligned predominantly parallel to the collagen fibers. The organization of elastic fibres under low magnification, in both inter- and intra-lamellar regions, was studied by light microscopic analysis of histologically prepared samples; however, little is known about their ultrastructure. An ultrastructural visualization of elastic fibres in the inter-lamellar matrix is crucial for describing their contribution to structural integrity, as well as mechanical properties of the annulus fibrosus. The aims of this study were twofold: first, to present an ultrastructural analysis of the elastic fiber network in the ILM and intra-lamellar region, including cross section (CS) and in-plane (IP) lamellae, of the AF using Scanning Electron Microscopy (SEM) and second, to -compare the elastic fiber orientation between the ILM and intra-lamellar region. Four samples (lumbar sheep discs) from adjacent sections (30 μm thickness) of anterior annulus were partially digested by a developed NaOH-sonication method for visualization of elastic fibers by SEM. Elastic fiber orientation and distribution were quantified relative to the tangential to circumferential reference axis. Visualization of the ILM under high magnification revealed a dense network of elastic fibers that has not been previously described. Within the ILM, elastic fibres form a complex network, consisting of different size and shape fibers, which differed to those located in the intra-lamellar region. For both regions, the majority of fibers were oriented near 0° with respect to tangential to circumferential (TCD) direction and two minor symmetrical orientations of approximately ±45°. Statistically, the orientation of elastic fibers between the ILM and intra-lamellar region was not different (p= 0.171). The present study used extracellular matrix partial digestion to address significant gaps in understanding of disc microstructure and will contribute to multidisciplinary ultrastructure-function studies. Statement of significance Visualization of the Intra-lamellar matrix under high magnification revealed a dense network of elastic fibers that has not been previously described. The present study used extracellular matrix partial digestion to address significant gaps in understanding of disc microstructure and will contribute to multidisciplinary ultrastructure-function studies.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.036
  • Autophagy plays a dual role during intracellular siRNA delivery by
           lipoplex and polyplex nanoparticles
    • Authors: Wen Song; Zhiwei Ma; Yumei Zhang; Chuanxu Yang
      Abstract: Publication date: Available online 17 May 2017
      Source:Acta Biomaterialia
      Author(s): Wen Song, Zhiwei Ma, Yumei Zhang, Chuanxu Yang
      Growing evidence indicates that autophagy plays a vital role during the intracellular DNA delivery mediated by lipoplex and polyplex nanoparticles. However, autophagy in intracellular siRNA delivery has not been well understood. In this study, lipofectamine 2000 and chitosan were used to formulate lipoplex and polyplex with siRNA for systematically investigating the interplay between siRNA delivery and autophagy. After transfection of H1299 cells with lipoplex and polyplex, the number of autophagic vacuoles was increased significantly indicated by the accumulation of monodansylcadaverine (MDC) staining. Western blot revealed that the LC3-II expression was significantly increased after transfection, whereas p-mTOR expression was not influenced apparently. In addition, small-molecule autophagy modulators significantly affected transfection efficiency. Specifically, the mTOR-dependent autophagy inducer rapamycin enhanced the knockdown efficiency of both lipoplex and polyplex, whereas mTOR-dependent autophagy inhibitor 3-methyladenine (3-MA) suppressed their silencing efficiency. On the contrary, mTOR-independent autophagy inducer LiBr decreased whereas mTOR-independent autophagy inhibitor thapsigargin (TG) increased the knockdown efficacy. Immunofluorescence staining showed that siRNA was partially co-localized with autophagosomes and the percentage of co-localized siRNA was significantly affected by autophagy modulators in the opposite trend of gene knockdown efficacy. In conclusion, our study suggests that autophagy plays an important role during the intracellular siRNA trafficking mediated by both lipoplex and polyplex. Modulating autophagy process will result in distinct knockdown efficiency, which may be applied as a potential convenient way for improving siRNA delivery efficacy. Statement of significance Although tremendous effects has been made in the development of non-viral siRNA delivery systems, the intracellular siRNA trafficking has not been elucidated clearly. In this study, we systematically investigated the relationship between autophagy and intracellular siRNA delivery. We found that the non-viral siRNA delivery by both lipoplex and polyplex could induce mTOR-independent autophagy response. More interestingly, knockdown efficiency of both lipoplex and polyplex could be modulated with different autophagy regulators. Specifically, the mTOR-dependent autophagy inducer rapamycin enhances the knockdown efficiency of both lipoplex and polyplex, whereas mTOR-dependent autophagy inhibitor 3-methyladenine suppresses their silencing efficiency. On the contrary, mTOR-independent autophagy inducer lithium bromide decreases, whereas mTOR-independent autophagy inhibitor thapsigargin increases the knockdown efficacy. These findings suggest that the mTOR-dependent and -independent autophagy play a distinct role in the intracellular siRNA trafficking. Furthermore, co-administration with proper autophagy regulators could be potential convenient method to modulate siRNA transfection efficacy.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.038
  • pH-controllable cell-penetrating polypeptide possessing cancer targeting
    • Authors: DaeYong Lee; IlKoo Noh; Jisang Yoo; N.Sanoj Rejinold; Yeu-Chun Kim
      Abstract: Publication date: Available online 17 May 2017
      Source:Acta Biomaterialia
      Author(s): DaeYong Lee, IlKoo Noh, Jisang Yoo, N.Sanoj Rejinold, Yeu-Chun Kim
      Helical peptides were naturally-occurring ordered conformations that mediated various biological functions essential for biotechnology. However, it was difficult for natural helical polypeptides to be applied in biomedical fields due to low bioavailability. To avoid these problems, synthetic alpha-helical polypeptides have recently been introduced by further modifying pendants in the side chain. In spite of an attractive biomimetic helical motif, these systems could not be tailored for targeted delivery mainly due to nonspecific binding events. To address these issues, we created a conformation-transformable polypeptide capable of eliciting a pH-activated cell-penetrating property solely at the cancer region. The developed novel polypeptide showed that the bare helical conformation had a function at physiological conditions while the pH-induced helical motif provided an active cell-penetrating characteristic at a tumor extracellular matrix pH. The unusual conformation-transformable system can elicit bioactive properties exclusively at mild acidic pH. Statement of Significance We developed pH-controllable cell-penetrating polypeptides (PCCPs) undergoing pH-induced conformational transitions. Unlike natural cell-penetrating peptides, PCCPs was capable of penetrating the plasma membranes dominantly at tumor pH, driven by pH-controlled helicity. The conformation of PCCPs at neutral pH showed low helical propensity because of dominant electrostatic attractions within the side chains. However, the helicity of PCCPs was considerably augmented by the balance of electrostatic interactions, thereby inducing selective cellular penetration. Three polypeptides undergoing different conformational transitions were prepared to verify the selective cellular uptake influenced by their structures. The PCCP undergoing low-to-high helical conformation provided the tumor specificity and enhanced uptake efficiency. pH-induced conformation-transformable polypeptide might provide a novel platform for stimuli-triggered targeting systems.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.040
  • Composite elastomeric polyurethane scaffolds incorporating small
           intestinal submucosa for soft tissue engineering
    • Authors: Lincui Da; Mei Gong; Anjing Chen; Yi Zhang; Yizhou Huang; Zhijun Guo; Shengfu Li; Jesse Li-Ling; Li Zhang; Huiqi Xie
      Abstract: Publication date: Available online 17 May 2017
      Source:Acta Biomaterialia
      Author(s): Lincui Da, Mei Gong, Anjing Chen, Yi Zhang, Yizhou Huang, Zhijun Guo, Shengfu Li, Jesse Li-Ling, Li Zhang, Huiqi Xie
      Although soft tissue replacement has been clinically successful in many cases, the corresponding procedure has many limitations including the lack of resilience and mechanical integrity, significant donor-site morbidity, volume loss with time, and fibrous capsular contracture. These disadvantages can be alleviated by utilizing bio-absorbable scaffolds with high resilience and large strain, which are capable of stimulating natural tissue regeneration. Hence, the chemically crosslinked tridimensional scaffolds obtained by incorporating water-based polyurethane (PU) (which was synthesized from polytetramethylene ether glycol, isophorone diisocyanate, and 2,2-bis(hydroxymethyl) butyric acid) into a bioactive extracellular matrix consisting of small intestinal submucosa (SIS) have been tested in this study to develop a new approach for soft tissue engineering. After characterizing the structure and properties of the produced PU/SIS composites, the strength, Young’s modulus, and resilience of wet PU/SIS samples were compared with those of crosslinked PU. In addition, the fabricated specimens were investigated using human umbilical vein endothelial cells to evaluate their ability to enhance cell attachment and proliferation. As a result, the synthesized PU/SIS samples exhibited high resilience and were capable of enhancing cell viability with no evidence of cytotoxicity. Subcutaneous implantation in animals and the subsequent testing conducted after 2, 4, and 8 weeks indicated that sound implant integration and vascularization occurred inside the PU/SIS composites, while the presence of SIS promoted cell infiltration, angiogenesis, and ultimately tissue regeneration. The obtained results revealed that the produced PU/SIS composites were characterized by high bioactivity and resilience, and, therefore, could be used for soft tissue engineering applications. Statement of Significance Hybrid composites containing synthetic polymers with high mechanical strength and naturally derived components, which create a bio-mimetic environment, are one of the most promising biomaterials. Although synthetic polymer/ECM composites have been previously used for soft tissue repair, their resilience properties were not investigated in sufficient detail, while the development of elastic composites composed of synthetic polymers and ECMs in nontoxic aqueous solutions remains a rather challenging task. In this study, porous PU/SIS composites were fabricated in a non-toxic manner; the obtained materials exhibited sufficient mechanical support, which promote cell growth, angiogenesis, and tissue regeneration. The described method can be adapted for the development of scaffolds with various acellular matrices and subsequently used during the restoration of particular types of tissue.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.041
  • Calcium supplementation decreases bcp-induced inflammatory processes in
           blood cells through the nlrp3 inflammasome down-regulation
    • Authors: Patricia Lagadec; Thierry Balaguer; Florian Boukhechba; Grégory Michel; Sébastien Bouvet-Gerbettaz; Jean-Michel Bouler; Jean-Claude Scimeca; Nathalie Rochet
      Abstract: Publication date: Available online 17 May 2017
      Source:Acta Biomaterialia
      Author(s): Patricia Lagadec, Thierry Balaguer, Florian Boukhechba, Grégory Michel, Sébastien Bouvet-Gerbettaz, Jean-Michel Bouler, Jean-Claude Scimeca, Nathalie Rochet
      Interaction of host blood with biomaterials is the first event occurring after implantation in a bone defect. This study aimed at investigating the cellular and molecular consequences arising at the interface between whole blood and biphasic calcium phosphate (BCP) particles. We observed that, due to calcium capture, BCP inhibited blood coagulation, and that this inhibition was reversed by calcium supplementation. Therefore, we studied the impact of calcium supplementation on BCP effects on blood cells. Comparative analysis of BCP and calcium supplemented-BCP (BCP/Ca) effects on blood cells showed that BCP as well as BCP/Ca induced monocyte proliferation, as well as a weak but significant hemolysis. Our data showed for the first time that calcium supplementation of BCP microparticles had anti-inflammatory properties compared to BCP alone that induced an inflammatory response in blood cells. Our results strongly suggest that the anti-inflammatory property of calcium supplemented-BCP results from its down-modulating effect on P2X7R gene expression and its capacity to inhibit ATP/P2X7R interactions, decreasing the NLRP3 inflammasome activation. Considering that monocytes have a vast regenerative potential, and since the excessive inflammation often observed after bone substitutes implantation limits their performance, our results might have great implications in terms of understanding the mechanisms leading to an efficient bone reconstruction. Statement of significance Although scaffolds and biomaterials unavoidably come into direct contact with blood during bone defect filling, whole blood-biomaterials interactions have been poorly explored. By studying in 3D the interactions between Biphasic Calcium Phosphate (BCP) in microparticulate form and blood, we showed for the first time that calcium supplementation of BCP microparticles (BCP/Ca) has anti-inflammatory properties compared to BCP-induced inflammation in whole blood cells and provided information related to the molecular mechanisms involved. The present study also showed that BCP, as well as BCP/Ca particles stimulate monocyte proliferation. As monocytes represent a powerful target for regenerative therapies and as an excessive inflammation limits the performance of biomaterials in bone tissue engineering, our results might have great implications to improve bone reconstruction.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.039
