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Publisher: Elsevier   (Total: 3051 journals)

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Showing 1 - 200 of 3048 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 7)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 24, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 86, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 30, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 358, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 226, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 24, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
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Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 4)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 6)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 21)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 133, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 26, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
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Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 9, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 6)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 43, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 42, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 50, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 22, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 8, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 62)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 2, SJR: 0.1, h-index: 2)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 362, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 16)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 43, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 326, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 411, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 16, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 40, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 54, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access   (Followers: 1)
Algal Research     Partially Free   (Followers: 8, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 46, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 49, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 40, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 9, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 26, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 46, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 200, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 59, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 26, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 24, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 35, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 58, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 12)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 165, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 12)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 168, SJR: 1.907, h-index: 126)

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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  [3051 journals]
  • Hierarchical structure and compressive deformation mechanisms of bighorn
           sheep (Ovis canadensis) horn
    • Authors: Wei Huang; Alireza Zaheri; Jae-Young Jung; Horacio D. Espinosa; Joanna Mckittrick
      Pages: 1 - 14
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Wei Huang, Alireza Zaheri, Jae-Young Jung, Horacio D. Espinosa, Joanna Mckittrick
      Bighorn sheep (Ovis canadensis) rams hurl themselves at each other at speeds of ∼9 m/s (20 mph) to fight for dominance and mating rights. This necessitates impact resistance and energy absorption mechanisms, which stem from material-structure components in horns. In this study, the material hierarchical structure as well as correlations between the structure and mechanical properties are investigated. The major microstructural elements of horns are found as tubules and cell lamellae, which are oriented with (∼30⁰) angle with respect to each other. The cell lamellae contain keratin cells, in the shape of pancakes, possessing an average thickness of ∼2 µm and diameter of ∼20–30 µm. The morphology of keratin cells reveals the presence of keratin fibers and intermediate filaments with diameter of ∼200 nm and ∼12 nm, respectively, parallel to the cell surface. Quasi-static and high strain rate impact experiments, in different loading directions and hydration states, revealed a strong strain rate dependency for both dried and hydrated conditions. A strong anisotropy behavior was observed under impact for the dried state. The results show that the radial direction is the most preferable impact orientation because of its superior energy absorption. Detailed failure mechanisms under the aforementioned conditions are examined by bar impact recovery experiments. Shear banding, buckling of cell lamellae, and delamination in longitudinal and transverse direction were identified as the cause for strain softening under high strain rate impact. While collapse of tubules occurs in both quasi-static and impact tests, in radial and transverse directions, the former leads to more energy absorption and impact resistance. Statement of Significance Bighorn sheep (Ovis canadensis) horns show remarkable impact resistance and energy absorption when undergoing high speed impact during the intraspecific fights. The present work illustrates the hierarchical structure of bighorn sheep horn at different length scales and investigates the energy dissipation mechanisms under different strain rates, loading orientations and hydration states. These results demonstrate how horn dissipates large amounts of energy, thus provide a new path to fabricate energy absorbent and crashworthiness engineering materials.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.043
      Issue No: Vol. 64 (2017)
       
  • Viscoelastic properties of α-keratin fibers in hair
    • Authors: Yang Yu; Wen Yang; Marc André Meyers
      Pages: 15 - 28
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Yang Yu, Wen Yang, Marc André Meyers
      Considerable viscoelasticity and strain-rate sensitivity are a characteristic of α-keratin fibers, which can be considered a biopolymer. The understanding of viscoelasticity is an important part of the knowledge of the overall mechanical properties of these biological materials. Here, horse and human hairs are examined to analyze the sources of this response. The dynamic mechanical response of α-keratin fibers over a range of frequencies and temperatures is analyzed using a dynamic mechanical analyzer. The α-keratin fibers behave more elastically at higher frequencies while they become more viscous at higher temperatures. A glass transition temperature of ∼55°C is identified. The stress relaxation behavior of α-keratin fibers at two strains, 0.02 and 0.25, is established and fit to a constitutive equation based on the Maxwell-Wiechert model. The constitutive equation is further compared to the experimental results within the elastic region and a good agreement is obtained. The two relaxation constants, 14s and 359s for horse hair and 11s and 207s for human hair, are related to two hierarchical levels of relaxation: the amorphous matrix-intermediate filament interfaces, for the short term, and the cellular components for the long term. Results of the creep test also provide important knowledge on the uncoiling and phase transformation of the α-helical structure as hair is uniaxially stretched. SEM results show that horse hair has a rougher surface morphology and damaged cuticles. It also exhibits a lower strain-rate sensitivity of 0.05 compared to that of 0.11 for human hair. After the horse and human hairs are chemically treated and the disulfide bonds are cleaved, they exhibit a similar strain-rate sensitivity of ∼0.05. FTIR results confirms that the human hair is more sensitive to the –S–S– cleavage, resulting in an increase of cysteic acid content. Therefore, the disulfide bonds in the matrix are experimentally identified as one source of the strain-rate sensitivity and viscoelasticity in α-keratin fibers. Statement of significance Hair has outstanding mechanical strength which is equivalent to metals on a density-normalized basis. It possesses, in addition to the strength, a large ductility that is enabled by either the unfolding of the alpha helices and/or the transformation of these helices to beta sheets. We identify the deformation and failure mechanisms and connect them to the hierarchical structure, with emphasis on the significant viscoelasticity of these unique biological materials.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.012
      Issue No: Vol. 64 (2017)
       
  • Temporal development of near-native functional properties and correlations
           with qMRI in self-assembling fibrocartilage treated with exogenous lysyl
           oxidase homolog 2
    • Authors: Pasha Hadidi; Derek D. Cissell; Jerry C. Hu; Kyriacos A. Athanasiou
      Pages: 29 - 40
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Pasha Hadidi, Derek D. Cissell, Jerry C. Hu, Kyriacos A. Athanasiou
      Advances in cartilage tissue engineering have led to constructs with mechanical integrity and biochemical composition increasingly resembling that of native tissues. In particular, collagen cross-linking with lysyl oxidase has been used to significantly enhance the mechanical properties of engineered neotissues. In this study, development of collagen cross-links over time, and correlations with tensile properties, were examined in self-assembling neotissues. Additionally, quantitative MRI metrics were examined in relation to construct mechanical properties as well as pyridinoline cross-link content and other engineered tissue components. Scaffold-free meniscus fibrocartilage was cultured in the presence of exogenous lysyl oxidase, and assessed at multiple time points over 8weeks starting from the first week of culture. Engineered constructs demonstrated a 9.9-fold increase in pyridinoline content, reaching 77% of native tissue values, after 8weeks of culture. Additionally, engineered tissues reached 66% of the Young’s modulus in the radial direction of native tissues. Further, collagen cross-links were found to correlate with tensile properties, contributing 67% of the tensile strength of engineered neocartilages. Finally, examination of quantitative MRI metrics revealed several correlations with mechanical and biochemical properties of engineered constructs. This study displays the importance of culture duration for collagen cross-link formation, and demonstrates the potential of quantitative MRI in investigating properties of engineered cartilages. Statement of Significance This is the first study to demonstrate near-native cross-link content in an engineered tissue, and the first study to quantify pyridinoline cross-link development over time in a self-assembling tissue. Additionally, this work shows the relative contributions of collagen and pyridinoline to the tensile properties of collagenous tissue for the first time. Furthermore, this is the first investigation to identify a relationship between qMRI metrics and the pyridinoline cross-link content of an engineered collagenous tissue.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.035
      Issue No: Vol. 64 (2017)
       
  • Indentation mapping revealed poroelastic, but not viscoelastic, properties
           spanning native zonal articular cartilage
    • Authors: Joseph A. Wahlquist; Frank W. DelRio; Mark A. Randolph; Aaron H. Aziz; Chelsea M. Heveran; Stephanie J. Bryant; Corey P. Neu; Virginia L. Ferguson
      Pages: 41 - 49
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Joseph A. Wahlquist, Frank W. DelRio, Mark A. Randolph, Aaron H. Aziz, Chelsea M. Heveran, Stephanie J. Bryant, Corey P. Neu, Virginia L. Ferguson
      Osteoarthrosis is a debilitating disease affecting millions, yet engineering materials for cartilage regeneration has proven difficult because of the complex microstructure of this tissue. Articular cartilage, like many biological tissues, produces a time-dependent response to mechanical load that is critical to cell’s physiological function in part due to solid and fluid phase interactions and property variations across multiple length scales. Recreating the time-dependent strain and fluid flow may be critical for successfully engineering replacement tissues but thus far has largely been neglected. Here, microindentation is used to accomplish three objectives: (1) quantify a material’s time-dependent mechanical response, (2) map material properties at a cellular relevant length scale throughout zonal articular cartilage and (3) elucidate the underlying viscoelastic, poroelastic, and nonlinear poroelastic causes of deformation in articular cartilage. Untreated and trypsin-treated cartilage was sectioned perpendicular to the articular surface and indentation was used to evaluate properties throughout zonal cartilage on the cut surface. The experimental results demonstrated that within all cartilage zones, the mechanical response was well represented by a model assuming nonlinear biphasic behavior and did not follow conventional viscoelastic or linear poroelastic models. Additionally, 10% (w/w) agarose was tested and, as anticipated, behaved as a linear poroelastic material. The approach outlined here provides a method, applicable to many tissues and biomaterials, which reveals and quantifies the underlying causes of time-dependent deformation, elucidates key aspects of material structure and function, and that can be used to provide important inputs for computational models and targets for tissue engineering. Statement of Significance Elucidating the time-dependent mechanical behavior of cartilage, and other biological materials, is critical to adequately recapitulate native mechanosensory cues for cells. We used microindentation to map the time-dependent properties of untreated and trypsin treated cartilage throughout each cartilage zone. Unlike conventional approaches that combine viscoelastic and poroelastic behaviors into a single framework, we deconvoluted the mechanical response into separate contributions to time-dependent behavior. Poroelastic effects in all cartilage zones dominated the time-dependent behavior of articular cartilage, and a model that incorporates tension–compression nonlinearity best represented cartilage mechanical behavior. These results can be used to assess the success of regeneration and repair approaches, as design targets for tissue engineering, and for development of accurate computational models.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.003
      Issue No: Vol. 64 (2017)
       