  • Heparin-based hydrogels induce human renal tubulogenesis in vitro
    • Authors: Heather M. Weber; Mikhail V. Tsurkan; Valentina Magno; Uwe Freudenberg; Carsten Werner
      Abstract: Publication date: Available online 17 May 2017
      Source:Acta Biomaterialia
      Author(s): Heather M. Weber, Mikhail V. Tsurkan, Valentina Magno, Uwe Freudenberg, Carsten Werner
      Dialysis or kidney transplantation is the only therapeutic option for end stage renal disease. Accordingly, there is a large unmet clinical need for new causative therapeutic treatments. Obtaining robust models that mimic the complex nature of the human kidney is a critical step in the development of new therapeutic strategies. Here we establish a synthetic in vitro human renal tubulogenesis model based on a tunable glycosaminoglycan-hydrogel platform. In this system, renal tubulogenesis can be modulated by the adjustment of hydrogel mechanics and degradability, growth factor signaling, and the presence of insoluble adhesion cues, potentially providing new insights for regenerative therapy. Different hydrogel properties were systematically investigated for their ability to modulate renal tubulogenesis. Hydrogels based on heparin and matrix metalloproteinase cleavable peptide linker units were found to induce the morphogenesis of single human proximal tubule epithelial cells into physiologically sized tubule structures. The generated tubules display polarization markers, extracellular matrix components, and organic anion transport functions of the in vivo renal proximal tubule and respond to nephrotoxins comparable to the human clinical response. The established hydrogel-based human renal tubulogenesis model is thus considered highly valuable for renal regenerative medicine and personalized nephrotoxicity studies. Statement of Significance The only cure for end stage kidney disease is kidney transplantation. Hence, there is a huge need for reliable human kidney models to study renal regeneration and establish alternative treatments. Here we show the development and application of an in vitro human renal tubulogenesis model using heparin-based hydrogels. To the best of our knowledge, this is the first system where human renal tubulogenesis can be monitored from single cells to physiologically sized tubule structures in a tunable hydrogel system. To validate the efficacy of our model as a drug toxicity platform, a chemotherapy drug was incubated with the model, resulting in a drug response similar to human clinical pathology. The established model could have wide applications in the field of nephrotoxicity and renal regenerative medicine and offer a reliable alternative to animal models.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.035
  • Dynamic Fatigue Measurement of Human Erythrocytes using Dielectrophoresis
    • Authors: Yuhao Qiang; Jia Liu; E Du
      Abstract: Publication date: Available online 17 May 2017
      Source:Acta Biomaterialia
      Author(s): Yuhao Qiang, Jia Liu, E Du
      Erythrocytes must undergo severe deformation to pass through narrow capillaries and submicronic splenic slits for several hundred thousand times in their normal lifespan. Studies of erythrocyte biomechanics have been mainly focused on cell deformability and rheology measured from a single application of stress and mostly under a static or quasi-static state using classical biomechanical techniques, such as optical tweezers and micropipette aspiration. Dynamic behavior of erythrocytes in response to cyclic stresses that contributes to the membrane failure in blood circulation is not fully understood. This paper presents a new experimental method for dynamic fatigue analysis of erythrocytes, using amplitude modulated electrokinetic force field in a microfluidic platform. We demonstrate the capability of this new technique using a low cycle fatigue analysis of normal human erythrocytes and ATP-depleted erythrocytes. Cyclic tensile stresses are generated to induce repeated uniaxial stretching and extensional recovery of single erythrocytes. Results of morphological and biomechanical parameters of individually tracked erythrocytes show strong correlations with the number of the loading cycles. Under a same strength of electric field, after 180 stress cycles, for normal erythrocytes, maximum stretch ratio decreases from 3.80 to 2.86, characteristic time of cellular extensional recovery increases from 0.16 s to 0.37 s, membrane shear viscosity increases from1.0 (µN/m)·s to 1.6 (µN/m)·s. Membrane deformation in a small number of erythrocytes becomes irreversible after large deformation for about 200 cyclic loads. ATP-depleted cells show similar trends in decreased deformation and increased characteristic time with the loading cycles. These results show proof of concept of the new microfluidics technique for dynamic fatigue analysis of human erythrocytes. Significance Red blood cells (RBCs) experience a tremendous number of deformation in blood circulation before losing their mechanical deformability and eventually being degraded in the reticuloendothelial system. Prior efforts in RBC biomechanics have mostly focused on a single-application of stress, or quasi-static loading through physical contact to deform cell membranes, thus with limited capabilities in probing cellular dynamic responses to cyclic stresses. We present a unique electrokinetic microfluidic system for the study of dynamic fatigue behavior of RBCs subjected to cyclic loads. Our work shows quantitatively how the cyclic stretching loads cause membrane mechanical degradation and irreversibly deformed cells. This new technique can be useful to identify biomechanical markers for prediction of the mechanical stability and residual lifespan of circulating RBCs.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.037
  • Halloysite and chitosan oligosaccharide nanocomposite for wound healing
    • Authors: Giuseppina Sandri; Carola Aguzzi; Silvia Rossi; Maria Cristina Bonferoni; Giovanna Bruni; Cinzia Boselli; Antonia Icaro Cornaglia; Federica Riva; Cesar Viseras; Carla Caramella; Franca Ferrari
      Abstract: Publication date: Available online 15 May 2017
      Source:Acta Biomaterialia
      Author(s): Giuseppina Sandri, Carola Aguzzi, Silvia Rossi, Maria Cristina Bonferoni, Giovanna Bruni, Cinzia Boselli, Antonia Icaro Cornaglia, Federica Riva, Cesar Viseras, Carla Caramella, Franca Ferrari
      Halloysite is a natural nanotubular clay mineral (HNTs, Halloysite Nano Tubes) chemically identical to kaolinite and, due to its good biocompatibility, is an attractive nanomaterial for a vast range of biological applications. Chitosan oligosaccharides are homo- or heterooligomers of N-acetylglucosamine and D-glucosamine, that accelerate wound healing by enhancing the functions of inflammatory and repairing cells. The aim of the work was the development of a nanocomposite based on HNTs and chitosan oligosaccharides, to be used as pour powder to enhance healing in the treatment of chronic wounds. A 1:0.05 weight ratio HTNs/chitosan oligosaccharide nanocomposite was obtained by simply stirring the HTNs powder in a 1% aqueous chitosan oligosaccharide solution and was formed by spontaneous ionic interaction resulting in 98.6% w/w HTNs and 1.4% w/w chitosan oligosaccharide composition. Advanced electron microscopy techniques were considered to confirm the structure of the hybrid nanotubes. Both HTNs and HTNs/chitosan oligosaccharide nanocomposite showed good in vitro biocompatibility with normal human dermal fibroblasts up to 300 μg/ml concentration and enhanced in vitro fibroblast motility, promoting both proliferation and migration. The HTNs/chitosan oligosaccharide nanocomposite and the two components separately were tested for healing capacity in a murine (rat) model. HTNs/chitosan oligosaccharide allowed better skin reepithelization and reorganization than HNTs or chitosan oligosaccharide separately. The results suggest to develop the nanocomposite as a medical device for wound healing. Statement of significance The research paper entitled “Halloysite and chitosan oligosaccharide nanocomposite for wound healing” considers a therapeutic option for difficult to heal skin lesions and burns. The aim of work submitted was the development of a nanocomposite based on halloysite nanotubes and chitosan oligosaccharide, to be used as pour powder to enhance healing in the treatment of chronic wounds. The significance of the research consider two fundamental aspects: the first one is related to the development of a self-assembled nanocomposite, formed by spontaneous ionic interaction, while the second one is related to the possibility to find an effective treatment for cutaneous non healing lesions. The characterization of this hybrid system involved a multidisciplinary approach considering integrated techniques of solid state investigation and advanced electron microscopy techniques, and in vitro/in vivo models to understand biocompatibility and proliferation properties (enhancement of in vitro fibroblast motility, promoting both proliferation and migration, healing of burns in vivo), by using molecular biology test and histological evaluation to understand safety and effectiveness of the developed nanocomposite.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.032
  • Athero-Inflammatory Nanotherapeutics: Ferulic Acid-based
           Poly(anhydride-ester) Nanoparticles Attenuate Foam Cell Formation by
           Regulating Macrophage Lipogenesis and Reactive Oxygen Species Generation
    • Authors: Rebecca A. Chmielowski; Dalia S. Abdelhamid; Jonathan J. Faig; Latrisha K. Petersen; Carol R. Gardner; Kathryn E. Uhrich; Laurie B. Joseph; Prabhas V. Moghe
      Abstract: Publication date: Available online 15 May 2017
      Source:Acta Biomaterialia
      Author(s): Rebecca A. Chmielowski, Dalia S. Abdelhamid, Jonathan J. Faig, Latrisha K. Petersen, Carol R. Gardner, Kathryn E. Uhrich, Laurie B. Joseph, Prabhas V. Moghe
      Enhanced bioactive anti-oxidant formulations are critical for treatment of inflammatory diseases, such as atherosclerosis. A hallmark of early atherosclerosis is the uptake of oxidized low density lipoprotein (oxLDL) by macrophages, which results in foam cell and plaque formation in the arterial wall. The hypolipidemic, anti-inflammatory, and antioxidative properties of polyphenol compounds make them attractive targets for treatment of atherosclerosis. However, high concentrations of antioxidants can reverse their anti-atheroprotective properties and cause oxidative stress within the artery. Here, we designed a new class of nanoparticles with anti-oxidant polymer cores and shells comprised of scavenger receptor targeting amphiphilic macromolecules (AMs). Specifically, we designed ferulic acid-based poly(anhydride-ester) nanoparticles to counteract the uptake of high levels of oxLDL and regulate reactive oxygen species generation (ROS) in human monocyte derived macrophages (HMDMs). Compared to all compositions examined, nanoparticles with core ferulic acid-based polymers linked by diglycolic acid (PFAG) showed the greatest inhibition of oxLDL uptake. At high oxLDL concentrations, the ferulic acid diacids and polymer nanoparticles displayed similar oxLDL uptake. Treatment with the PFAG nanoparticles downregulated the expression of macrophage scavenger receptors, CD-36, MSR-1, and LOX-1 by about 20-50%, one of the causal factors for the decrease in oxLDL uptake. The PFAG nanoparticle lowered ROS production by HMDMs, which is important for maintaining macrophage growth and prevention of apoptosis. Based on these results, we propose that ferulic acid-based poly(anhydride ester) nanoparticles may offer an integrative strategy for the localized passivation of the early stages of the atheroinflammatory cascade in cardiovascular disease. Statement of Significance Future development of anti-oxidant formulations for atherosclerosis applications is essential to deliver an efficacious dose while limiting localized concentrations of pro-oxidants. In this study, we illustrate the potential of degradable ferulic acid-based polymer nanoparticles to control macrophage foam cell formation by significantly reducing oxLDL uptake through downregulation of scavenger receptors, CD-36, MSR-1, and LOX-1. Another critical finding is the ability of the degradable ferulate-based polymer nanoparticles to lower macrophage reactive oxygen species (ROS) levels, a precursor to apoptosis and plaque escalation. The degradable ferulic acid-based polymer nanoparticles hold significant promise as a means to alter the treatment and progression of atherosclerosis.
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      PubDate: 2017-05-20T09:17:28Z
      DOI: 10.1016/j.actbio.2017.05.029
  • Visible light-switched cytosol release of siRNA by amphiphilic fullerene
           derivative to enhance RNAi efficacy in vitro and in vivo
    • Authors: Jing Wang; Lifei Xie; Tao Wang; Fengxin Wu; Jie Meng; Jian Liu; Haiyan Xu
      Abstract: Publication date: Available online 13 May 2017
      Source:Acta Biomaterialia
      Author(s): Jing Wang, Lifei Xie, Tao Wang, Fengxin Wu, Jie Meng, Jian Liu, Haiyan Xu
      Cationic macromolecules are attractive for use as small interfering RNA (siRNA) carriers due to their performance in non-immunological reactions, customization during synthesis, and low costs compared to viral carriers. However, their low transfection efficiency substantially hinders their application in both clinical practices and academic research, which is mostly attributable to the low capacity of siRNA/cationic macromolecule complexes to escape lysosomes. To address this challenge, we designed an amphiphilic fullerene derivative (C60-Dex-NH2) for efficient and controllable siRNA delivery. To synthesize C60-Dex-NH2, terminally aminated dextran was conjugated to C60. The conjugate was further cationized by covalently introducing ethylenediamine to the dextran. The physicochemical characteristics of C60-Dex-NH2 was examined with elemental analyses, gel permeation chromatography, solid-state nuclear magnetic resonance (13C, HPDEC), agarose gel electrophoresis, and dynamic light scattering. The cytotoxicity, cellular uptake, intracellular distribution, and in vitro RNA interference (RNAi) of siRNA/C60-Dex-NH2 complex was evaluated in the human breast cancer cell line MDA-MB-231. The RNAi efficiencies mediated by C60-Dex-NH2 in vivo was evaluated in subcutaneous tumor-bearing mice. The results showed that C60-Dex-NH2 has a specific amphiphilic skeleton and could form micelle-like aggregate structures in water, which could prevent siRNA from destroying by reactive oxygen species (ROS). When exposed to visible light, C60-Dex-NH2 could trigger controllable ROS generation which could destroy the lysosome membrane, promote the lysosomal escape, and enhance the gene silencing efficiency of siRNA in vitro and in vivo. The gene silencing efficiency could reach a maximum of 53% in the MDA-MB-231-EGFP cells and 69% in the 4T1-GFP-Luc2 tumor-bearing mice. Statement of Significance We designed a novel photosensitive amphiphilic carrier (C60-Dex-NH2) for efficient and controllable siRNA delivery, which can be used in gene therapy. We showed that C60-Dex-NH2 could destroy lysosome membrane via controllable generation of ROS when exposed to light, which can help siRNA to escape from lysosome before degradation. This can enhance the gene silencing efficiency significantly and provides a useful way to regulate RNAi efficiency by light. One advantage for C60-Dex-NH2 system is C60 has broad absorbance spectrum and can be activated by weak visible light; Furthermore, C60-Dex-NH2 has a specific amphiphilic structure, which may prevent siRNA from degrading and allows C60-Dex-NH2 to embed into the lipid membrane of lysosome to improve the ROS induced lysosomal disturbance after internalization.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.031
  • Chondroitin Sulfate-Functionalized Polyamidoamine as a Tumor-targeted
           Carrier for miR-34a Delivery
    • Authors: Wenqi Chen; Yong Liu; Xiao Liang; Yu Huang; Quanshun Li
      Abstract: Publication date: Available online 13 May 2017
      Source:Acta Biomaterialia
      Author(s): Wenqi Chen, Yong Liu, Xiao Liang, Yu Huang, Quanshun Li
      Chondroitin sulfate (CS) was modified on a polyamidoamine dendrimer (PAMAM) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The derivative CS-PAMAM was demonstrated to achieve an efficient cellular uptake of miR-34a in a CD44-dependent endocytosis way and further facilitate the endosomal escape of miR-34a after 4 h. Through the miR-34a delivery, obvious inhibition of cell proliferation could be detected which was attributed to the enhancement of cell apoptosis and cell cycle arrest, and meanwhile the cell migration and invasion has been observed to be inhibited. Finally, the intravenous injection of CS-PAMAM/miR-34a formulation into mice bearing human lung adenocarcinoma cell A549 xenografts could efficiently inhibit the tumor growth and induce the tumor apoptosis owing to the enhanced accumulation of miR-34a in tumor tissue. Overall, CS-PAMAM is potential to be used as a tumor-targeted oligonucleotide carrier for achieving tumor gene therapy. Statement of Significance The cationic dendrimer PAMAM was modified by chondroitin sulfate (CS) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The introduction of CS could achieve an efficient cellular uptake and intracellular transfection of miR-34a in a CD44-dependent endocytosis manner. The miR-34a delivery could execute the anti-proliferation activity by simultaneously inducing cell apoptosis and cell cycle arrest, and also the anti-migration activity. The CS-PAMAM-mediated systemic delivery of miR-34a showed significant inhibition of tumor growth and induction of tumor apoptosis using a mice model of subcutaneously implanted tumors.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.030
  • Photothermal and photodynamic activity of polymeric nanoparticles based on
           α-tocopheryl succinate-RAFT block copolymers conjugated to IR-780.
    • Authors: Raquel Palao-Suay; Francisco M. Martin-Saavedra; María Rosa Aguilar; Clara Escudero Duch; Sergio Martín-Saldaña; Francisco J. Parra-Ruiz; Nathan A. Rohner; Susan N. Thomas; Nuria Vilaboa; Julio San Román
      Abstract: Publication date: Available online 13 May 2017
      Source:Acta Biomaterialia
      Author(s): Raquel Palao-Suay, Francisco M. Martin-Saavedra, María Rosa Aguilar, Clara Escudero Duch, Sergio Martín-Saldaña, Francisco J. Parra-Ruiz, Nathan A. Rohner, Susan N. Thomas, Nuria Vilaboa, Julio San Román
      The aim of this work was the generation of a multifunctional nanopolymeric system that incorporates IR-780 dye, a near-infrared (NIR) imaging probe that exhibits photothermal and photodynamic properties; and a derivate of α-tocopheryl succinate (α-TOS), a mitochondria-targeted anticancer compound. IR-780 was conjugated to the hydrophilic segment of copolymer PEG-b-polyMTOS, based on poly(ethylene glycol) (PEG) and a methacrylic derivative of α-tocopheryl succinate (MTOS), to generate IR-NP, self-assembled nanoparticles (NPs) in aqueous media which exhibit a hydrophilic shell and a hydrophobic core. During assembly, the hydrophobic core of IR-NP could encapsulate additional IR-780 to generate derived subspecies carrying different amount of probe (IR-NP-eIR). Evaluation of photo-inducible properties of IR-NP and IR-NP-eIR were thoroughly assessed in vitro. Developed nanotheranostic particles showed distinct fluorescence and photothermal behavior after excitation by a laser light emitting at 808 nm. Treatment of MDA-MB-453 cells with IR-NP or IR-NP-eIR resulted in an efficient internalization of the IR-780 dye, while subsequent NIR-laser irradiation led to a severe decrease in cell viability. Photocytoxicity conducted by IR-NP, which could not be attributed to the generation of lethal hyperthermia, responded to an increase in the levels of intracellular reactive oxygen species (ROS). Therefore, the fluorescence imaging and inducible phototoxicity capabilities of NPs derived from IR-780-PEG-b-polyMTOS copolymer confer high value to these nanotheranostics tools in clinical cancer research. State of significance Multifunctional polymeric nanoparticles (NPs) that combine imaging and therapeutic properties are highly valuable in cancer treatment. In this paper we describe the development of NPs that are fluorescent in the near-infrared (NIR). This is important for their visualization in living tissues that present low absorption and low autofluorescence in this wavelength region (between 700 and 1000 nm). Moreover, NPs present photothermal and photodynamic properties when NIR irradiated: the NPs produce an efficient increment of temperature and increase the intracellular reactive oxygen species (ROS) when laser irradiated at 808 nm. These tuneable photoinduced properties make the NPs highly cytotoxic after NIR irradiation and provides a new tool for highly precise cancer treatment.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.028
  • Direct Quantification of Dual Protein Adsorption Dynamics in Three
           Dimensional Systems in Presence of Cells
    • Authors: Melika Sarem; Daniel Vonwil; Steffen Lüdeke; V. Prasad Shastri
      Abstract: Publication date: Available online 11 May 2017
      Source:Acta Biomaterialia
      Author(s): Melika Sarem, Daniel Vonwil, Steffen Lüdeke, V. Prasad Shastri
      Understanding the composition of the adsorbed protein layer on a biomaterial surface is of an extreme importance as it directs the primary biological response. Direct detection using labeled proteins and indirect detection based on enzymatic assays or changes to mass, refractive index or density of a surface have been so far established. Nevertheless, using current methodologies, detection of multiple proteins simultaneously and particularly in a three-dimensional (3D) substrates is challenging, with the exception of radiolabeling. Here using fluorescence molecular tomography (FMT), we present a non-destructive and versatile approach to quantify adsorption of multiple proteins within 3D environments and reveal the dynamics of adsorption of human serum albumin (HSA) and fibrinogen (Fib) on 3D polymeric scaffold. Furthermore, we show that serum starved human articular chondrocytes in 3D environment preferentially uptake HSA over Fib and as far as our knowledge this represents the first example of direct visualization and quantification of protein adsorption in a 3D cell culture system. Statement of Significance The biomaterial surface upon exposure to biological fluids is covered by a layer of proteins, which is modified over a period time and dictates the fate of the biomaterial. In this study, we present and validate a new methodology for quantification of protein adsorption on to a three –dimensional polymer scaffold from unitary and binary systems, using fluorescence molecular tomography, an optical trans-illumination technique with picomolar sensitivity. In additional to being able to follow behavior of two proteins simultaneously, this methodology is also suitable for studying protein uptake in cells situated in a polymer environment. The ability to follow protein adsorption/uptake in a continuous manner opens up new possibilities to study the role of serum proteins in biomaterial compatibility.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.021
  • Biomimetic Tendon Extracellular Matrix Composite Gradient Scaffold
           Enhances Ligament-to-Bone Junction Reconstruction
    • Authors: Huanhuan Liu; Long Yang; Erchen Zhang; Rui Zhang; Dandan Cai; Shouan Zhu; Jisheng Ran; Varitsara Bunpetch; Youzhi Cai; Boon Chin Heng; Yejun Hu; Xuesong Dai; Xiao Chen; Hongwei Ouyang
      Abstract: Publication date: Available online 11 May 2017
      Source:Acta Biomaterialia
      Author(s): Huanhuan Liu, Long Yang, Erchen Zhang, Rui Zhang, Dandan Cai, Shouan Zhu, Jisheng Ran, Varitsara Bunpetch, Youzhi Cai, Boon Chin Heng, Yejun Hu, Xuesong Dai, Xiao Chen, Hongwei Ouyang
      Management of ligament/tendon-to-bone-junction healing remains a formidable challenge in the field of orthopedic medicine to date, due to deficient vascularity and multi-tissue transitional structure of the junction. Numerous strategies have been employed to improve ligament-bone junction healing, including delivery of stem cells, bioactive factors, and synthetic materials, but these methods are often inadequate at recapitulating the complex structure-function relationships at native tissue interfaces. Here, we developed an easily-fabricated and effective biomimetic composite to promote the regeneration of ligament-bone junction by physically modifying the tendon extracellular matrix (ECM) into a Random-Aligned-Random composite using ultrasound treatment. The differentiation potential of rabbit bone marrow stromal cells on the modified ECM were examined in vitro. The results demonstrated that the modified ECM enhanced expression of chondrogenesis and osteogenesis-associated epigenetic genes (Jmjd1c, Kdm6b), transcription factor genes (Sox9, Runx2) and extracellular matrix genes (Col2a1, Ocn), resulting in higher osteoinductivity than the untreated tendon ECM in vitro. In the rabbit anterior cruciate ligament (ACL) reconstruction model in vivo, micro-computed tomography (Micro-CT) and histological analysis showed that the modified Random-Aligned-Random composite scaffold enhanced bone and fibrocartilage formation at the interface, more efficaciously than the unmodified tendon ECM. Therefore, these results demonstrated that the biomimetic Random-Aligned-Random composite could be a promising scaffold for ligament/tendon-bone junction repair. Statement of significance The native transitional region consists of several distinct yet contiguous tissue regions, composed of soft tissue, non-calcified fibrocartilage, calcified fibrocartilage, and bone. A stratified graft whose phases are interconnected with each other is essential for supporting the formation of functionally continuous multi-tissue regions. Various techniques have been attempted to improve adherence of the ligament/tendon graft to bone, including utilization of stem cells, growth factors and biomaterials, but these methods are often inadequate at recapitulating the complex structure-function relationships at native tissue interfaces. Here, we developed an easily-fabricated and effective biomimetic composite to promote the regeneration of ligament-bone junction by physically modifying the tendon extracellular matrix (ECM) into a Random-Aligned-Random composite using ultrasound treatment. The modified ECM enhanced expression of chondrogenesis and osteogenesis-associated epigenetic genes expression in vitro. In the rabbit anterior crucial ligament reconstruction model in vivo, results showed that the modified Random-Aligned-Random composite enhances the bone and fibrocartilage formation in the interface, proving to be more efficient than the unmodified tendon ECM. Therefore, these results demonstrated that the biomimetic Random-Aligned-Random composite could be a promising scaffold for ligament/tendon-bone junction repair.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.027