  • Constitutive modeling of human femoropopliteal artery biaxial stiffening
           due to aging and diabetes
    • Authors: Anastasia Desyatova; Jason MacTaggart; Alexey Kamenskiy
      Pages: 50 - 58
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Anastasia Desyatova, Jason MacTaggart, Alexey Kamenskiy
      Atherosclerotic obstructive disease of the femoropopliteal artery (Peripheral Arterial Disease, PAD) is notorious for high treatment failure rates. Older age and diabetes mellitus (DM) are among the major risk factors for PAD, and both are associated with increased arterial stiffness. Our goal was to develop a constitutive model describing multiaxial arterial stiffening, and use it to portray aging of normal and diabetic human femoropopliteal arteries (FPA). Fresh human FPAs (n=744) were obtained from 13–82-year-old donors. Arteries were tested using planar biaxial extension, and their behavior was modeled with a constitutive relation that included stiffening functions of age. FPA diameter, wall thickness, circumferential, and longitudinal opening angles increased with age, while longitudinal pre-stretch decreased. Diameter and circumferential opening angle did not change with age in subjects with DM. Younger FPAs were more compliant longitudinally but became more isotropic with age. Arteries with DM stiffened significantly faster in the circumferential direction than arteries without DM. Constitutive model accurately portrayed orthotropic stiffening with age of both normal and diabetic arteries. Constitutive description of FPA aging contributes to understanding of arterial pathophysiology and can help improve fidelity of computational models investigating device-artery interaction in PAD repair by providing more personalized arterial properties. Statement of Significance We have analyzed n=744 human femoropopliteal artery (FPA) specimens using biaxial tensile testing to derive constitutive description of FPA aging in diabetic and non-diabetic subjects. The proposed model allows determination of FPA mechanical properties for subjects of any given age in the range of 13–82years. These results contribute to understanding of FPA pathophysiology and can help improve fidelity of computational models investigating device-artery interaction in peripheral arterial disease repair by providing more personalized arterial properties. In addition, they can guide the development of new materials tunable to diabetic and non-diabetic arteries.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.042
      Issue No: Vol. 64 (2017)
       
  • Quantitative multiphoton microscopy of murine urinary bladder morphology
           during in situ uniaxial loading
    • Authors: Jack Hornsby; Donna M. Daly; David Grundy; Fangzhou Cheng; Anne M. Robertson; Paul N. Watton; Mark S. Thompson
      Pages: 59 - 66
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Jack Hornsby, Donna M. Daly, David Grundy, Fangzhou Cheng, Anne M. Robertson, Paul N. Watton, Mark S. Thompson
      Urodynamic tests are the gold standard for the diagnosis of bladder dysfunction, and the mechanical compliance of the bladder is an important parameter in these tests. The bladder wall has a layered structure, differentially affected by pathology, so knowledge of the contribution and role of these layers and their constituents to overall bladder compliance will enhance interpretation of these clinical tests. In this study we document the functional morphology of the detrusor and lamina propria of the murine bladder wall using a custom in-situ tensile loading system under multiphoton microscopy (MPM) observation in unloaded state and under incremental uniaxial stretch. Features in the stress-stretch curves of bladder samples were then directly related to corresponding MPM images. Collagen organisation across wall depth was quantified using image analysis techniques. The hypothesis that the lamina propria deformed at low strain by unfolding of the rugae and rearranging collagen fibrils was confirmed. A novel ‘pocket’ feature in the detrusor was observed along with extensive rearrangement of fibrils in two families at different depths, providing higher stiffness at high stretches in the detrusor. The very different deformations of detrusor and lamina propria were accommodated by the highly coiled structure of collagen in the lamina propria. Imaging and mechanical studies presented here allow gross mechanical response to be attributed to specific components of the bladder wall and further, may be used to investigate the impact of microstructural changes due to pathology or aging, and how they impair tissue functionality. Statement of Significance This article reports the first in-situ multiphoton microscopy observations of microstructural deformation under uniaxial tensile loading of ex vivo bladder. We describe collagen rearrangement through the tissue thickness and relate this directly to the stress-stretch behaviour. We confirm for the first time the unfolding of rugae and realignment of fibrils in the lamina propria during extension and the rapid stiffening as two fibril families in the detrusor are engaged. This technique provides new insight into microstructure function and will enhance understanding of the impact of changes due to pathology or aging.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.029
      Issue No: Vol. 64 (2017)
       
  • Elasticity-based development of functionally enhanced multicellular 3D
           liver encapsulated in hybrid hydrogel
    • Authors: Ho-Joon Lee; Myung Jin Son; Jiwon Ahn; Soo Jin Oh; Mihee Lee; Ansoon Kim; Yun-Ji Jeung; Han-Gyeul Kim; Misun Won; Jung Hwa Lim; Nam-Soon Kim; Cho-Rock Jung; Kyung-Sook Chung
      Pages: 67 - 79
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Ho-Joon Lee, Myung Jin Son, Jiwon Ahn, Soo Jin Oh, Mihee Lee, Ansoon Kim, Yun-Ji Jeung, Han-Gyeul Kim, Misun Won, Jung Hwa Lim, Nam-Soon Kim, Cho-Rock Jung, Kyung-Sook Chung
      Current in vitro liver models provide three-dimensional (3-D) microenvironments in combination with tissue engineering technology and can perform more accurate in vivo mimicry than two-dimensional models. However, a human cell-based, functionally mature liver model is still desired, which would provide an alternative to animal experiments and resolve low-prediction issues on species differences. Here, we prepared hybrid hydrogels of varying elasticity and compared them with a normal liver, to develop a more mature liver model that preserves liver properties in vitro. We encapsulated HepaRG cells, either alone or with supporting cells, in a biodegradable hybrid hydrogel. The elastic modulus of the 3D liver dynamically changed during culture due to the combined effects of prolonged degradation of hydrogel and extracellular matrix formation provided by the supporting cells. As a result, when the elastic modulus of the 3D liver model converges close to that of the in vivo liver (≅ 2.3 to 5.9 kPa), both phenotypic and functional maturation of the 3D liver were realized, while hepatic gene expression, albumin secretion, cytochrome p450-3A4 activity, and drug metabolism were enhanced. Finally, the 3D liver model was expanded to applications with embryonic stem cell-derived hepatocytes and primary human hepatocytes, and it supported prolonged hepatocyte survival and functionality in long-term culture. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. Statement of Significance We provide a functionally improved 3D liver model that recapitulates in vivo liver stiffness. We have experimentally addressed the issues of orchestrated effects of mechanical compliance, controlled matrix formation by stromal cells in conjunction with hepatic differentiation, and functional maturation of hepatocytes in a dynamic 3D microenvironment. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. Additionally, recent advances in the stem-cell technologies have made the development of 3D organoid possible, and thus, our study also provides further contribution to the development of physiologically relevant stem-cell-based 3D tissues that provide an elasticity-based predefined biomimetic 3D microenvironment.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.041
      Issue No: Vol. 64 (2017)
       
  • Peritoneal pre-conditioning reduces macrophage marker expression in
           collagen-containing engineered vascular grafts
    • Authors: Mozhgan Shojaee; Kristin B. Wood; Lisa K. Moore; Chris A. Bashur
      Pages: 80 - 93
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Mozhgan Shojaee, Kristin B. Wood, Lisa K. Moore, Chris A. Bashur
      Engineered vascular grafts have shown promise as arteriovenous shunts, but they have not yet progressed to clinical trials for coronary arteries <4 mm in diameter such as the coronary arteries. Control over initial biomaterial properties and remodeling are necessary to generate viable grafts. In this study, we blended collagen with a synthetic material, poly(ε-caprolactone), to modulate the post-grafting inflammatory response while avoiding aneurysmal-like dilation and failure that can occur with pure collagen grafts. We also used pre-implantation in an “in vivo bioreactor” to recruit autologous cells and improve patency after grafting. Electrospun conduits were pre-implanted within rat peritoneal cavities and then grafted autologously into abdominal aortae. Conduit collagen percentages and pre-implantation were tested for their impact on graft remodeling and patency. Burst pressures >2000 mmHg, reproducible expansion with systole/diastole, and maintenance of mechanical integrity were observed. More importantly, peritoneal pre-implantation reduced overall lipid oxidation, intimal layer thickness, and expression of an M1 macrophage marker. The condition with the most collagen, 25%, exhibited the lowest expression of macrophage markers but also resulted in a thicker intimal layer. Overall, the 10% collagen/PCL with peritoneal pre-implantation condition appeared to exhibit the best combination of responses, and may result in improved clinical graft viability. Statement of Significance This manuscript describes a rodent study to systematically determine the benefits of both pre-implantation in the peritoneal cavity and specific ratios of collagen on engineered vascular graft viability. We show that pre-implantation had a significant benefit, including decreasing the expression of macrophage markers and reducing lipid oxidation after grafting. This study is the first time that the benefits of peritoneal pre-implantation have been compared to an “off the shelf,” directly grafted control condition. We also demonstrated the importance of specific collagen ratio on the response after grafting. Overall, we feel that this article will be of interest to the field and it has the potential to address a significant clinical need: a graft for coronary arteries <4 mm in diameter.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.006
      Issue No: Vol. 64 (2017)
       