  • Carbon nanotubes, graphene and boron nitride nanotubes reinforced
           bioactive ceramics for bone repair
    • Authors: Chengde Gao; Pei Feng; Shuping Peng; Cijun Shuai
      Abstract: Publication date: Available online 10 May 2017
      Source:Acta Biomaterialia
      Author(s): Chengde Gao, Pei Feng, Shuping Peng, Cijun Shuai
      The high brittleness and low strength of bioactive ceramics severely restricted their applications in bone repair despite they have been regarded as the most promising biomaterials. In the last few years, low-dimensional nanomaterials (LDNs), including carbon nanotubes, graphene and boron nitride nanotubes, have gained increasing attention owing to the favorable biocompatibility, large surface specific area and super mechanical properties, which makes LDNs potential nanofillers in reinforcing bioactive ceramics. In this review, the types, characteristics and applications of the commonly used LDNs in ceramic composites are summarized. And the fabrication methods for LDNs/ceramic composites, such as hot pressing, spark plasma sintering and selective laser sintering, are systematically reviewed and compared. Emphases are placed on how to obtain the uniform dispersion of LDNs in ceramic matrix and maintain the structural stability of LDNs during the high-temperature fabrication process of ceramics. Afterwards, the reinforcing mechanisms of LDNs in ceramic composites are discussed in-depth. Moreover, the in vitro and in vivo studies of LDNs/ceramic in bone repair are summarized and discussed. Finally, new developments and potential applications of LDNs/ceramic composites are further prospected on the basis of experimental and theoretical studies. Statement of Significance Despite bioactive ceramics have been regarded as promising biomaterials, the high brittleness and low strength severely restrict their applications in bone scaffolds. In recent years, low-dimensional nanomaterials (LDNs), including carbon nanotubes, graphene and boron nitride nanotubes, have shown great potential in reinforcing bioactive ceramics owing to their unique structures and properties. However, the fabrication methods for LDNs/ceramic composites so far are difficult to maintain the structural stability of LDNs due to the long-time and high-temperature process. This review presents a comprehensive overview of the developments and applications of LDNs in bioactive ceramics. Moreover, the newly-developed fabrication methods for LDNs/ceramic composites, the reinforcing mechanisms and in vitro and in vivo performance of LDNs are also summarized and discussed in details.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.020
  • A ‘degradable’ poly(vinyl alcohol) iron oxide nanoparticle
    • Authors: Dawn Bannerman; Xinyi Li; Wankei Wan
      Abstract: Publication date: Available online 10 May 2017
      Source:Acta Biomaterialia
      Author(s): Dawn Bannerman, Xinyi Li, Wankei Wan
      Polymeric materials that contain magnetic nanoparticles are extremely useful in many applications including as multifunctional drug carriers, imaging contrast agents, or scaffold material. There is a need for biomaterials with appropriate chemical, mechanical, and magnetic properties that also have the ability to degrade or dissolve over time so they can be eliminated from the body following use. In this work, we explore the use of iron oxide nanoparticle (IONP) formation in poly(vinyl alcohol) (PVA) as a crosslinking method in conjunction with physical crosslinking achieved using low temperature thermal cycling (LTTC). PVA-IONP hydrogels were fabricated and characterized. IONPs contribute to the crosslinking of the PVA-IONP material, and their subsequent removal reduces crosslinking, and therefore stability, of the material, allowing dissolution to occur. Dissolution studies were performed on PVA-IONP hydrogels and dissolution was compared for films in solutions of varying pH, in the presence of iron chelating agents, and in simulated physiological and tumor conditions in cell culture media. Iron release, mass loss, and mechanical testing data were collected. This work demonstrates the ability of this biomaterial to ‘degrade’ over time, which may be very advantageous for applications such as drug delivery. This importance of this work extends to other areas such as the use of stimuli-responsive hydrogels. Statement of Significance This manuscript explores the stability of an iron oxide nanoparticle (IONP)-containing, physically crosslinked poly(vinyl alcohol) (PVA) hydrogel. The PVA-IONP hydrogel’s stability is imparted through crosslinks created through a low temperature thermal cycling process and through the IONPs. Subsequent IONP removal reduces crosslinks so material dissolution can occur, resulting in a ‘degradable’ and multifunctional biomaterial. PVA-IONP films were fabricated, characterized and evaluated in terms of dissolution in solutions of varying pH and in the presence of chelating agents. Iron release, mass loss, and mechanical testing data demonstrate the ability of the PVA-IONP biomaterial to ‘degrade’ over time. This degradability has not yet been demonstrated for crosslinked PVA hydrogels. These results are relevant to the development of degradable multifunctional drug carriers, image contrast agents, or magnetic scaffold materials.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.018
  • Protection of cortex by overlying meninges tissue during dynamic
           indentation of the adolescent brain
    • Authors: David B. MacManus; Baptiste Pierrat; Jeremiah G. Murphy; Michael D. Gilchrist
      Abstract: Publication date: Available online 10 May 2017
      Source:Acta Biomaterialia
      Author(s): David B. MacManus, Baptiste Pierrat, Jeremiah G. Murphy, Michael D. Gilchrist
      Traumatic brain injury (TBI) has become a recent focus of biomedical research with a growing international effort targeting material characterization of brain tissue and simulations of trauma using computer models of the head and brain to try to elucidate the mechanisms and pathogenesis of TBI. The meninges, a collagenous protective tri-layer which encloses the entire brain and spinal cord has been largely overlooked in these material characterization studies. This has resulted in a lack of accurate constitutive data for the cranial meninges, particularly under dynamic conditions such as those experienced during head impacts. The work presented here addresses this lack of data by providing for the first time, in situ large deformation material properties of the porcine dura-arachnoid mater composite under dynamic indentation. It is demonstrated that this tissue is substantially stiffer (shear modulus, μ = 19.10 ± 8.55 kPa) and relaxes at a slower rate (τ1 = 0.034 ± 0.008 s, τ2 = 0.336 ± 0.077 s) than the underlying brain tissue (μ = 6.97 ± 2.26 kPa, τ1 = 0.021 ± 0.007 s, τ2 = 0.199 ± 0.036 s), reducing the magnitudes of stress by 250% and 65% for strains that arise during indentation-type deformations in adolescent brains. Statement of Significance We present the first mechanical analysis of the protective capacity of the cranial meninges using in situ micro-indentation techniques. Force-relaxation tests are performed on in situ meninges and cortex tissue, under large strain dynamic micro-indentation. A quasi-linear viscoelastic model is used subsequently, providing time-dependent mechanical properties of these neural tissue under loading conditions comparable to what is experienced in TBI. The reported data highlights the large differences in mechanical properties between these two tissues. Finite element simulations of the indentation experiments are also performed to investigate the protective capacity of the meninges. These simulations show that the meninges protect the underlying brain tissue by reducing the overall magnitude of stress by 250% and up to 65% for strains.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.022
  • 3D Bioprinting for Drug Discovery and Development in Pharmaceutics
    • Authors: Weijie Peng; Pallab Datta; Bugra Ayan; Veli Ozbolat; Donna Sosnoski; Ibrahim T. Ozbolat
      Abstract: Publication date: Available online 10 May 2017
      Source:Acta Biomaterialia
      Author(s): Weijie Peng, Pallab Datta, Bugra Ayan, Veli Ozbolat, Donna Sosnoski, Ibrahim T. Ozbolat
      Successful launch of a commercial drug requires significant investment of time and financial resources wherein late-stage failures become a reason for catastrophic failures in drug discovery. This calls for infusing constant innovations in technologies, which can give reliable prediction of efficacy, and more importantly, toxicology of the compound early in the drug discovery process before clinical trials. Though computational advances have resulted in more rationale in silico designing, in vitro experimental studies still require gaining industry confidence and improving in vitro-in vivo correlations. In this quest, due to their ability to mimic the spatial and chemical attributes of native tissues, three-dimensional (3D) tissue models have now proven to provide better results for drug screening compared to traditional two-dimensional (2D) models. However, in vitro fabrication of living tissues has remained a bottleneck in realizing the full potential of 3D models. Recent advances in bioprinting provide a valuable tool to fabricate biomimetic constructs, which can be applied in different stages of drug discovery research. This paper presents the first comprehensive review of bioprinting techniques applied for fabrication of 3D tissue models for pharmaceutical studies. A comparative evaluation of different bioprinting modalities is performed to assess the performance and ability of fabricating 3D tissue models for pharmaceutical use as the critical selection of bioprinting modalities indeed plays a crucial role in efficacy and toxicology testing of drugs and accelerates the drug development cycle. In addition, limitations with current tissue models are discussed thoroughly and future prospects of the role of bioprinting in pharmaceutics are provided to the reader.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.025
  • An in situ Photocrosslinkable Platelet Rich Plasma - Complexed Hydrogel
           Glue with Growth Factor Controlled Release Ability to Promote Cartilage
           Defect Repair
    • Authors: Xiaolin Liu; Yunlong Yang; Xin Niu; Qiuning Lin; Bizeng Zhao; Yang Wang; Linyong Zhu
      Abstract: Publication date: Available online 10 May 2017
      Source:Acta Biomaterialia
      Author(s): Xiaolin Liu, Yunlong Yang, Xin Niu, Qiuning Lin, Bizeng Zhao, Yang Wang, Linyong Zhu
      The repair of articular cartilage injury is a great clinical challenge. Platelet-rich plasma (PRP) has attracted much attention for the repair of articular cartilage injury, because it contains various growth factors that are beneficial for wound repair. However, current administration methods of PRP face many shortcomings, such as unstable biological fixation and burst release of growth factors, all of which will bring troubles to its application in the repair of articular cartilage and compromise its therapeutic efficacy. In this study, based on our previously reported photoinduced imine crosslinking (PIC) reaction, we developed an in situ photocrosslinkable PRP hydrogel glue (HNPRP) through adding a photoresponsive hyaluronic acid (HA-NB) which could generate aldehyde groups upon light irradiation and subsequently react with amino groups, into autologous PRP. Our study showed that HNPRP hydrogel glue was cytocompatible and could be conveniently and rapidly prepared in situ, forming robust hydrogel scaffold. Besides, our results demonstrated that HNPRP hydrogel not only achieved controlled release of growth factors, but also showed strong tissue adhesive ability. Therefore, HNPRP hydrogel was quite suitable for cartilage defect regeneration. Our further in vitro experiment showed that HNPRP hydrogel could promote the proliferation and migration of chondrocytes and bone marrow stem cells (BMSCs). In vivo test using rabbit full-thickness cartilage defect model demonstrated that HNPRP hydrogel could achieve integrative hyaline cartilage regeneration and its therapeutic efficacy was better than thrombin activated PRP gel. Statement of Significance In this study, we have developed a photocrosslinkable platelet rich plasma (PRP) - complexed hydrogel glue (HNPRP) for cartilage regeneration. The in situ formed HNPRP hydrogel glue showed not only the controlled release ability of growth factors, but also strong tissue adhesiveness, which could conquer the current problems in clinical application of PRP. Furthermore, HNPRP hydrogel glue could promote integrative hyaline cartilage regeneration, and its reparative efficacy for cartilage defect was better than thrombin activated PRP gel. This study provided not only an effect repair material for cartilage regeneration, but also developed an advanced method for PRP application.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.023
  • Calcium ion coordinated dexamethasone supramolecular hydrogel as
           therapeutic alternative for control of non-infectious uveitis
    • Authors: Wei Wu; Zhaoliang Zhang; Taotao Xiong; Wenguang Zhao; Rou Jiang; Hao Chen; Xingyi Li
      Abstract: Publication date: Available online 10 May 2017
      Source:Acta Biomaterialia
      Author(s): Wei Wu, Zhaoliang Zhang, Taotao Xiong, Wenguang Zhao, Rou Jiang, Hao Chen, Xingyi Li
      Supramolecular hydrogel formed by the self-assembly of therapeutic agents have received considerable attention due to its high drug payload, carrier-free features. Herein, we constructed a dexamethasone sodium phosphate (Dex) supramolecular hydrogel in combination of Dex and calcium ion (Ca2+) and further demonstrated its therapeutic efficacy in the control of ocular inflammation. The developed supramolecular hydrogel was thoroughly characterized by rheology, TEM, FTIR and XRD. Calcium ions and Dex concentration had markedly influence on the sol-gel transition behavior of hydrogel and the proposed Dex supramolecular hydrogel displayed thixotropic property. Drug release rate from Dex supramolecular hydrogel was dependent on the Ca2+ concentration. In comparison with Dex aqueous solution, single intravitreal injection of Dex supramolecular hydrogel up to 30μg/eye were well ocular tolerated without causing undesirable complications of fundus blood vessel tortuosity and lens opacity, as indicated by electroretinograms (ERGs), fundus photography and histopathology. Moreover, medication by Dex supramolecular hydrogel exhibited a comparable anti-inflammatory efficacy with native Dex solution on an experimental autoimmune uveitis (EAU) model induced in Lewis rat with IRBP peptide and the therapeutic efficacy had a dosage-dependent manner. Histological observation and cytokines measurements indicated that both Dex solution and Dex supramolecular hydrogel (30μg/eye) treatment could significantly attenuate the inflammatory response in both anterior and posterior chamber via the downregulation of Th1 and Th17 effector response. All these data suggested that the developed Dex supramolecular hydrogel might be a therapeutic alternative for non-infectious uveitis with the minimal risk of the induction of lens opacity and fundus blood vessel tortuosity. Statement of significance A facile ionic cross-linking strategy were exploited to construct a dexamethasone sodium phosphate (Dex) supramolecular hydrogel composed of Dex and calcium ion. Intravitreal injection of Dex hydrogel displayed excellent intraocular biocompatibility without causing the complications of fundus blood vessel tortuosity and cataract formation. More importantly, the proposed Dex hydrogel exhibited a comparative anti-inflammatory response with native Dex formulation in experimental autoimmune uveitis (EAU) model via the downregulation of Th1 and Th17 effector response.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.024
  • Effect of surface alkali-based treatment of titanium implants on ability
           to promote in-vitro mineralization and in-vivo bone formation
    • Authors: Winston A. Camargo; Shinji Takemoto; Jan Willem Hoekstra; Sander C.G. Leeuwenburgh; John A. Jansen; Jeroen J.J.P. van den Beucken; Hamdan S. Alghamdi
      Abstract: Publication date: Available online 9 May 2017
      Source:Acta Biomaterialia
      Author(s): Winston A. Camargo, Shinji Takemoto, Jan Willem Hoekstra, Sander C.G. Leeuwenburgh, John A. Jansen, Jeroen J.J.P. van den Beucken, Hamdan S. Alghamdi
      This study investigated whether a novel alkali-based surface modification enhances in-vitro mineralization as well as in-vivo bone formation around titanium (Ti) implants in a femoral condyle model of 36 male Wister rats. All implant surfaces were grit-blasted and then received either acid-etching treatment, alkali-based treatment, or were left untreated (controls). Histological and histomorphometrical analyses were performed on retrieved specimens after 4 and 8 weeks of healing to assess peri-implant bone formation. Results of implants surface characterisation showed notable differences in the topography and composition of alkali-treated surfaces, reflecting the formation of submicron-structured alkali-titanate layer. In the in-vitro test, alkalitreated Ti surfaces showed the ability to stimulate mineralization upon soaking in simulated body fluid (SBF). In-vivo histomorphometrical analyses showed similar values for bone area (BA%) and bone-to-implant contact (BIC%) for all experimental groups after both 4- and 8-week implantation periods. In conclusion, the surface topography and composition of the grit-blasted Ti implants was significantly modified using alkali-based treatment. With respect to the present in-vivo model, the biological performance of alkali-treated Ti implants is comparable to the commercially available, grit-blasted, acid-etched Ti implants. Statement of Significance Since success rate of dental implants might be challenged in bone of low density, an optimum implant surface characteristic is demanding. In this work, alkali treatment of Ti implants showed significant advantage of surface mineralization upon soaking in simulated body fluid. Using an in vivo rat model, Ti surfaces with either acid-etching treatment or alkali-based treatment evoked robust bone formation around Ti implants. Such information may be utilized for the advancement of biomaterials research for bone implants in future.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.016
  • A comprehensive study of layer-specific morphological changes in the
           microstructure of carotid arteries under uniaxial load
    • Authors: Witold Krasny; Claire Morin; Hélène Magoariec; Stéphane Avril
      Abstract: Publication date: Available online 9 May 2017
      Source:Acta Biomaterialia
      Author(s): Witold Krasny, Claire Morin, Hélène Magoariec, Stéphane Avril
      The load bearing properties of large blood vessels are principally conferred by collagen and elastin networks and their microstructural organization plays an important role in the outcomes of various arterial pathologies. In particular, these fibrous networks are able to rearrange and reorient spatially during mechanical deformations. In this study, we investigate for the first time whether these well-known morphological rearrangements are the same across the whole thickness of blood vessels, and subsequently if the underlying mechanisms that govern these rearrangements can be predicted using affine kinematics. To this aim, we submitted rabbit carotid samples to uniaxial load in three distinct deformation directions, while recording live images of the 3D microstructure using multiphoton microscopy. Our results show that the observed realignment of collagen and elastin in the media layer, along with elastin of the adventitia layer, remained limited to small angles that can be predicted by affine kinematics. We show also that collagen bundles of fibers in the adventitia layer behaved in significantly different fashion. They showed a remarkable capacity to realign in the direction of the load, whatever the loading direction. Measured reorientation angles of the fibers were significantly higher than affine predictions. This remarkable property of collagen bundles in the adventitia was never observed before, it shows that the medium surrounding collagen in the adventitia undergoes complex deformations challenging traditional hyperelastic models based on mixture theories. Statement of significance The biomechanical properties of arteries are conferred by the rearrangement under load of the collagen and elastin fibers making up the arterial microstructure. Their kinematics under deformation is not yet characterized for all fiber networks. In this respect we have submitted samples of arterial tissue to uniaxial tension, simultaneously to confocal imaging of their microstructure. Our method allowed identifying for the first time the remarkable ability of adventitial collagen fibers to reorient in the direction of the load, achieving reorientation rotations that exceeded those predicted by affine kinematics, while all other networks followed the affine kinematics. Our results highlight new properties of the microstructure, which might play a role in the outcomes of vascular pathologies like aneurysms.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.04.033
  • Controllable release of nitric oxide and doxorubicin from engineered
           nanospheres for synergistic tumor therapy
    • Authors: Lianjiang Tan; Ran Huang; Xiaoqiang Li; Shuiping Liu; Yu-Mei Shen
      Abstract: Publication date: Available online 9 May 2017
      Source:Acta Biomaterialia
      Author(s): Lianjiang Tan, Ran Huang, Xiaoqiang Li, Shuiping Liu, Yu-Mei Shen
      NaYF4:Yb,Er upconversion nanoparticles (UCNPs) capped with long-chain carboxylic acid were synthesized and then conjugated with chitosan (CS) in the aid of N-hydroxysuccinimide. The resultant nanocompound was integrated with doxorubicin (DOX) and Roussin’s black salt (RBS), a photosensitive nitric oxide (NO) donor to produce stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres as nanocarriers for controllable drug delivery. On the one hand, the encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible photons to trigger NO release. On the other hand, the entrapped DOX can be released at lowered pH from the swollen nanospheres caused by stretched oleoyl-CS chains under acidic conditions. The UCNPs(DOX)@CS-RBS nanospheres exhibit great therapeutic efficacy, which is attributable to the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study highlights the controllable release of NO and DOX from the same nanocarriers and the synergistic therapeutic effect on tumors, which could give new insights into improving cancer nanotherapeutics. Statement of significance In this paper, core-shell structured UCNPs(DOX)@CS-RBS nanospheres have been designed and synthesized via a step-by-step procedure. The stimuli-responsive UCNPs(DOX)@CS-RBS nanospheres act as nanocarriers for controllable drug delivery towards cancer therapy. The encapsulated UCNPs can efficiently absorb NIR photons and convert them into visible light to trigger NO release. Meanwhile, the entrapped DOX can be released from the swollen nanospheres caused by stretched oleoyl-CS chains at lowered pH typical of intracellular environment. Synergistic cancer therapy will be achieved through the combination of NO and DOX releases based on NO dose-dependent mechanisms. This study provides new drug nanocarriers with high antitumor efficacy for synergistic cancer therapy.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.019
  • Extrafibrillar collagen demineralization-based chelate-and-rinse technique
           bridges the gap between wet and dry dentin bonding
    • Authors: Sui Mai; Chin-Chuan Wei; Li-sha Gu; Fu-cong Tian; Dwayne D. Arola; Ji-hua Chen; Yang Jiao; David H. Pashley; Li-na Niu; Franklin R. Tay
      Abstract: Publication date: Available online 9 May 2017
      Source:Acta Biomaterialia
      Author(s): Sui Mai, Chin-Chuan Wei, Li-sha Gu, Fu-cong Tian, Dwayne D. Arola, Ji-hua Chen, Yang Jiao, David H. Pashley, Li-na Niu, Franklin R. Tay
      Limitations associated with wet-bonding led to the recent development of a selective demineralization strategy in which dentin was etched with a reduced concentration of phosphoric acid to create exclusive extrafibrillar demineralization of the collagen matrix. However, the use of acidic conditioners removes calcium via diffusion of very small hydronium ions into the intrafibrillar collagen water compartments. This defeats the purpose of limiting the conditioner to the extrafibrillar space to create a collagen matrix containing only intrafibrillar minerals to prevent collapse of the collagen matrix. The present work examined the use of polymeric chelators (the sodium salt of polyacrylic acid) of different molecular weights to selectively demineralize extrafibrillar dentin. These polymeric chelators exhibit different affinities for calcium ions (isothermal titration calorimetry), penetrated intrafibrillar dentin collagen to different extents based on their molecular sizes (modified size-exclusion chromatography), and preserve the dynamic mechanical properties of mineralized dentin more favorably compared with completely demineralized phosphoric acid-etched dentin (nanoscopical dynamic mechanical analysis). Scanning and transmission electron microscopy provided evidence for retention of intrafibrillar minerals in dentin surfaces conditioned with polymeric chelators. Microtensile bond strengths to wet-bonded and dry-bonded dentin conditioned with these polymeric chelators showed that the use of sodium salts of polyacrylic acid for chelating dentin prior to bonding did not result in significant decline in resin-dentin bond strength. Taken together, the findings led to the conclusion that a chelate-and-rinse conditioning technique based on extrafibrillar collagen demineralization bridges the gap between wet and dry dentin bonding. Statement of significance The chelate-and-rinse dental adhesive bonding concept differentiates from previous research in that it is based on the size-exclusion characteristics of fibrillar collagen; molecules larger than 40 kDa are prevented from accessing the intrafibrillar water compartments of the collagen fibrils. Using this chelate-and-rinse extrafibrillar calcium chelation concept, collagen fibrils with retained intrafibrillar minerals will not collapse upon air-drying. This enables adhesive infiltration into the mineral-depleted extrafibrillar spaces without relying on wet-bonding. By bridging the gap between wet and dry dentine bonding, the chelate-and-rinse concept introduces additional insight to the field by preventing exposure of endogenous proteases via preservation of the intrafibrillar minerals within a collagen matrix. If successfully validated, this should help prevent degradation of resin-dentine bonds by collagenolytic enzymes.