  • Chitosan-doxycycline hydrogel: An MMP inhibitor/sclerosing embolizing
           agent as a new approach to endoleak prevention and treatment after
           endovascular aneurysm repair
    • Authors: Fatemeh Zehtabi; Pompilia Ispas-Szabo; Djahida Djerir; Lojan Sivakumaran; Borhane Annabi; Gilles Soulez; Mircea Alexandru Mateescu; Sophie Lerouge
      Pages: 94 - 105
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Fatemeh Zehtabi, Pompilia Ispas-Szabo, Djahida Djerir, Lojan Sivakumaran, Borhane Annabi, Gilles Soulez, Mircea Alexandru Mateescu, Sophie Lerouge
      The success of endovascular repair of abdominal aortic aneurysms remains limited due to the development of endoleaks. Sac embolization has been proposed to manage endoleaks, but current embolizing materials are associated with frequent recurrence. An injectable agent that combines vascular occlusion and sclerosing properties has demonstrated promise for the treatment of endoleaks. Moreover, the inhibition of aneurysmal wall degradation via matrix metalloproteinases (MMPs) may further prevent aneurysm progression. Thus, an embolization agent that promotes occlusion, MMP inhibition and endothelial ablation was hypothesized to provide a multi-faceted approach for endoleak treatment. In this study, an injectable, occlusive chitosan (CH) hydrogel containing doxycycline (DOX)—a sclerosant and MMP inhibitor—was developed. Several CH-DOX hydrogel formulations were characterized for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo. All formulations were injectable and gelled rapidly at body temperature. Only hydrogels prepared with 0.075M sodium bicarbonate and 0.08M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel was in a two-stage pattern: a burst release followed by a slow continuous release. Released DOX was bioactive and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appear to be promising new multifunctional embolic agents for the treatment of endoleaks. Statement of Significance An injectable embolizing chitosan hydrogel releasing doxycycline (DOX) was developed as the first multi-faceted approach for the occlusion of blood vessels. It combines occlusive properties with DOX sclerosing and MMP inhibition properties, respectively known to prevent recanalization process and to counteract the underlying pathophysiology of vessel wall degradation and aneurysm progression. After drug release, the biocompatible scaffold can be invaded by cells and slowly degrade. Local DOX delivery requires lower drug amount and decreases risks of side effects compared to systemic administration. This new gel could be used for the prevention or treatment of endoleaks after endovascular aneurysm repair, but also for the embolization of other blood vessels such as venous or vascular malformations.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.021
      Issue No: Vol. 64 (2017)
       
  • Entirely S-protected chitosan: A promising mucoadhesive excipient for
           metronidazole vaginal tablets
    • Authors: Noemi Lupo; Benjamin Fodor; Ijaz Muhammad; Muhammad Yaqoob; Barbara Matuszczak; Andreas Bernkop-Schnürch
      Pages: 106 - 115
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Noemi Lupo, Benjamin Fodor, Ijaz Muhammad, Muhammad Yaqoob, Barbara Matuszczak, Andreas Bernkop-Schnürch
      Aim Synthesis and evaluation of an entirely S-protected chitosan as mucoadhesive excipient for vaginal drug delivery. Methods N-acetyl-cysteine was linked to 6-mercaptonicotinamide via disulphide exchange reaction. The obtained ligand, NAC-6-MNA, was subsequently attached to chitosan by carbodiimide mediated amide bond formation in two concentrations. The synthesized S-protected chitosan was chemically characterized and mucoadhesive properties and stability against oxidation were investigated. Moreover, metronidazole tablets comprising the S-protected chitosan were evaluated regarding water uptake capacity, disintegration behaviour, residence time on vaginal mucosa, release of the encapsulated drug and antimicrobial activity. Results S-protected chitosan displayed 160±19 (CS-MNA-160) and 320±38 (CS-MNA-320)µmol of ligand per gram of polymer. At pH 4.2, CS-MNA-160 and CS-MNA-320 showed 5.2-fold and 6.2-fold increase in mucus viscosity in comparison to unmodified chitosan (One-way ANOVA, p <.001), whereas, 9.9-fold (CS-MNA-160) and 15.6-fold (CS-MNA-320) (One-way ANOVA, p <.001) increase in viscosity was measured at pH 6. The S-protected chitosan remained stable against oxidation in presence of 0.5%v/v hydrogen peroxide. Metronidazole tablets consisting in S-protected chitosan showed prolonged residence time on vaginal mucosa and improved water uptake capacity and disintegration time in comparison to tablets consisting of unmodified chitosan. Moreover, CS-MNA-320 metronidazole tablets displayed prolonged drug release and antimicrobial activity. Conclusions On the basis of the achieved results, entirely S-protected chitosan represents a promising excipient for the development of metronidazole vaginal tablets. Statement of Significance S-protected thiomers are polymers modified with thiol groups protected by aromatic ligands and characterized by strong mucoadhesive properties and high stability against oxidation. Up to date, the entirely S-protection of thiol groups was achieved via the synthesis of the ligand 2-((2-amino-2-carboxyethyl)disulfanyl)nicotinic acid) which can be directly bound to the backbone of polymers bearing carboxylic moieties as pectin. However, this ligand is not suitable for positively charged polymers due to the negative charge. In this paper, the synthesis of a suitable ligand for the entirely S-protection of positively charged polymers is presented. The first entirely S-protected chitosan was synthesized, characterized and its mucoadhesive properties were assessed. Moreover, metronidazole tablets comprising the entirely S-protected chitosan were developed and evaluated as vaginal drug delivery system.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.014
      Issue No: Vol. 64 (2017)
       
  • In situ depot formation of anti-HIV fusion-inhibitor peptide in
           recombinant protein polymer hydrogel
    • Authors: Daisuke Asai; Taisei Kanamoto; Mitsuko Takenaga; Hideki Nakashima
      Pages: 116 - 125
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Daisuke Asai, Taisei Kanamoto, Mitsuko Takenaga, Hideki Nakashima
      Most peptide drugs have short half-lives, necessitating frequent injections that may induce skin sensitivity reactions; therefore, versatile prolonged-release delivery platforms are urgently needed. Here, we focused on an oxidatively and thermally responsive recombinant elastin-like polypeptide with periodic cysteine residues (cELP), which can rapidly and reversibly form a disulfide cross-linked network in which peptide can be physically incorporated. As a model for proof of concept, we used enfuvirtide, an antiretroviral fusion-inhibitor peptide approved for treatment of human immunodeficiency virus (HIV) infection. cELP was mixed with enfuvirtide and a small amount of hydrogen peroxide (to promote cross-linking), and the soluble mixture was injected subcutaneously. The oxidative cross-linking generates a network structure, causing the mixture to form a hydrogel in situ that serves as an enfuvirtide depot. We fabricated a series of enfuvirtide-containing hydrogels and examined their stability, enfuvirtide-releasing profile and anti-HIV potency in vitro. Among them, hydrophobic cELP hydrogel provided effective concentrations of enfuvirtide in blood of rats for up to 8 h, and the initial concentration peak was suppressed compared with that after injection of enfuvirtide alone. cELP hydrogels should be readily adaptable as platforms to provide effective depot systems for delivery of other anti-HIV peptides besides enfuvirtide. Statement of Significance In this paper, we present an anti-HIV peptide delivery system using oxidatively and thermally responsive polypeptides that contain multiple periodic cysteine residues as an injectable biomaterial capable of in situ self-gelation, and we demonstrate its utility as an injectable depot capable of sustained release of anti-HIV peptides. The novelty of this work stems from the platform employed to provide the depot encapsulating the peptide drugs (without chemical conjugation), which consists of rationally designed, genetically engineered polypeptides that enable the release rate of the peptide drugs to be precisely controlled.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.024
      Issue No: Vol. 64 (2017)
       
  • Electrospun formulations of bevacizumab for sustained release in the eye
    • Authors: Ukrit Angkawinitwong; Sahar Awwad; Peng T. Khaw; Steve Brocchini; Gareth R. Williams
      Pages: 126 - 136
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Ukrit Angkawinitwong, Sahar Awwad, Peng T. Khaw, Steve Brocchini, Gareth R. Williams
      Medicines based on vascular endothelial growth factor (VEGF) neutralising antibodies such as bevacizumab have revolutionized the treatment of age related macular degeneration (AMD), a common blinding disease, and have great potential in preventing scarring after surgery or accelerating the healing of corneal injuries. However, at present frequent invasive injections are required to deliver these antibodies. Such administration is uncomfortable for patients and expensive for health service providers. Much effort is thus focused on developing dosage forms that can be administered less frequently. Here we use electrospinning to prepare a solid form of bevacizumab designed for prolonged release while maintaining antibody stability. Electrospun fibers were prepared with bevacizumab encapsulated in the core, surrounded by a poly-ε-caprolactone sheath. The fibers were generated using aqueous bevacizumab solutions buffered at two different pH values: 6.2 (the pH of the commercial product; Fbeva) and 8.3 (the isoelectric point of bevacizumab; FbevaP). The fibers had smooth and cylindrical morphologies, with diameters of ca. 500nm. Both sets of bevacizumab loaded fibers gave sustained release profiles in an in vitro model of the subconjunctival space of the eye. Fbeva displayed first order kinetics with t 1/2 of 11.4±4.4 days, while FbevaP comprises a zero-order reservoir type release system with t 1/2 of 52.9±14.8 days. Both SDS-PAGE and surface plasmon resonance demonstrate that the bevacizumab in FbevaP did not undergo degradation during fiber fabrication or release. In contrast, the antibody released from Fbeva had degraded, and failed to bind to VEGF. Our results demonstrate that pH control is crucial to maintain antibody stability during the fabrication of core/shell fibers and ensure release of functional protein. Statement of Significance Bevacizumab is a potent protein drug which is highly effective in the treatment of degenerative conditions in the eye. To be effective, frequent injections into the eye are required, which is deeply unpleasant for patients and expensive for healthcare providers. Alternative methods of administration are thus highly sought after. In our work, we use the electrospinning technique to prepare fiber-based formulations loaded with bevacizumab. By careful control of the experimental parameters we are able to stabilize the protein during processing and ensure a constant rate of release over more than two months in vitro. These fibers could thus be used to reduce the frequency of dosing required, reducing cost and improving patient outcomes.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.015
      Issue No: Vol. 64 (2017)
       