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      PubDate: 2017-05-14T14:13:52Z
      DOI: 10.1016/j.actbio.2017.05.017
  • Towards rebuilding vaginal support utilizing an extracellular matrix
    • Authors: Rui Liang; Katrina Knight; Deanna Easley; Stacy Palcsey; Steven Abramowitch; Pamela A. Moalli
      Abstract: Publication date: Available online 6 May 2017
      Source:Acta Biomaterialia
      Author(s): Rui Liang, Katrina Knight, Deanna Easley, Stacy Palcsey, Steven Abramowitch, Pamela A. Moalli
      As an alternative to polypropylene mesh, we explored an extracellular matrix (ECM) bioscaffold derived from urinary bladder matrix (MatriStem™) in the repair of vaginal prolapse. We aimed to restore disrupted vaginal support simulating application via transvaginal and transabdominal approaches in a macaque model focusing on the impact on vaginal structure, function, and the host immune response. In 16 macaques, after laparotomy, the uterosacral ligaments and paravaginal attachments to pelvic side wall were completely transected (IACUC# 13081928). 6ply MatriStem was cut into posterior and anterior templates with a portion covering the vagina and arms simulating uterosacral ligaments and paravaginal attachments, respectively. After surgically exposing the correct anatomical sites, in 8 animals, a vaginal incision was made on the anterior and posterior vagina and the respective scaffolds were passed into the vagina via these incisions (transvaginal insertion) prior to placement. The remaining 8 animals underwent the same surgery without vaginal incisions (transabdominal insertion). Three months post implantation, firm tissue bands extending from vagina to pelvic side wall appeared in both MatriStem groups. Experimental endpoints examining impact of MatriStem on the vagina demonstrated that vaginal biochemical and biomechanical parameters, smooth muscle thickness and contractility, and immune responses were similar in the MatriStem no incision group and sham-operated controls. In the MatriStem incision group, a 41% decrease in vaginal stiffness (P=0.042), a 22% decrease in collagen content (P=0.008) and a 25% increase in collagen subtypes III/I was observed vs. Sham. Active MMP2 was increased in both Matristem groups vs. Sham (both P=0.002). This study presents a novel application of ECM bioscaffolds as a first step towards the rebuilding of vaginal support. Statement of Significance Pelvic organ prolapse is a common condition related to failure of the supportive soft tissues of the vagina; particularly at the apex and mid-vagina. Few studies have investigated methods to regenerate these failed structures. The overall goal of the study was to determine the feasibility of utilizing a regenerative bioscaffold in prolapse applications to restore apical (level I) and lateral (level II) support to the vagina without negatively impacting vaginal structure and function. The significance of our findings is two fold: 1. Implantation of properly constructed extracellular matrix grafts promoted rebuilding of level I and level II support to the vagina and did not negatively impact the overall functional, morphological and biochemical properties of the vagina. 2. The presence of vaginal incisions in the transvaginal insertion of bioscaffolds may compromise vaginal structural integrity in the short term.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.015
  • Mechanical Phenotyping of Cells and Extracellular Matrix as Grade and
           Stage Markers of Lung Tumor Tissues
    • Authors: Valeria Panzetta; Ida Musella; Ida Rapa; Marco Volante; Paolo A. Netti; Sabato Fusco
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): Valeria Panzetta, Ida Musella, Ida Rapa, Marco Volante, Paolo A. Netti, Sabato Fusco
      The mechanical cross-talk between cells and the extra-cellular matrix (ECM) regulates the properties, functions and healthiness of the tissues. When this is disturbed it changes the mechanical state of the tissue components, singularly or together, and cancer, along with other diseases, may start and progress. However, the bi-univocal mechanical interplay between cells and the ECM is still not properly understood. In this study we show how a microrheology technique gives us the opportunity to evaluate the mechanics of cells and the ECM at the same time. The mechanical phenotyping was performed on the surgically removed tissues of 10 patients affected by adenocarcinoma of the lung. A correlation between the mechanics and the grade and stage of the tumor was reported and compared to the mechanical characteristics of the healthy tissue. Our findings suggest a sort of asymmetric modification of the mechanical properties of the cells and the extra-cellular matrix in the tumor, being the more compliant cell even though it resides in a stiffer matrix. Overall, the simultaneous mechanical characterization of the tissues constituents (cells and ECM) provided new support for diagnosis and offered alternative points of analysis for cancer mechanobiology. Statement of significance When the integrity of the mechanical cross-talk between cells and the extra-cellular matrix is disturbed cancer, along with other diseases, may initiate and progress. Here, we show how a new technique gives the opportunity to evaluate the mechanics of cells and the ECM at the same time. It was applied on surgically removed tissues of 10 patients affected by adenocarcinoma of the lung and a correlation between the mechanics and the grade and stage of the tumor was reported and compared to the mechanical characteristics of the healthy tissue.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.002
  • Prevention of Bacterial Adhesion to Zwitterionic Biocompatible Mesoporous
    • Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): S. Sánchez-Salcedo, A. García, María Vallet-Regí
      Novel materials, based on Mesoporous Bioactive Glasses (MBGs) in the ternary system SiO2-CaO-P2O5, decorated with (3-aminopropyl)triethoxysilane (APTES) and subsequently with amino acid Lysine (Lys), by post-grafting method on the external surface of the glasses (named MBG-NH2 and MBG-Lys), are reported. The surface functionalization with organic groups did not damage the mesoporous network and their structural and textural properties were also preserved despite the high solubility of MBG matrices. The incorporation of Lys confers a zwitterionic nature to these MBG materials due to the presence of adjacent amine and carboxylic groups in the external surface. At physiologic pH, this coexistence of basic amine and carboxilic acid groups from anchored Lys provided zero surface charge named zwitterionic effect. This behaviour could give rise to potential applications of antibacterial adhesion. Therefore, in order to assess the influence of zwitterionic nature in in vitro bacterial adhesion, studies were carried out with Staphylococcus aureus. It was demonstrated that the efficient interaction of these zwitterionic pairs onto the MBG surfaces reduced bacterial adhesion up to 99.9% compared to bare MBGs. In order to test the suitability of zwitterionic MBGs materials as bone grafts, their cytocompatibility was investigated in vitro with MC3T3-E1 preosteoblasts. These findings suggested that the proposed surface functionalization strategy provided MBG materials with notable antibacterial adhesion properties, hence making these materials promising candidates for local bone infection therapy. Statement of significance The present research work is focused in finding a preventive treatment of bone infection based on Mesoporous Bioactive Glasses (MBGs) with antibacterial adhesion properties obtained by zwitterionic surface modification. MBGs exhibit unique nanostructural, textural and bioactive characteristics. The novelty and originality of this manuscript is based on the design and optimization of a straightforward functionalization method capable of providing MBGs with zwitterionic surfaces that are able to inhibit bacterial adhesion without affecting their cytocompatibility. This new characteristic enhanced the MBG properties to avoid the bacterial adherence onto the implant surfaces for bone tissue engineering applications. Subsequently, it could help to decrease the infection rates after implantation surgery, which represents one of the most serious complications associated to surgical treatments of bone diseases and fractures.
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      PubDate: 2017-05-09T14:07:20Z
  • Spatial distributions of pericellular stiffness in natural extracellular
           matrices are dependent on cell-mediated proteolysis and contractility
    • Authors: M. Keating; A. Kurup; M. Alvarez-Elizondo; A.J. Levine; E. Botvinick
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): M. Keating, A. Kurup, M. Alvarez-Elizondo, A.J. Levine, E. Botvinick
      Bulk tissue stiffness has been correlated with regulation of cellular processes and conversely cells have been shown to remodel their pericellular tissue according to a complex feedback mechanism critical to development, homeostasis, and disease. However, bulk rheological methods mask the dynamics within a heterogeneous fibrous extracellular matrix (ECM) in the region proximal to a cell (pericellular region). Here, we use optical tweezers active microrheology (AMR) to probe the distribution of the complex material response function (α = α’ + α’’, in units of µm/nN) within a type I collagen ECM, a biomaterial commonly used in tissue engineering. We discovered cells both elastically and plastically deformed the pericellular material. α’ is wildly heterogeneous, with 1/α’ values spanning three orders of magnitude around a single cell. This was observed in gels having a cell-free 1/α’ of approximately 0.5 nN/µm. We also found that inhibition of cell contractility instantaneously softens the pericellular space and reduces stiffness heterogeneity, suggesting the system was strain hardened and not only plastically remodeled. The remaining regions of high stiffness strongly suggest cellular remodeling of their surrounding matrix. To test this hypothesis, cells were incubated within the type I collagen gel for 24 hours in a media containing a broad-spectrum matrix metalloproteinase (MMP) inhibitor. While the pericellular material maintained stiffness asymmetry, stiffness magnitudes were reduced. Dual inhibition demonstrates that the combination of MMP activity and contractility is necessary to establish the pericellular stiffness landscape. This heterogeneity in stiffness suggests the distribution of pericellular stiffness, and not bulk stiffness alone, must be considered in the study of cell-ECM interactions and design of complex biomaterial scaffolds. Statement of Significance Collagen is a fibrous extracellular matrix (ECM) protein that has been widely used to study cell-ECM interactions. Stiffness of ECM has been shown to instruct cells, which can in turn modify their ECM, as has been shown for cancer and regenerative medicine. Here we measure the stiffness of the collagen microenvironment surrounding cells and quantitatively observe the dependence of pericellular stiffness on MMP activity and cytoskeletal contractility. Competent cell-mediated stiffening results in a wildly heterogeneous micromechanical topography, with values spanning orders of magnitude around a single cell. We speculate studies must consider this notable heterogeneity that can be generated by cells when testing theories regarding the role of ECM mechanics in health and disease.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.008
  • Selective phenylalanine to proline substitution for improved antimicrobial
           and anticancer activities of peptides designed on phenylalanine heptad
    • Authors: Amit Kumar Tripathi; Tripti Kumari; Anshika Tandon; Mohd. Sayeed; Tayyaba Afshan; Manoj Kathuria; P.K. Shukla; Kalyan Mitra; Jimut Kanti Ghosh
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): Amit Kumar Tripathi, Tripti Kumari, Anshika Tandon, Mohd. Sayeed, Tayyaba Afshan, Manoj Kathuria, P.K. Shukla, Kalyan Mitra, Jimut Kanti Ghosh
      Introducing cell-selectivity in antimicrobial peptides (AMPs) without compromising the antimicrobial and anti-endotoxin properties is a crucial step towards the development of new antimicrobial agents. A peptide designed on phenylalanine heptad repeat possesses significant cytotoxicity along with desired antimicrobial and anti-endotoxin properties. Amino-acid substitutions at ‘a’ and/or ‘d’ positions of heptad repeats of AMPs could alter their helical structure in mammalian membrane-mimetic environments and cytotoxicity towards mammalian cells. Since proline is a helix breaker, effects of selective proline substitution(s) at ‘a’ and/or ‘d’ positions of a 15-residue peptide designed on phenylalanine heptad repeat (FR-15) were investigated. Proline-substituted FR-15 variants were highly selective toward bacteria and fungi over hRBCs and murine 3T3 cells and also retained their antibacterial activities at high salt, serum and elevated temperatures. These non-cytotoxic variants also inhibited LPS-induced production of pro-inflammatory cytokines/chemokines in human monocytes, THP-1, RAW 264.7 and in Balb/c mice. The two non-cytotoxic variants (FR8P and FR11P) showed potent anti-cancer activity against highly metastatic human breast cancer cell line MDA-MB-231 with IC50 values less than 10 μM. At sub-IC50 concentrations, FR8P and FR11P also showed anti-migratory and anti-invasive effects against MDA-MB-231 cells. FR8P and FR11P induced cellular apoptosis by triggering intrinsic apoptotic pathway through depolarization of mitochondrial membrane potential and activation of caspases. Overall the results demonstrated the utilization of selective phenylalanine to proline substitution in a heptad repeat of phenylalanine residues for the design of cell-selective, broad-spectrum AMPs with significant anti-cancer properties. Statement of significance We have demonstrated a methodology to design cell-selective potent antimicrobial and anti-endotoxin peptides by utilizing phenylalanine zipper as a template and replacement of phenylalanine residue(s) from “a” and/or “d” position(s) with proline residue(s) produced non-cytotoxic AMPs with improved antibacterial properties against the drug-resistant strains of bacteria. The work showed that the ‘a’ and ‘d’ positions of the phenylalanine heptad repeat could act as switches that could be replaced by an appropriate amino acid to control cytotoxicity of the peptide without compromising its potency in antimicrobial and anti-endotoxin properties. The direct bacterial membrane targeting mechanism of proline substituted analogs of parent peptide makes difficult for bacteria to grow resistance against them. The peptides designed could be lead molecules in the area of sepsis as they possess significant anti-LPS activities for in vitro and in vivo. Interestingly since cancer cells and bacterial cell membranes possess the structural resemblances, the cancer cells are also targets for these peptides making them lead molecules in this field. However, unlike in bacteria where the peptides showed membrane permeabilization property to lyse them, the peptides induced apoptosis in MDA-MB-231 breast cancer cells to inhibit their proliferation and growth. The results are significant because it reveals that “a” and “d” positions of a phenylalanine zipper can be utilized as switches to design cell selective, antimicrobial,anti-endotoxin and anticancer peptides.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.007
  • Combined delivery of a TGF-β inhibitor and an adenoviral vector
           expressing interleukin-12 potentiates cancer immunotherapy
    • Authors: Jiayu Jiang; Yuandong Zhang; Ke Peng; Qin Wang; Xiaoyu Hong; Hanmei Li; Gerui Fan; Zhirong Zhang; Tao Gong; Xun Sun
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): Jiayu Jiang, Yuandong Zhang, Ke Peng, Qin Wang, Xiaoyu Hong, Hanmei Li, Gerui Fan, Zhirong Zhang, Tao Gong, Xun Sun
      Cancer immunotherapy appears a promising future, but it can be thwarted by secretion of immunosuppressive factors, such as transforming growth factor-β (TGF-β), which inhibits local immune responses to tumors. To weaken immune resistance of tumors and simultaneously strengthen immune responses, we developed a multifunctional polymer that could co-deliver hydrophobic TGF-β inhibitor and an adenovirus gene vector to tumor sites. This co-delivery system sustainably released TGF-β inhibitor SB-505124 and effectively transferred the adenovirus vector carrying the interleukin-12 gene. Besides it significantly delayed growth of B16 melanoma xenografts in mice and increased animal survival. Mechanistic studies showed that this combination therapy enhanced anti-tumor immune response by activating CD4+ and CD8+ T cells, natural killer cells and interferon-γ secretion in the tumor microenvironment. Statement of Significance To weak immune resistance of tumors and simultaneously strengthened tumors immune responses, we synthesized a structurally simple, low-toxic but functional polymer β-cyclodextrin-PEI to encapsulate a hydrophobic TGF-β inhibitor SB-505124 and to complex adenovirus vectors expressing IL-12. This was the first report demonstrating that combining TGF-β inhibitor with IL-12 could provide effective immunotherapy against melanoma by the sustainable release of SB-505124 and the effectible transduction of IL-12 gene in tumor cells. The rational delivery system presented a comprehensive and valued platform to be a candidate vector for co-delivering hydrophobic small-molecule drug and therapeutic gene for treating cancer and provided a new approach for cancer immunotherapy.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.009
  • Preparation and evaluation of human choroid extracellular matrix scaffolds
           for the study of cell replacement strategies
    • Authors: Kathleen R. Chirco; Kristan S. Worthington; Miles J. Flamme-Wiese; Megan J. Riker; Joshua D. Andrade; Beatrix M. Ueberheide; Edwin M. Stone; Budd A. Tucker; Robert F. Mullins
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): Kathleen R. Chirco, Kristan S. Worthington, Miles J. Flamme-Wiese, Megan J. Riker, Joshua D. Andrade, Beatrix M. Ueberheide, Edwin M. Stone, Budd A. Tucker, Robert F. Mullins
      Endothelial cells (ECs) of the choriocapillaris are one of the first cell types lost during age-related macular degeneration (AMD), and cell replacement therapy is currently a very promising option for patients with advanced AMD. We sought to develop a reliable method for the production of human choroidal extracellular matrix (ECM) scaffolds, which will allow for the study of choroidal EC (CEC) replacement strategies in an environment that closely resembles the native tissue. Human RPE/choroid tissue was treated sequentially with Triton X-100, SDS, and DNase to remove all native cells. While all cells were successfully removed from the tissue, collagen IV, elastin, and laminin remained, with preserved architecture of the acellular vascular tubes. The ECM scaffolds were then co-cultured with exogenous ECs to determine if the tissue can support cell growth and allow EC reintegration into the decellularized choroidal vasculature. Both monkey and human ECs took up residence in the choriocapillary tubes of the decellularized tissue. Together, these data suggest that our decellularization methods are sufficient to remove all cellular material yet gentle enough to preserve tissue structure and allow for the optimization of cell replacement strategies. Statement of Significance Age-related macular degeneration (AMD) is a devastating disease affecting more than 600 million people worldwide. Endothelial cells of the choriocapillaris (CECs) are among the first cell types lost in early AMD, and cell replacement therapy is currently the most promising option for restoring vision in patients with advanced AMD. In order to study CEC replacement strategies we have generated a 3D choroid scaffold using a novel decellularization method in human RPE/choroid tissue. To our knowledge, this is the first report describing decellularization of human RPE/choroid, as well as recellularization of a choroid scaffold with CECs. This work will aid in our development and optimization of cell replacement strategies using a tissue scaffold that is similar to the in vivo environment.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.011
  • Augmented liver targeting of exosomes by surface modification with
           cationized pullulan
    • Authors: Ryo Tamura; Shinji Uemoto; Yasuhiko Tabata
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): Ryo Tamura, Shinji Uemoto, Yasuhiko Tabata
      Exosomes are membrane nanoparticles containing biological substances that are employed as therapeutics in experimental inflammatory models. Surface modification of exosomes for better tissue targetability and enhancement of their therapeutic ability was recently attempted mainly using gene transfection techniques. Here, we show for the first time that the surface modification of exosomes with cationized pullulan, which has the ability to target hepatocyte asialoglycoprotein receptors, can target injured liver and enhance the therapeutic effect of exosomes. Surface modification can be achieved by a simple mixing of original exosomes and cationized pullulan and through an electrostatic interaction of both substances. The exosomes modified with cationized pullulan were internalized into HepG2 cells in vitro to a significantly greater extent than unmodified ones and this internalization was induced through the asialoglycoprotein receptor that was specifically expressed on HepG2 cells and hepatocytes. When injected intravenously into mice with concanavalin A-induced liver injury, the modified exosomes accumulated in the liver tissue, resulting in an enhanced anti-inflammatory effect in vivo. It is concluded that the surface modification with cationized pullulan promoted accumulation of the exosomes in the liver and the subsequent biological function, resulting in a greater therapeutic effect on liver injury. Statement of significance Exosomes have shown potentials as therapeutics for various inflammatory disease models. This study is the first to show the specific accumulation of exosomes in the liver and enhanced anti-inflammatory effect via the surface modification of exosomes using pullulan, which is specifically recognized by the asialoglycoprotein receptor (AGPR) on HepG2 cells and hepatocytes. The pullulan was expressed on the surface of PKH-labeled exosomes, and it led increased accumulation of PKH into HepG2 cells, whereas the accumulation was canceled by AGPR inhibitor. In the mouse liver injury model, the modification of PKH-labeled exosomes with pullulan enabled increased accumulation of PKH specifically in the injured liver. Furthermore the greater therapeutic effects against the liver injury compared with unmodified original exosomes was observed.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.013
  • Chemosensitizing indomethacin-conjugated chitosan oligosaccharide
           nanoparticles for tumor-targeted drug delivery
    • Authors: Jae-Young Lee; Ubonvan Termsarasab; Mee Yeon Lee; Dong-Hwan Kim; Song Yi Lee; Jung Sun Kim; Hyun-Jong Cho; Dae-Duk Kim
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): Jae-Young Lee, Ubonvan Termsarasab, Mee Yeon Lee, Dong-Hwan Kim, Song Yi Lee, Jung Sun Kim, Hyun-Jong Cho, Dae-Duk Kim
      A chitosan oligosaccharide (CSO)-indomethacin (IDM) conjugate (CI) was synthesized to fabricate chemosensitizing nanoparticles (NPs) for tumor-targeted drug delivery. IDM was conjugated to a CSO backbone via amide bond formation, of which successful synthesis was confirmed by proton-nuclear magnetic resonance analyses. Doxorubicin (DOX)-loaded CI (CI10/DOX; CI:DOX = 10:1 [w/w]) NPs with < 75 nm of mean diameter, polydispersity index of ∼0.2, and positive zeta potential were prepared. The release of DOX from the NPs was enhanced at acidic pH (pH 5.5 and 6.8) compared to physiological pH (pH 7.4). The release of IDM increased in the presence of A549 cell lysates. In A549 cells (human lung carcinoma cell), more efficient cellular uptake of CI10/DOX NPs than that of free DOX was observed by using confocal laser scanning microscopy and flow cytometry. The in vitro cytotoxicity of CI10/DOX NPs in A549 cells was higher than those of free DOX and CI NPs with free DOX groups. In vivo pharmacokinetic studies after intravenous administration in rats showed significantly lower clearance of DOX from NPs compared with the free DOX group. Tumor targetability of the developed CI NPs was also verified by a real-time optical imaging study. In summary, the chemosensitizing CI/DOX NP with enhanced anticancer activity, prolonged blood circulation, and passive tumor targeting can be a promising anticancer drug delivery system for tumor-targeted therapy. statement of significance Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the antiproliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse model by a real-time optical imaging. Developed CI NPs can be used as a multifunctional nanosystem for the therapy of MRP-expressed cancers.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.012
  • Biocompatible nanostructured solid adhesives for biological soft tissues
    • Authors: Masahiro Okada; Akira Nakai; Emilio Satoshi Hara; Tetsushi Taguchi; Takayoshi Nakano; Takuya Matsumoto
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): Masahiro Okada, Akira Nakai, Emilio Satoshi Hara, Tetsushi Taguchi, Takayoshi Nakano, Takuya Matsumoto
      Over the past few years, the development of novel adhesives for biological soft tissue adhesion has gained significant interest. Such adhesives should be non-toxic and biocompatible. In this study, we synthesized a novel solid adhesive using nanostructured hydroxyapatite (HAp) and evaluated its physical adhesion properties through in vitro testing with synthetic hydrogels and mice soft tissues. The results revealed that the HAp-nanoparticle dispersions and HAp-nanoparticle-assembled nanoporous plates showed efficient adhesion to the hydrogels. Interestingly, the HAp plates showed different adhesive properties depending upon the shape of their nanoparticles. The HAp plate made up of 17 nm-sized nanoparticles showed an adhesive strength 2.2 times higher than the conventional fibrin glue for mice skin tissues. Statement of Significance The present study indicates a new application of inorganic biomaterials (bioceramics) as a soft tissue adhesive. Organic adhesives such as fibrin glues or cyanoacrylate derivatives have been commonly used clinically. However, their limited biocompatibility or low adhesion strength are some drawbacks that impair their clinical application. In this study, we synthesized a novel solid adhesive with biocompatible and biodegradable hydroxyapatite (HAp) nanoparticles without the aid of organic molecules, and showed an immediate and superior (i.e., 2.2 times higher) adhesion strength of mouse soft tissues compared to conventional fibrin glues. Given the importance of wet adhesion to biomedicine and biotechnology, our results suggest ways to develop new soft tissue adhesives as well as new applications of inorganic biomaterials.
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      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.014
  • 3D Tumor Microtissues as an In Vitro Testing Platform for
           Microenvironmentally-triggered Drug Delivery Systems
    • Authors: Virginia Brancato; Filomena Gioiella; Martina Profeta; Giorgia Imparato; Daniela Guarnieri; Francesco Urciuolo; Pietro Melone; Paolo A. Netti
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): Virginia Brancato, Filomena Gioiella, Martina Profeta, Giorgia Imparato, Daniela Guarnieri, Francesco Urciuolo, Pietro Melone, Paolo A. Netti
      Therapeutic approaches based on nanomedicine have garnered great attention in cancer research. In vitro biological models that better mimic in vivo conditions are crucial tools to more accurately predict their therapeutic efficacy in vivo. In this work, a new 3D breast cancer microtissue has been developed to recapitulate the complexity of the tumor microenvironment and to test its efficacy as screening platform for drug delivery systems. The proposed 3D cancer model presents human breast adenocarcinoma cells and cancer-associated fibroblasts embedded in their own ECM, thus showing several features of an in vivo tumor, such as overexpression of metallo-proteinases (MMPs). After demonstrating at molecular and protein level the MMP2 overexpression in such tumor microtissues, we used them to test a recently validated formulation of endogenous MMP2-responsive nanoparticles (NP). The presence of the MMP2-sensitive linker allows doxorubicin release from NP only upon specific enzymatic cleavage of the peptide. The same NP without the MMP-sensitive linker and healthy breast microtissues were also produced to demonstrate NP specificity and selectivity. Cell viability after NP treatment confirmed that controlled drug delivery is achieved only in 3D tumor microtissues suggesting that the validation of therapeutic strategies in such 3D tumor model could predict human response. Statement of significance A major issue of modern cancer research is the development of accurate and predictive experimental models of human tumors consistent with tumor microenvironment and applicable as screening platforms for novel therapeutic strategies. In this work, we developed and validated a new 3D microtissue model of human breast tumor as a testing platform of anti-cancer drug delivery systems. To this aim, biodegradable nanoparticles responsive to physiological changes specifically occurring in tumor microenvironment were used. Our findings clearly demonstrate that the breast tumor microtissue well recapitulates in vivo physiological features of tumor tissue and elicits a specific response to microenvironmentally-responsive nanoparticles compared to healthy tissue. We believe this study is of particular interest for cancer research and paves the way to exploit tumor microtissues for several testing purposes.