  • Electrospraying of microfluidic encapsulated cells for the fabrication of
           cell-laden electrospun hybrid tissue constructs
    • Authors: L. Weidenbacher; A. Abrishamkar; M. Rottmar; A.G. Guex; K. Maniura-Weber; A.J. deMello; S.J. Ferguson; R.M. Rossi; G. Fortunato
      Pages: 137 - 147
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): L. Weidenbacher, A. Abrishamkar, M. Rottmar, A.G. Guex, K. Maniura-Weber, A.J. deMello, S.J. Ferguson, R.M. Rossi, G. Fortunato
      The fabrication of functional 3D tissues is a major goal in tissue engineering. While electrospinning is a promising technique to manufacture a structure mimicking the extracellular matrix, cell infiltration into electrospun scaffolds remains challenging. The robust and in situ delivery of cells into such biomimetic scaffolds would potentially enable the design of tissue engineered constructs with spatial control over cellular distribution but often solvents employed in the spinning process are problematic due to their high cytotoxicity. Herein, microfluidic cell encapsulation is used to establish a temporary protection vehicle for the in situ delivery of cells for the development of a fibrous, cell-laden hybrid biograft. Therefore a layer-by-layer process is used by alternating fiber electrospinning and cell spraying procedures. Both encapsulation and subsequent electrospraying of capsules has no negative effect on the viability and myogenic differentiation of murine myoblast cells. Propidium iodide positive stained cells were analyzed to quantify the amount of dead cells and the presence of myosin heavy chain positive cells after the processes was shown. Furthermore, encapsulation successfully protects cells from cytotoxic solvents (such as dimethylformamide) during in situ delivery of the cells into electrospun poly(vinylidene fluoride-co-hexafluoropropylene) scaffolds. The resulting cell-populated biografts demonstrate the clear potential of this approach in the creation of viable tissue engineering constructs. Statement of Significance Infiltration of cells and their controlled spatial distribution within fibrous electrospun membranes is a challenging task but allows for the development of functional highly organized 3D hybrid tissues. Combining polymer electrospinning and cell electrospraying in a layer-by-layer approach is expected to overcome current limitations of reduced cell infiltration after traditional static seeding. However, organic solvents, used during the electrospinning process, impede often major issues due to their high cytotoxicity. Utilizing microfluidic encapsulation as a mean to embed cells within a protective polymer casing enables the controlled deposition of viable cells without interfering with the cellular phenotype. The presented techniques allow for novel cell manipulation approaches being significant for enhanced 3D tissue engineering based on its versatility in terms of material and cell selection.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.012
      Issue No: Vol. 64 (2017)
       
  • Modulating microfibrillar alignment and growth factor stimulation to
           regulate mesenchymal stem cell differentiation
    • Authors: Dinorath Olvera; Binulal N. Sathy; Simon F. Carroll; Daniel J. Kelly
      Pages: 148 - 160
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Dinorath Olvera, Binulal N. Sathy, Simon F. Carroll, Daniel J. Kelly
      The ideal tissue engineering (TE) strategy for ligament regeneration should recapitulate the bone – calcified cartilage – fibrocartilage – soft tissue interface. Aligned electrospun-fibers have been shown to guide the deposition of a highly organized extracellular matrix (ECM) necessary for ligament TE. However, recapitulating the different tissues observed in the bone-ligament interface using such constructs remains a challenge. This study aimed to explore how fiber alignment and growth factor stimulation interact to regulate the chondrogenic and ligamentous differentiation of mesenchymal stem cells (MSCs). To this end aligned and randomly-aligned electrospun microfibrillar scaffolds were seeded with bone marrow derived MSCs and stimulated with transforming growth factor β3 (TGFβ3) or connective tissue growth factor (CTGF), either individually or sequentially. Without growth factor stimulation, MSCs on aligned-microfibers showed higher levels of tenomodulin (TNMD) and aggrecan gene expression compared to MSCs on randomly-oriented fibers. MSCs on aligned-microfibers stimulated with TGFβ3 formed cellular aggregates and underwent robust chondrogenesis, evidenced by increased type II collagen expression and sulphated glycosaminoglycans (sGAG) synthesis compared to MSCs on randomly-oriented scaffolds. Bone morphogenetic protein 2 (BMP2) and type I collagen gene expression were higher on randomly-oriented scaffolds stimulated with TGFβ3, suggesting this substrate was more supportive of an endochondral phenotype. In the presence of CTGF, MSCs underwent ligamentous differentiation, with increased TNMD expression on aligned compared to randomly aligned scaffolds. Upon sequential growth factor stimulation, MSCs expressed types I and II collagen and deposited higher overall levels of collagen compared to scaffolds stimulated with either growth factor in isolation. These findings demonstrate that modulating the alignment of microfibrillar scaffolds can be used to promote either an endochondral, chondrogenic, fibrochondrogenic or ligamentous MSC phenotype upon presentation of appropriate biochemical cues. Statement of Significance Polymeric electrospun fibers can be tuned to match the fibrillar size and anisotropy of collagen fibers in ligaments, and can be mechanically competent. Therefore, their use is attractive when attempting to tissue engineer the bone-ligament interface. A central challenge in this field is recapitulating the cellular phenotypes observed across the bone-ligament interface. Here we demonstrated that it is possible to direct MSCs seeded onto aligned electrospun fibres towards either a ligamentogenic, chondrogenic or fibrochondrogenic phenotype upon presentation of appropriate biochemical cues. This opens the possibility of using aligned microfibrillar scaffolds that are spatially functionalized with specific growth factors to direct MSC differentiation for engineering the bone-ligament interface.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.010
      Issue No: Vol. 64 (2017)
       
  • Hybrid-spheroids incorporating ECM like engineered fragmented fibers
           potentiate stem cell function by improved cell/cell and cell/ECM
           interactions
    • Authors: Taufiq Ahmad; Jinkyu Lee; Young Min Shin; Hyeok Jun Shin; Sajeesh Kumar Madhurakat Perikamana; Sun Hwa Park; Sung Won Kim; Heungsoo Shin
      Pages: 161 - 175
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Taufiq Ahmad, Jinkyu Lee, Young Min Shin, Hyeok Jun Shin, Sajeesh Kumar Madhurakat Perikamana, Sun Hwa Park, Sung Won Kim, Heungsoo Shin
      Extracellular matrix (ECM) microenvironment is critical for the viability, stemness, and differentiation of stem cells. In this study, we developed hybrid-spheroids of human turbinate mesenchymal stem cells (hTMSCs) by using extracellular matrix (ECM) mimicking fragmented fibers (FFs) for improvement of the viability and functions of hTMSCs. We prepared FFs with average size of 68.26 µm by partial aminolysis of poly L-lactide (PLLA) fibrous sheet (FS), which was coated with polydopamine for improved cell adhesion. The proliferation of hTMSCs within the hybrid-spheroids mixed with fragmented fibers was significantly increased as compared to that from the cell-only group. Cells and fragmented fibers were homogenously distributed with the presence of pore like empty spaces in the structure. LOX-1 staining revealed that the hybrid-spheroids improved the cell viability, which was potentially due to enhanced transport of oxygen through void space generated by engineered ECM. Transmission electron microscopy (TEM) analysis confirmed that cells within the hybrid-spheroid formed strong cell junctions and contacts with fragmented fibers. The expression of cell junction proteins including connexin 43 and E-cadherin was significantly upregulated in hybrid-spheroids by 16.53 ± 0.04 and 28.26 ± 0.11-fold greater than that from cell-only group. Similarly, expression of integrin α2, α5, and β1 was significantly enhanced at the same group by 25.72 ± 0.13, 27.48 ± 0.49, and 592.78 ± 0.06-fold, respectively. In addition, stemness markers including Oct-4, Nanog, and Sox2 were significantly upregulated in hybrid-spheroids by 96.56 ± 0.06, 158.95 ± 0.06, and 115.46 ± 0.47-fold, respectively, relative to the cell-only group. Additionally, hTMSCs within the hybrid-spheroids showed significantly greater osteogenic differentiation under osteogenic media conditions. Taken together, our hybrid-spheroids can be an ideal approach for stem cell expansion and serve as a potential carrier for bone regeneration. Statement of Significance Cells are spatially arranged within extracellular matrix (ECM) and cell/ECM interactions are crucial for cellular functions. Here, we developed a hybrid-spheroid system incorporating engineered ECM prepared from fragmented electrospun fibers to tune stem cell functions. Conventionally prepared cell spheroids with large diameters (>200 µm) is often prone to hypoxia. In contrast, the hybrid-spheroids significantly enhanced viability and proliferation of human turbinate mesenchymal stem cells (hTMSCs) as compared to spheroid prepared from cell only. Under these conditions, the presence of fragmented fibers also improved maintenance of stemness of hTMSCs for longer time cultured in growth media and demonstrated significantly greater osteogenic differentiation under osteogenic media conditions. Thus, the hybrid-spheroids can be used as a delivery carrier for stem cell based therapy or a 3D culture model for in vitro assay.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.022
      Issue No: Vol. 64 (2017)
       
  • Engineering fibrin hydrogels to promote the wound healing potential of
           mesenchymal stem cell spheroids
    • Authors: Kaitlin C. Murphy; Jacklyn Whitehead; Dejie Zhou; Steve S. Ho; J. Kent Leach
      Pages: 176 - 186
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Kaitlin C. Murphy, Jacklyn Whitehead, Dejie Zhou, Steve S. Ho, J. Kent Leach
      Mesenchymal stem cells (MSCs) secrete endogenous factors such as vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2) that promote angiogenesis, modulate the inflammatory microenvironment, and stimulate wound repair, and MSC spheroids secrete more trophic factors than dissociated, individual MSCs. Compared to injection of cells alone, transplantation of MSCs in a biomaterial can enhance their wound healing potential by localizing cells at the defect site and upregulating trophic factor secretion. To capitalize on the therapeutic potential of spheroids, we engineered a fibrin gel delivery vehicle to simultaneously enhance the proangiogenic and anti-inflammatory potential of entrapped human MSC spheroids. We used multifactorial statistical analysis to determine the interaction between four input variables derived from fibrin gel synthesis on four output variables (gel stiffness, gel contraction, and secretion of VEGF and PGE2). Manipulation of the four input variables tuned fibrin gel biophysical properties to promote the simultaneous secretion of VEGF and PGE2 by entrapped MSC spheroids while maintaining overall gel integrity. MSC spheroids in stiffer gels secreted the most VEGF, while PGE2 secretion was highest in more compliant gels. Simultaneous VEGF and PGE2 secretion was greatest using hydrogels with intermediate mechanical properties, as small increases in stiffness increased VEGF secretion while maintaining PGE2 secretion by entrapped spheroids. The fibrin gel formulation predicted to simultaneously increase VEGF and PGE2 secretion stimulated endothelial cell proliferation, enhanced macrophage polarization, and promoted angiogenesis when used to treat a wounded three-dimensional human skin equivalent. These data demonstrate that a statistical approach is an effective strategy to formulate fibrin gel formulations that enhance the wound healing potential of human MSCs. Statement of Significance Mesenchymal stem cells (MSCs) are under investigation for wound healing applications due to their secretion of bioactive factors that enhance granulation tissue formation, blood vessel ingrowth, and reduce inflammation. However, the effectiveness of cell-based therapies is reduced due to poor engraftment and high rates of cell death when transplanted into harsh environments characteristic of large wounds. Compared to dissociated cells, MSCs exhibit increased overall function when aggregated into three-dimensional spheroids, and transplantation of cells using biomaterials is one strategy for guiding cell function in the defect site. The present study demonstrates that the biophysical properties of fibrin hydrogels, designed for use as a cell carrier, can be engineered to dictate the secretion of bioactive factors by entrapped MSC spheroids. This strategy enables MSCs to contribute to wound healing by synergistically promoting neovascularization and modulating the inflammatory milieu.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.007
      Issue No: Vol. 64 (2017)
       
  • Galloyl groups-regulated fibrinogen conformation: Understanding
           antiplatelet adhesion on tannic acid coating
    • Authors: Liwei Yang; Lulu Han; Qi Liu; Yige Xu; Lingyun Jia
      Pages: 187 - 199
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Liwei Yang, Lulu Han, Qi Liu, Yige Xu, Lingyun Jia
      Fibrinogen (Fgn) has been identified as the key protein in the process of biomaterial-induced platelet adhesion. We have recently reported a facile and effective method for constructing platelet-repellent surface using a natural polyphenol component tannic acid (TA). However, the mechanism by which the TA surface repels platelets was not fully understood. To address this issue, we investigated the adsorption of Fgn (amount and conformation) on four TA-functionalized surfaces with different amounts of galloyl groups and the potential for platelet adherence on these surfaces. The experimental results indicated that the four TA-functionalized surfaces adsorbed a similar amount of Fgn, but the conformation and bioactivity of the adsorbed Fgn and the subsequent platelet adherence were quite different among the surfaces. The TA surface with the most galloyl groups induced minimal changes in the conformation of Fgn, a result of the α and γ chains of the adsorbed Fgn being highly inactive on the surface, thus leading to an outstanding antiplatelet adhesion performance. With a decreased amount of galloyl groups, the activity of the α chain in the adsorbed Fgn remained unchanged, but the activity of the γ chain and the extent of platelet adhesion gradually increased. This work provided a new concept for controlling platelet adhesion on solid materials, and we envision that the TA film could have potential applications in the development of new blood-contacting biomaterials in the future. Statement of Significance Reducing platelet adhesion on material surfaces is of tremendous scientific interest in the field of blood-contacting biomaterials, but it remains a big challenge due to the highly adhesive nature of the platelets. In this study, we demonstrated for the first time that tannic acid surface with abundant galloyl groups could induce minimal conformational changes of fibrinogen, eventually leading to an outstanding antiplatelet adhesion effect. In addition, the platelet adhesion response could be easily controlled through regulating the amount of galloyl groups on the surface. This work provided a new strategy for controlling platelet adhesion on solid materials, which was totally different from existing methods such as construction of physically patterned surfaces, modification of inert hydrophilic polymers or appending bioactive moieties to target surfaces.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.034
      Issue No: Vol. 64 (2017)
       
  • Coating of silicone with mannoside-PAMAM dendrimers to enhance formation
           of non-pathogenic Escherichia coli biofilms against colonization of
           uropathogens
    • Authors: Zhiling Zhu; Fei Yu; Haoqing Chen; Jun Wang; Analette I. Lopez; Quan Chen; Siheng Li; Yuyu Long; Rabih O. Darouiche; Richard A. Hull; Lijuan Zhang; Chengzhi Cai
      Pages: 200 - 210
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Zhiling Zhu, Fei Yu, Haoqing Chen, Jun Wang, Analette I. Lopez, Quan Chen, Siheng Li, Yuyu Long, Rabih O. Darouiche, Richard A. Hull, Lijuan Zhang, Chengzhi Cai
      Bacterial interference using non-pathogenic Escherichia coli 83972 is a novel strategy for preventing catheter-associated urinary tract infection (CAUTI). Crucial to the success of this strategy is to establish a high coverage and stable biofilm of the non-pathogenic bacteria on the catheter surface. However, this non-pathogenic strain is sluggish to form biofilms on silicone as the most widely used material for urinary catheters. We have addressed this issue by modifying the silicone catheter surfaces with mannosides that promote the biofilm formation, but the stability of the non-pathogenic biofilms challenged by uropathogens over long-term remains a concern. Herein, we report our study on the stability of the non-pathogenic biofilms grown on propynylphenyl mannoside-modified silicone. The result shows that 94% non-pathogenic bacteria were retained on the modified silicone under >0.5 Pa shear stress. After being challenged by three multidrug-resistant uropathogenic isolates in artificial urine for 11 days, large amounts (>4 × 106 CFU cm−2) of the non-pathogenic bacteria remained on the surfaces. These non-pathogenic biofilms reduced the colonization of the uropathogens by >3.2-log. Statement of Significance In bacterial interference, the non-pathogenic Escherichia coli strains are sluggish to form biofilms on the catheter surfaces, due to rapid removal by urine flow. We have demonstrated a solution to this bottleneck by pre-functionalization of mannosides on the silicone surfaces to promote E. coli biofilm formation. A pre-conjugated high affinity propynylphenyl mannoside ligand tethered to the nanometric amino-terminated poly(amido amine) (PAMAM) dendrimer is used for binding to a major E. coli adhesin FimH. It greatly improves the efficiency for the catheter modification, the non-pathogenic biofilm coverage, as well as the (long-term) stability for prevention of uropathogen infections.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.008
      Issue No: Vol. 64 (2017)
       
  • mPEGylated solanesol micelles as redox-responsive nanocarriers with
           synergistic anticancer effect
    • Authors: Benkai Qin; Lei Liu; Xiaohe Wu; Fengguang Liang; Tian Hou; Yangyang Pan; Shiyong Song
      Pages: 211 - 222
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Benkai Qin, Lei Liu, Xiaohe Wu, Fengguang Liang, Tian Hou, Yangyang Pan, Shiyong Song
      We prepared an amphiphilic redox-responsive conjugate based on mPEGylated solanesol, solanesyl poly(ethylene glycol) dithiodipropionate (SPDP), along with its inert counterpart solanesyl poly(ethylene glycol) succinate (SPGS), which self-assembled in aqueous solution to form redox-responsive micelles. Used as efficient drug carriers for doxorubicin (DOX), the micelles acted as synergistic agents for cancer therapy. Dynamic light scattering (DLS) measurements showed that the SPDP micelles had average diameters of 111nm, which decreased to 88nm after the encapsulation of DOX. The mean diameters and size distribution of the disulfide-containing micelles changed obviously in the presence of the reducing agent glutathione (GSH), whereas no changes occurred in the case of redox-insensitive SPGS micelles. DOX could be loaded into both types of micelles, with drug loading content of about 4.0%. A significantly accelerated release of DOX was triggered by GSH for DOX-loaded SPDP micelles, compared with DOX-loaded SPGS micelles. Blank SPGS and SPDP micelles displayed higher inhibition of HeLa and MCF-7 cell proliferation but less cytotoxicity to normal L-02 cells at similar concentrations. Confocal microscopic observation indicated that a greater amount of DOX was delivered into the nuclei of cells following 9 or 12h incubation with DOX-loaded micelles. In vivo studies on H22-bearing Swiss mice demonstrated the superior anticancer activity of DOX-loaded SPDP micelles over free DOX and DOX-loaded SPGS micelles. All of the data presented here suggested that these SPDP micelles may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs. Statement of Significance Various nanoscale drug carriers were used to enhance therapeutic effect of many drugs. While, the metabolites of high quantities of carriers may cause additional short- or long-term toxicities. In this study, a new systems based on solanesol derivatives was developed for anticancer drug delivery. There are two features for this system. One is solanesol originated bioactivity of the carrier, which will synergistically facilitate therapeutic effect of the encapsulated drug. The other is the redox-responsive drug release behavior adaptable to the glutathione-rich atmosphere of tumor cell. All the hypothesis have been elucidated in this work through in vitro and in vivo studies. It was found that this drug delivery system may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.040
      Issue No: Vol. 64 (2017)
       