      Graphical abstract image

      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.004
  • Controlling nucleation and growth of nano-CaCO3 via CO2 sequestration by a
           calcium alkoxide solution to produce nanocomposites for drug delivery
    • Authors: N.G. Martin Palmqvist; Jean-Marie Nedelec; Gulaim A. Seisenbaeva; Vadim G. Kessler
      Abstract: Publication date: Available online 5 May 2017
      Source:Acta Biomaterialia
      Author(s): N.G. Martin Palmqvist, Jean-Marie Nedelec, Gulaim A. Seisenbaeva, Vadim G. Kessler
      Calcium carbonate is an extremely attractive material in a plethora of biomedical applications. Intensive efforts have recently been made to achieve the control over its nucleation and subsequent aggregation, growth and crystallization; focusing on bringing insight into the role of precursors, solvents and templates. Having analyzed the recently acquired knowledge, we addressed this challenge using CO2 sequestration synthesis, using an unusual reactant, a solution of calcium ethoxide, Ca(OC2H5)2, as precursor. By tailoring the reaction conditions, it was possible to produce extremely small and rather size-uniform single-phase calcite CaCO3 nanoparticles, forming sols and subsequently gels in the applied medium. According to DLS and Nanoparticle tracking analysis the particles are only to a minor extent aggregated in the mother liquor and can form transparent gels on concentration in less polar media, but produce large aggregates 400-800 nm in size when dried and subsequently transferred to aqueous media. Complete drying of solutions renders xerogel type materials with only moderate active surface area, as identified by nitrogen adsorption, due to aggregation with development of densified surface layers. Such behaviour is typical for the sol-gel synthesis of particles possessing enhanced surface reactivity. The aggregation on drying was used to produce hybrid nanocomposites, with the hydrophobic model component, β-carotene, introduced in solution in a non-polar co-solvent and model medicine - ibuprofen. The obtained nanocomposite particles, characterized by SEM, TEM, XRD, AFM and FTIR studies, are hierarchically structured spheroidal aggregates about 200 nm in size with uniform distribution of the organic components present in the amorphous state. The composite particles are stable in neutral aqueous environments but are readily dissolved in acidic medium or even in PBS at pH = 7.40, releasing the hydrophobic organic component in the form of a relatively stable colloid solution. Efficient release of ibuprofen as model drug was achieved in both acidic and PBS medium and could be slowed down by the addition of β-carotene as hydrophobic component. Statement of significance The proposed sol-gel synthesis of CaCO3 proved to create unprecedented size of CaCO3 nanoparticles with striking size uniformity. The obtained results clearly demonstrate their ability to incorporate hydrophobic components in a nanocomposite matrix converting them into amorphous nano sized particles, building stable colloids via release in acidic medium. Transfer of a sol produced in organic medium into water in the presence of albumen surfactant results in relatively uniform micro particles about 1 μm size. The obtained materials show characteristics attractive for use in drug delivery and potentially also a variety of other industrial applications.
      Graphical abstract image

      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.006
  • pH-triggered chitosan nanogels via an ortho ester-based linkage for
           efficient chemotherapy
    • Authors: Guanqing Yang; Xin Wang; Shengxiang Fu; Rupei Tang; Jun Wang
      Abstract: Publication date: Available online 4 May 2017
      Source:Acta Biomaterialia
      Author(s): Guanqing Yang, Xin Wang, Shengxiang Fu, Rupei Tang, Jun Wang
      Herein, we report a new type of chitosan-based nanogels via an ortho ester-based linkage, used as drug carriers for efficient chemotherapy. First, we synthesize a novel diacrylamide containing ortho ester (OEAM) as an acid-labile cross-linker. Subsequently, methacrylated succinyl-chitosan (MASCS) was prepared and polymerized with OEAM at different molar ratio to give a series of pH-triggered MASCS nanogels. Doxorubicin (DOX) as a model anticancer drug was loaded into MASCS nanogels with a loading content of 16.5%. As expected, with the incorporation of orthoester linkages, these nanogels showed pH-triggered degradation and drug release at acidic pH values. In vitro cellular uptake shows that the DOX-loaded nanogels could be preferentially internalized by two-dimensional (2D) cells and three-dimensional (3D) multicellular spheroids (MCs), resulting higher inhibition on the proliferation of tumor cells. In vivo biodistribution and anti-tumor effect were determined in H22 tumor-bearing mice, and the results demonstrate that the acid-labile MASCS nanogels can significantly prolong the blood circulation time of DOX and improve the accumulation in tumor areas, leading to higher therapeutic efficacy. Statement of Significance We design new pH-triggered chitosan nanogels via an ortho ester-based cross-linker for efficient drug-loading and chemotherapy. These drug-loaded nanogels exhibit excellent pH-triggered drug release behavior due to the degradation of ortho ester linkages at mildly acid environment. In vitro and in vivo results demonstrate that the nanogels could be efficiently internalized by 2D cells and 3D-MCs, improve drug concentration in solid tumor, and lead to higher therapeutic efficacy. To the best of our knowledge, this is the first report on using an ortho ester-based cross-linker to prepare pH-triggered chitosan nanogels as tumor carriers, which may provide a potential route for improved safety and to increase the therapeutic efficacy of anticancer therapy.
      Graphical abstract image

      PubDate: 2017-05-09T14:07:20Z
      DOI: 10.1016/j.actbio.2017.05.003
  • Manipulating the Membrane Penetration Mechanism of Helical Polypeptides
           via Aromatic Modification for Efficient Gene Delivery
    • Authors: Nan Zheng; Ziyuan Song; Jiandong Yang; Yang Liu; Fangfang Li; Jianjun Cheng; Lichen Yin
      Abstract: Publication date: Available online 3 May 2017
      Source:Acta Biomaterialia
      Author(s): Nan Zheng, Ziyuan Song, Jiandong Yang, Yang Liu, Fangfang Li, Jianjun Cheng, Lichen Yin
      The delivery performance of non-viral gene vectors is greatly related to their intracellular kinetics. Cationic helical polypeptides with potent membrane penetration properties and gene transfection efficiencies have been recently developed by us. However, they suffer from severe drawbacks in terms of their membrane penetration mechanisms that mainly include endocytosis and pore formation. The endocytosis mechanism leads to endosomal entrapment of gene cargos, while the charge- and helicity-induced pore formation causes appreciable cytotoxicity at high concentrations. With the attempt to overcome such critical challenges, we incorporated aromatic motifs into the design of helical polypeptides to enhance their membrane activities and more importantly, to manipulate their membrane penetration mechanisms. The aromatically modified polypeptides exhibited higher cellular internalization level than the unmodified analogue by up to 2.5 folds. Such improvement is possibly because aromatic domains promoted the polypeptides to penetrate cell membranes via direct transduction, a non-endocytosis and non-pore formation mechanism. As such, gene cargos were more efficiently delivered into cells by bypassing endocytosis and subsequently avoiding endosomal entrapment, and the material toxicity associated with excessive pore formation was also reduced. The top-performing aromatic polypeptide containing naphthyl side chains at the incorporated content of 20 mol% revealed notably higher transfection efficiencies than commercial reagents in melanoma cells in vitro (by 11.7 folds) and in vivo (by 9.1 folds), and thus found potential utilities toward topical gene delivery for cancer therapy. Statement of Significance Cationic helical polypeptides, as efficient gene delivery materials, suffer from severe drawbacks in terms of their membrane penetration mechanisms. The main cell penetration mechanisms involved are endocytosis and pore formation. However, the endocytosis mechanism has the limitation of endosomal entrapment of gene cargos, while the charge- and helicity-induced pore formation causes cytotoxicity at high concentrations. To address such critical issues toward the maximization of gene delivery efficiency, we incorporated aromatic domains into helical polypeptides to promote the cell membrane penetrations via direct transduction, which is a non-endocytosis and non-pore formation mechanism. The manipulation of their membrane penetration mechanisms allows gene cargos to be more efficiently delivered by bypassing endocytosis and subsequently avoiding endosomal entrapment.
      Graphical abstract image

      PubDate: 2017-05-04T12:57:27Z
      DOI: 10.1016/j.actbio.2017.05.001
  • Preparation and in vivo evaluation of cationic elastic liposomes
           comprising highly skin-permeable growth factors combined with hyaluronic
           acid for enhanced diabetic wound-healing therapy
    • Authors: Jeong Uk Choi; Seong Wook Lee; Rudra Pangeni; Youngro Byun; In-Soo Yoon; Jin Woo Park
      Abstract: Publication date: Available online 2 May 2017
      Source:Acta Biomaterialia
      Author(s): Jeong Uk Choi, Seong Wook Lee, Rudra Pangeni, Youngro Byun, In-Soo Yoon, Jin Woo Park
      To enhance the therapeutic effects of exogenous administration of growth factors (GFs) in the treatment of chronic wounds, we constructed GF combinations of highly skin-permeable epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and platelet-derived growth factor-A (PDGF-A). We genetically conjugated a low-molecular-weight protamine (LMWP) to the N-termini of these GFs to form LMWP-EGF, LMWP-IGF-I, and LMWP-PDGF-A. Subsequently, these molecules were complexed with hyaluronic acid (HA). Combinations of native or LMWP-fused GFs significantly promoted fibroblast proliferation and the synthesis of procollagen, with a magnification of these results observed after the GFs were complexed with HA. The optimal proportions of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and HA were 1, 1, 0.02, and 200, respectively. After confirming the presence of a synergistic effect, we incorporated the LMWP-fused GFs-HA complex into cationic elastic liposomes (ELs) of 107 ± 0.757 nm in diameter and a zeta potential of 56.5 ± 1.13 mV. The LMWP-fused GFs had significantly improved skin permeation compared with native GFs. The in vitro wound recovery rate of the LMWP-fused GFs-HA complex was 23% higher than that of cationic ELs composed of LMWP-fused GFs alone. Moreover, the cationic ELs containing the LMWP-fused GFs-HA complex significantly accelerated the wound closure rate in a diabetic mouse model and the wound size was maximally decreased by 65% and 58% compared to cationic ELs loaded with vehicle or native GFs-HA complex, respectively. Thus, topical treatment with cationic ELs loaded with the LMWP-fused GFs-HA complex synergistically enhanced the healing of chronic wounds, exerting both rapid and prolonged effects. Statement of Significance We believe that our study makes a significant contribution to the literature, because it demonstrated the potential application of cationic elastic liposomes as topical delivery systems for growth factors (GFs) that have certain limitations in their therapeutic effects (e.g., low percutaneous absorption of GFs at the lesion site and the requirement for various GFs at different healing stages). Topical treatment with cationic elastic liposomes loaded with highly skin-permeable low-molecular-weight protamine (LMWP)-fused GFs-hyaluronic acid (HA) complex synergistically enhanced the healing of diabetic wounds, exerting both rapid and prolonged effects.
      Graphical abstract image

      PubDate: 2017-05-04T12:57:27Z
      DOI: 10.1016/j.actbio.2017.04.034
  • Carbon Nanotube Capsules Enhance the In vivo Efficacy of Cisplatin
    • Authors: Adem Guven; Gabriel J. Villares; Susan G. Hilsenbeck; Alaina Lewis; John D. Landua; Lacey E. Dobrolecki; Lon J. Wilson; Michael T. Lewis
      Abstract: Publication date: Available online 2 May 2017
      Source:Acta Biomaterialia
      Author(s): Adem Guven, Gabriel J. Villares, Susan G. Hilsenbeck, Alaina Lewis, John D. Landua, Lacey E. Dobrolecki, Lon J. Wilson, Michael T. Lewis
      Over the past few years, numerous nanotechnology-based drug delivery systems have been developed in an effort to maximize therapeutic effectiveness of conventional drug delivery, while limiting undesirable side effects. Among these, carbon nanotubes (CNTs) are of special interest as potential drug delivery agents due to their numerous unique and advantageous physical and chemical properties. Here, we show in vivo favorable biodistribution and enhanced therapeutic efficacy of cisplatin (CDDP) encapsulated within ultra-short single-walled carbon nanotube capsules (CDDP@US-tubes) using three different human breast cancer xenograft models. In general, the CDDP@US-tubes demonstrated greater efficacy in suppressing tumor growth than free CDDP in both MCF-7 cell line xenograft and BCM-4272 patient-derived xenograft (PDX) models. The CDDP@US-tubes also demonstrated a prolonged circulation time compared to free CDDP which enhanced permeability and retention (EPR) effects resulting in significantly more CDDP accumulation in tumors, as determined by platinum (Pt) analysis via inductively-coupled plasma mass spectrometry (ICP-MS). Statement of Significance: Over the past decade, drug-loaded nanocarriers have been widely fabricated and studied to enhance tumor specific delivery. Among the diverse classes of nanomaterials, carbon nanotubes (CNTs), or more specifically ultra-short single-walled carbon nanocapsules (US-tubes), have been shown to be a popular, new platform for the delivery of various medical agents for both imaging and therapeutic purposes. Here, for the first time, we have shown that US-tubes can be utilized as a drug delivery platform in vivo to deliver the chemotherapeutic drug, cisplatin (CDDP) as CDDP@US-tubes. The studies have demonstrated the ability of the US-tube platform to promote the delivery of encapsulated CDDP by increasing the accumulation of drug in breast cancer resistance cells, which reveals how CDDP@US-tubes help overcome CDDP resistance.
      Graphical abstract image

      PubDate: 2017-05-04T12:57:27Z
      DOI: 10.1016/j.actbio.2017.04.035
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