  • Gold nanocage decorated pH-sensitive micelle for highly effective
           photothermo-chemotherapy and photoacoustic imaging
    • Authors: Guoyong Zhou; Hong Xiao; Xiaoxia Li; Yi Huang; Wei Song; Liang Song; Meiwan Chen; Du Cheng; Xintao Shuai
      Pages: 223 - 236
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Guoyong Zhou, Hong Xiao, Xiaoxia Li, Yi Huang, Wei Song, Liang Song, Meiwan Chen, Du Cheng, Xintao Shuai
      A pH-sensitive copolymer PAsp(DIP)-b-PAsp(MEA) (PDPM) was synthesized and self-assembled to micelle loading chemotherapeutic drug doxorubicin (DOX) and introducing a gold nanocage structure for photothermo-chemotherapy and photoacoustic imaging. After further surface modification with polyethylene glycol (PEG), the DOX-loaded pH-sensitive gold nanocage (D-PGNC) around 100 nm possessed a uniform spherical structure with a pH-sensitive core of PAsp(DIP) incorporating DOX, an interlayer crosslinked via disulfide bonds and decorated with discontinuous gold shell, and a PEG corona. The release of DOX from D-PGNC was turned off in bloodstream due to the cross-linking and gold decoration of interlayer but turned on inside tumor tissue by multiple stimulations including the low pH value of tumor tissue (≈6.8), the low lysosomal pH value of cancer cells (≈5.0) and near-infrared (NIR) irradiation. The gold nanocage receiving NIR irradiation could generate hyperthermia to ablate tumor cells. Moreover, the photoacoustic (PA) imaging and analysis of DOX fluorescence inside tumor tissue demonstrated that photothermal therapy based on the gold nanocage effectively drove DOX penetration inside tumor. Owing to the rapid intratumor release and deep tissue penetration of drug favorable for killing cancer cells survived the photothermal therapy, the combined therapy based on D-PGNC via NIR irradiation exhibited a synergistic treatment effect superior to either chemotherapy or NIR-induced photothermal therapy alone. Statement of Significance The novelty of the manuscript is its multifunctional system which incorporates anticancer drug DOX in its pH-sensitive core and acts as a template to introduce a gold nanocage. This nanomedicine presents potentials of sequestrating drug molecules in blood circulation but releasing them inside tumor upon responding to the acidic microenvironment therein. Exposure to NIR laser further expedited the pH-sensitive DOX release and promoted DOX penetration into cancer tissues far away from the vasculature. Consequently, the combined photothermo-chemotherapy showed synergistic effects to inhibit tumor growth and prolong animal survival in nude mice bearing human SKOV-3 ovarian tumor. Moreover, owing to the decoration with gold nanocage, the tumor accumulation and intratumor diffusion of the micelles were easily trackable using photoacoustic imaging.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.018
      Issue No: Vol. 64 (2017)
       
  • Engineering intranasal mRNA vaccines to enhance lymph node trafficking and
           immune responses
    • Authors: Man Li; You Li; Ke Peng; Ying Wang; Tao Gong; Zhirong Zhang; Qin He; Xun Sun
      Pages: 237 - 248
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Man Li, You Li, Ke Peng, Ying Wang, Tao Gong, Zhirong Zhang, Qin He, Xun Sun
      Intranasal mRNA vaccination provides immediate immune protection against pandemic diseases. Recent studies have shown that diverse forms of polyethyleneimine (PEI) have potent mucosal adjuvant activity, which could significantly facilitate the delivery of intranasal mRNA vaccines. Nevertheless, optimizing the chemical structure of PEI to maximize its adjuvanticity and decrease its toxicity remains a challenge. Here we show that the chemical structure of PEI strongly influences how well nanocomplexes of PEI and mRNA migrate to the lymph nodes and elicit immune responses. Conjugating cyclodextrin (CD) with PEI600 or PEI2k yielded CP (CD-PEI) polymers with different CD/PEI ratios. We analyzed the delivery efficacy of CP600, CP2k, and PEI25k as intranasal mRNA vaccine carriers by evaluating the lymph nodes migration and immune responses. Among these polymers, CP2k/mRNA showed significantly higher in vitro transfection efficiency, stronger abilities to migrate to lymph nodes and stimulate dendritic cells maturation in vivo, which further led to potent humoral and cellular immune responses, and showed lower local and systemic toxicity than PEI25k/mRNA. These results demonstrate the potential of CD-PEI2k/mRNA nanocomplex as a self-adjuvanting vaccine delivery vehicle that traffics to lymph nodes with high efficiency. Statement of Significance As we face outbreaks of pandemic diseases such as Zika virus, intranasal mRNA vaccination provides instant massive protection against highly variant viruses. Various polymer-based delivery systems have been successfully applied in intranasal vaccine delivery. However, the influence of molecular structure of the polymeric carriers on the lymph node trafficking and dendritic cell maturation is seldom studied for intranasal vaccination. Therefore, engineering polymer-based vaccine delivery system and elucidating the relationship between molecular structure and the intranasal delivery efficiency are essential for maximizing the immune responses. We hereby construct self-adjuvanting polymer-based intranasal mRNA vaccines to enhance lymph node trafficking and further improve immune responses.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.019
      Issue No: Vol. 64 (2017)
       
  • Interaction of cruciferin-based nanoparticles with Caco-2 cells and
           Caco-2/HT29-MTX co-cultures
    • Authors: Ali Akbari; Afsaneh Lavasanifar; Jianping Wu
      Pages: 249 - 258
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Ali Akbari, Afsaneh Lavasanifar, Jianping Wu
      The objective of this work was to assess the potential of Cruciferin/Calcium (Cru/Ca) and Cruciferin/Chitosan (Cru/Cs) nanoparticles for oral drug delivery. For this purpose, Cru/Ca and Cru/Cs nanoparticles were developed through cold gelation of Cruciferin, a major canola protein, and in interaction with calcium and chitosan, respectively. The extent and rate of particle uptake in Caco-2 cells and Caco-2/HT29 co-culture was then evaluated by fluorescence spectroscopy as well as flow cytometry. Through pre-incubation of Caco-2 cell monolayer with specific endocytosis inhibitors, the mechanism of cell uptake was investigated. Our results showed that the uptake of negatively-charged Cru/Ca particles to be ∼3 times higher than positively-charged Cru/Cs ones by Caco-2 cells. Presence of mucus secreted by HT29 cells in their co-culture with Caco-2 had negligible influence on the uptake and transport of both particles. In contrast to Cru/Ca particles which were dissociated in the simulated gastrointestinal conditions, digestion of Cru/Cs particles resulted in 6- and 2-fold increase in the cellular uptake and transport of encapsulated coumarin in the latter particles, respectively. While the presence of mucus in Caco-2/HT29 co-culture caused 40–50% decrease of cellular uptake and transport for coumarin encapsulated in digested Cru/Cs particles, it had no significant effect on the cell uptake and transport of coumarin associated with Cru/Ca particles after digestion. Energy-dependent mechanisms were the dominant mechanism for uptake of both undigested and digested particles. Therefore, in Caco-2/HT29 co-culture which closely simulated intestinal epithelial cells, undigested Cru/Ca and Cru/Cs particles had the ability to penetrate mucus layers, while digested Cru/Cs particles showed mucoadhesive property, and digested Cru/Ca particles were dissociated. Our results points to a potential for cruciferin based nanoparticles for oral drug delivery. Statement of Significance The long-term objective of this research is to investigate the potential of edible and safe biopolymer in enhanced oral delivery of drugs and/or vaccines. Here, we investigated the potential application of nanoparticles based on a protein extracted from Canola seeds, i.e., cruciferin, for oral delivery of a model small molecule, i.e., coumarin, through cells representing gastrointestinal epithelium, Caco-2 and Caco-2/HT29 cell monolayer. This study was completed for intact cruciferin nanoparticles and cruciferin coated chitosan nanoparticles, before and after digestion with gastric or intestine simulating fluids. This comparison was useful to understand the fate the cruciferin based particles in digestive mucosal tissues and their potential mucoadhesive and/or mucus-penetrating property.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.017
      Issue No: Vol. 64 (2017)
       
  • Vectofusin-1, a potent peptidic enhancer of viral gene transfer forms
           pH-dependent α-helical nanofibrils, concentrating viral particles
    • Authors: Louic S. Vermeer; Loic Hamon; Alicia Schirer; Michel Schoup; Jérémie Cosette; Saliha Majdoul; David Pastré; Daniel Stockholm; Nathalie Holic; Petra Hellwig; Anne Galy; David Fenard; Burkhard Bechinger
      Pages: 259 - 268
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Louic S. Vermeer, Loic Hamon, Alicia Schirer, Michel Schoup, Jérémie Cosette, Saliha Majdoul, David Pastré, Daniel Stockholm, Nathalie Holic, Petra Hellwig, Anne Galy, David Fenard, Burkhard Bechinger
      Gene transfer using lentiviral vectors has therapeutic applications spanning from monogenic and infectious diseases to cancer. Such gene therapy has to be improved by enhancing the levels of viral infection of target cells and/or reducing the amount of lentivirus for greater safety and reduced costs. Vectofusin-1, a recently developed cationic amphipathic peptide with a pronounced capacity to enhance such viral transduction, strongly promotes the entry of several retroviral pseudotypes into target cells when added to the culture medium. To clarify the molecular basis of its action the peptide was investigated on a molecular and a supramolecular level by a variety of biophysical approaches. We show that in culture medium vectofusin-1 rapidly forms complexes in the 10 nm range that further assemble into annular and extended nanofibrils. These associate with viral particles allowing them to be easily pelleted for optimal virus-cell interaction. Thioflavin T fluorescence, circular dichroism and infrared spectroscopies indicate that these fibrils have a unique α-helical structure whereas most other viral transduction enhancers form β-amyloid fibrils. A vectofusin-1 derivative (LAH2-A4) is inefficient in biological assays and does not form nanofibrils, suggesting that supramolecular assembly is essential for transduction enhancement. Our observations define vectofusin-1 as a member of a new class of α-helical enhancers of lentiviral infection. Its fibril formation is reversible which bears considerable advantages in handling the peptide in conditions well-adapted to Good Manufacturing Practices and scalable gene therapy protocols.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.009
      Issue No: Vol. 64 (2017)
       
  • Influence of dynamic compressive loading on the in vitro degradation
           behavior of pure PLA and Mg/PLA composite
    • Authors: Xuan Li; Chenxi Qi; Linyuan Han; Chenglin Chu; Jing Bai; Chao Guo; Feng Xue; Baolong Shen; Paul K. Chu
      Pages: 269 - 278
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Xuan Li, Chenxi Qi, Linyuan Han, Chenglin Chu, Jing Bai, Chao Guo, Feng Xue, Baolong Shen, Paul K. Chu
      The effects of dynamic compressive loading on the in vitro degradation behavior of pure poly-lactic acid (PLA) and PLA-based composite unidirectionally reinforced with micro-arc oxidized magnesium alloy wires (Mg/PLA) are investigated. Dynamic compressive loading is shown to accelerate degradation of pure PLA and Mg/PLA. As the applied stress is increased from 0.1MPa to 0.9MPa or frequency from 0.5Hz to 2.5Hz, the overall degradation rate goes up. After immersion for 21days at 0.9MPa and 2.5Hz, the bending strength retention of the composite and pure PLA is 60.1% and 50%, respectively. Dynamic loading enhances diffusion of small acidic molecules resulting in significant pH decrease in the immersion solution. The synergistic reaction between magnesium alloy wires and PLA in the composite is further clarified by electrochemical tests. The degradation behavior of the pure PLA and PLA matrix in the composite under dynamic conditions obey the first order degradation kinetics and a numerical model is postulated to elucidate the relationship of the bending strength, stress, frequency, and immersion time under dynamic conditions. Statement of significance We systematically study the influence of dynamic loading on the degradation behavior of pure PLA and Mg/PLA. Dynamic compressive loading is shown to accelerate degradation of pure PLA and Mg/PLA. The synergistic reaction between magnesium alloy wires and PLA in the composite is firstly clarified by electrochemical tests. The degradation behavior of the pure PLA and PLA matrix in the composite under dynamic conditions obey the first order degradation kinetics. Then, a numerical model is postulated to elucidate the relationship of the bending strength, stress, frequency, and immersion time under dynamic conditions.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.08.004
      Issue No: Vol. 64 (2017)
       
  • A pro-angiogenic degradable Mg-poly(lactic-co-glycolic acid) implant
           combined with rhbFGF in a rat limb ischemia model
    • Authors: Hanmei Bao; Feng Lv; Tianjun Liu
      Pages: 279 - 289
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Hanmei Bao, Feng Lv, Tianjun Liu
      Site-specific controlled release of exogenous angiogenic growth factors, such as recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. Here, we have developed an implant composed of spiral magnesium (Mg) and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The encapsulated protein could release continually for 4weeks with well preserved bioactivity. We compared the angiogenic effect produced by Mg-PLGA-rhbFGF with that of a PLGA implant loaded with rhbFGF (PLGA-rhbFGF). The incorporation of Mg in the implant raised the microclimate pH in the polymer, which preserved the stability of rhbFGF. Mg-PLGA-rhbFGF exhibited advantages over PLGA-rhbFGF implant in terms of a cytocompatibility evaluation. An in vivo angiogenesis test further confirmed the efficacy of released rhbFGF. HE, CD31 and α-SMA staining revealed that the controlled release of rhbFGF from the Mg-PLGA-rhbFGF implant was superior in promoting angiogenesis compared with that of the PLGA-rhbFGF implant. Four weeks post-implantation, the capillary density of the Mg-PLGA-rhbFGF group was significantly higher than that of the PLGA-rhbFGF, control and the normal group (p <0.05, p <0.01 and p <0.01, respectively). Furthermore, the limb blood perfusion ratios of the Mg-PLGA-rhbFGF and PLGA-rhbFGF groups were dramatically increased, at 99.1±2.9% and 80.7±3.2%, respectively, whereas the ischemic limb did not recover in the control group. The biocompatibility of the implants was also evaluated. In conclusion, Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery. The results suggest potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia. Statement of Significance Magnesium (Mg)-based implant has been already used in patients with critical limb ischemia. Site-specific controlled release of recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. We report here on a novel combination implant composed of spiral magnesium and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The preparation method does not involve any complex processes and results in a high encapsulation efficiency (approximately 100%). The degradation of metal Mg raise the microclimate pH in the PLGA polymer, which could well preserve the bioactivity of rhbFGF incorporated in the implant. Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery in rat limb ischemic model. This work marks the first report for controlled release of rhbFGF in combination with metal Mg, and suggests potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.033
      Issue No: Vol. 64 (2017)
       
  • Biodegradable zwitterionic sulfobetaine polymer and its conjugate with
           paclitaxel for sustained drug delivery
    • Authors: Haotian Sun; Michael Yu Zarng Chang; Wei-I Cheng; Qing Wang; Alex Commisso; Meghan Capeling; Yun Wu; Chong Cheng
      Pages: 290 - 300
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Haotian Sun, Michael Yu Zarng Chang, Wei-I Cheng, Qing Wang, Alex Commisso, Meghan Capeling, Yun Wu, Chong Cheng
      A fully biodegradable zwitterionic polymer and the corresponding conjugate with paclitaxel (PTX) were synthesized as promising biomaterials. Allyl-functionalized polylactide (PLA) was employed as the precursor of polymer backbones. UV-induced thiol-ene reaction was conducted to conjugate thiol-functionalized sulfobetaine (SB) with the PLA-based backbone. The resulting zwitterionic polymer did not exhibit considerable cytotoxicity. A polymer-drug conjugate was also obtained by thiol-ene reaction of both thiol-functionalized SB and PTX with allyl-functionalized PLA. The conjugate could readily form narrowly-dispersed nanoparticles in aqueous solutions with a volume-average hydrodynamic diameter (D h,V) of 19.3 ± 0.2 nm. Such a polymer-drug conjugate-based drug delivery system showed full degradability, well-suppressed non-specific interaction with biomolecules, and sustained drug release. In vitro assessments also confirmed the significant anti-cancer efficacy of the conjugate. After 72 h incubation with PLA-SB/PTX containing 10 µg/mL of PTX, the cell viabilities of A549, MCF7, and PaCa-2 cells were as low as 20.0 ± 2.5%, 1.7 ± 1.7%, and 14.8 ± 0.9%, respectively. Both flow cytometry and confocal microscopy suggested that the conjugates could be easily uptaken by A549 cells before the major release of PTX moieties. Overall, this work elucidates promising potentials of biodegradable zwitterionic polymer-based materials in biomedical applications. Statement of Significance The applicability of FDA-approved biodegradable aliphatic polyesters has been significantly restricted because they are hydrophobic and lack functionalities. Recently zwitterionic polymers have emerged as promising hydrophilic biomaterials, but most of the reported zwitterionic polymers are non-biodegradable. This study reports a novel aliphatic polyester-based zwitterionic polymer and the corresponding polymer-drug conjugate. Their aliphatic polyester and zwitterionic components provide them with high enzymatic degradability and low nonspecific interactions with biomolecules, respectively. While the zwitterionic polymer did not show noticeable cytotoxicity, the corresponding polymer-anticancer drug conjugate exhibited acid-sensitive sustained drug release, remarkable effectiveness in killing cancer cells, as well as the ready cellular internalization. This work lays a foundation for the further development of synthetic biodegradable zwitterionic polymer-based materials which potentially may have broad and significant biomedical applications.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.016
      Issue No: Vol. 64 (2017)
       
  • Sustained antimicrobial activity and reduced toxicity of oxidative
           biocides through biodegradable microparticles
    • Authors: Panagiotis Sofokleous; Shanom Ali; Peter Wilson; Asma Buanz; Simon Gaisford; Dharmit Mistry; Adrian Fellows; Richard M. Day
      Pages: 301 - 312
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Panagiotis Sofokleous, Shanom Ali, Peter Wilson, Asma Buanz, Simon Gaisford, Dharmit Mistry, Adrian Fellows, Richard M. Day
      The spread of antibiotic-resistant pathogens requires new treatments. Small molecule precursor compounds that produce oxidative biocides with well-established antimicrobial properties could provide a range of new therapeutic products to combat resistant infections. The aim of this study was to investigate a novel biomaterials-based approach for the manufacture, targeted delivery and controlled release of a peroxygen donor (sodium percarbonate) combined with an acetyl donor (tetraacetylethylenediamine) to deliver local antimicrobial activity via a dynamic equilibrium mixture of hydrogen peroxide and peracetic acid. Entrapment of the pre-cursor compounds into hierarchically structured degradable microparticles was achieved using an innovative dry manufacturing process involving thermally induced phase separation (TIPS) that circumvented compound decomposition associated with conventional microparticle manufacture. The microparticles provided controlled release of hydrogen peroxide and peracetic acid that led to rapid and sustained killing of multiple drug-resistant organisms (methicillin-resistant Staphylococcus aureus and carbapenem-resistant Escherichia coli) without associated cytotoxicity in vitro nor intracutaneous reactivity in vivo. The results from this study demonstrate for the first time that microparticles loaded with acetyl and peroxygen donors retain their antimicrobial activity whilst eliciting no host toxicity. In doing so, it overcomes the detrimental effects that have prevented oxidative biocides from being used as alternatives to conventional antibiotics. Statement of Significance The manuscript explores a novel approach to utilize the antimicrobial activity of oxidative species for sustained killing of multiple drug-resistant organisms without causing collateral tissue damage. The results demonstrate, for the first time, the ability to load pre-cursor compounds into porous polymeric structures that results in their release and conversion into oxidative species in a controlled manner. Until now, the use of oxidative species has not been considered as a candidate therapeutic replacement for conventional antibiotics due to difficulties associated with handling during manufacture and controlling sustained release without causing undesirable tissue damage. The ultimate impact of the research could be the creation of new materials-based anti-infective chemotherapeutic agents that have minimal potential for giving rise to antimicrobial resistance.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.001
      Issue No: Vol. 64 (2017)
       
  • Echogenicity enhancement by end-fluorinated polylactide perfluorohexane
           nanocapsules: Towards ultrasound-activable nanosystems
    • Authors: Guilherme Picheth; Sophie Houvenagel; Camille Dejean; Olivier Couture; Rilton Alves de Freitas; Laurence Moine; Nicolas Tsapis
      Pages: 313 - 322
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Guilherme Picheth, Sophie Houvenagel, Camille Dejean, Olivier Couture, Rilton Alves de Freitas, Laurence Moine, Nicolas Tsapis
      Polylactide (PLA) polymers containing five distinct lengths of fluorinated (from C3F7 to C13F27) and non-fluorinated (C6H13) end-groups were successfully synthesized by ring-opening polymerization of d,l-lactide. Fluorination was expected to increase the encapsulation efficiency of perfluorohexane (PFH). 150 nm nanocapsules were obtained and 19F nuclear magnetic resonance revealed that nanocapsules formulated with fluorinated polymers increased by 2-fold the encapsulation efficiency of PFH compared with non-fluorinated derivatives, without any effect of fluorine chain length. Fluorination of the polymers did not induce any specific in vitro cytotoxicity of nanocapsules towards HUVEC and J774.A1 cell lines. The echogenicity of fluorinated-shelled nanocapsules was increased by 3-fold to 40-fold compared to non-fluorinated nanocapsules or nanoparticles devoid of a perfluorohexane core for both conventional and contrast-specific ultrasound imaging modalities. In particular, an enhanced echogenicity and contrast-specific response was observed as the fluorinated chain-length increased, probably due to an increase of density and promotion of bubble nucleation. When submitted to focused ultrasound, both intact and exploded nanocapsules could be observed, also with end-group dependency, indicating that PFH was partly vaporized. These results pave the way to the design of theranostic perfluorohexane nanocapsules co-encapsulating a drug for precision delivery using focused ultrasound. Statement of Significance We have synthesized novel fluorinated polyesters and formulated them into nanocapsules of perfluorohexane as ultrasound contrast agents. This nanosystem has been thoroughly characterized by several techniques and we show that fluorination of the biodegradable polymer favors the encapsulation of perfluorohexane without producing further reduction of cell viability. Contrary to nanocapsules of perfluoroctyl bromide formulated with the fluorinated polymers [32], the presence of the fluorinated moieties leads to an increase of echogenicity that is dependent of the length of the fluorinated moiety. Morevover, the ability of nanocapsules to explode when submitted to focused ultrasound also depends on the length of the fluorinated chain. These results pave the way to theranostic perfluorohexane nanocapsules co-encapsulating a drug for precision delivery using focused ultrasound.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.002
      Issue No: Vol. 64 (2017)
       
  • EGFR-targeted multifunctional polymersomal doxorubicin induces selective
           and potent suppression of orthotopic human liver cancer in vivo
    • Authors: Yuan Fang; Weijing Yang; Liang Cheng; Fenghua Meng; Jian Zhang; Zhiyuan Zhong
      Pages: 323 - 333
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Yuan Fang, Weijing Yang, Liang Cheng, Fenghua Meng, Jian Zhang, Zhiyuan Zhong
      Liver cancer is a globally leading malignancy that has a poor five-year survival rate of less than 20%. The systemic chemotherapeutics are generally ineffective for liver cancers partly due to fast clearance and low tumor uptake. Here, we report that GE11 peptide functionalized polymersomal doxorubicin (GE11-PS-DOX) effectively targets and inhibits epidermal growth factor receptor (EGFR)-positive SMMC7721 orthotopic human liver tumor xenografts in mice. GE11-PS-DOX with a GE11 surface density of 10% displayed a high drug loading of 15.4 wt%, a small size of 78 nm, and glutathione-triggered release of DOX. MTT assays, flow cytometry and confocal microscopy studies revealed that GE11-PS-DOX mediated obviously more efficient DOX delivery into SMMC7721 cells than the non-targeting PS-DOX and clinically used liposomal doxorubicin (Lipo-DOX) controls. The in vivo studies showed that GE11-PS-DOX had a long circulation time and an extraordinary accumulation in the tumors (13.3 %ID/g). Interestingly, GE11-PS-DOX caused much better treatment of SMMC7721 orthotopic liver tumor-bearing mice as compared to PS-DOX and Lipo-DOX. The mice treated with GE11-PS-DOX (12 mg DOX equiv./kg) exhibited a significantly improved survival rate (median survival time: 130 days versus 70 and 38 days for PS-DOX at 12 mg DOX equiv./kg and Lipo-DOX at 6 mg DOX equiv./kg, respectively) and achieved 50% complete regression. Notably, GE11-PS-DOX induced obviously lower systemic toxicity than Lipo-DOX. EGFR-targeted multifunctional polymersomal doxorubicin with improved efficacy and safety has a high potential for treating human liver cancers. Statement of Significance Liver cancer is one of the top five leading causes of cancer death worldwide. The systemic chemotherapeutics and biotherapeutics generally have a low treatment efficacy for hepatocellular carcinoma partly due to fast clearance and/or low tumor uptake. Nanomedicines based on biodegradable micelle and polymersomes offer a most promising treatment for malignant liver cancers. Their clinical effectiveness remains, however, suboptimal owing to issues like inadequate systemic stability, low tumor accumulation and selectivity, and poor control over drug release. Here we report that GE11 peptide-functionalized, disulfide-crosslinked multifunctional polymersomal doxorubicin (GE11-PS-DOX) can effectively suppress the growth of orthotopic SMMC7721 human liver tumors in nude mice. They showed significantly decreased systemic toxicity and improved mouse survival rate with 3.4-fold longer median survival time as compared to clinically used pegylated liposomal doxorubicin (Lipo-DOX) and achieving 50% complete regression. GE11-PS-DOX, based on PEG-PTMC is biodegradable, nontoxic, and easy to prepare, appears as a safe, robust, versatile and all-function-in-one nanoplatform that has a high potential in targeted chemotherapy of EGFR expressed hepatocellular carcinoma.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.013
      Issue No: Vol. 64 (2017)
       
  • An injectable particle-hydrogel hybrid system for glucose-regulatory
           insulin delivery
    • Authors: Fuli Zhao; Di Wu; Dan Yao; Ruiwei Guo; Weiwei Wang; Anjie Dong; Deling Kong; Jianhua Zhang
      Pages: 334 - 345
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Fuli Zhao, Di Wu, Dan Yao, Ruiwei Guo, Weiwei Wang, Anjie Dong, Deling Kong, Jianhua Zhang
      Long-term and daily subcutaneous injections of insulin for the treatment of insulin-dependent diabetic patients often lead to poor patient compliance and undesired complications. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, their applications are limited by clinically irrelevant glucose-responsive range, slow response rate, low tissue-adhesiveness and poor biodegradability, undesirable leakage at normoglycemic state. Herein, we report a novel implantable insulin hydrogel for glucose-regulated delivery of insulin based on a unique particle-hydrogel hybrid platform featuring fast glucose responsiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, and full biodegradability for safe use. The system was thoroughly characterized both in vitro and in vivo and was demonstrated to hold these unique functions. Using streptozotocin-induced diabetic mice as a model, it was shown that a single subcutaneous injection of the insulin-loaded particle-hydrogel formulation led to quasi-steady-state blood glucose levels within the normal range for about two weeks. In addition, the preparation of the formulation only involved simple mixing and self-assembling processes, and thus it had great scalability and reproducibility for practical use. The highly feasible preparation, excellent performance, inherent biocompatibility and biodegradability make this novel composite hydrogel promising platform for diabetes therapy. Statement of Significance Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, these hydrogels, mostly based on a variety of PBA-containing acrylamide monomers, are still far from clinical reality. Building upon a unique particle-hydrogel hybrid platform, herein we report a novel implantable insulin storage and delivery system with multifunctionalities including fast glucose-sensitiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, biodegradable materials for safe use and well-controlled insulin release. These unique functions were demonstrated through research both in vitro and in vivo. In addition, the preparation of the formulation was simple, and thus it had great scalability and reproducibility for practical use.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.044
      Issue No: Vol. 64 (2017)
       
  • Mesenchymal stem cell therapy for retro-corneal membrane – A clinical
           challenge in full-thickness transplantation of biosynthetic corneal
           equivalents
    • Authors: Vijayalakshmi Rajendran; Magdalena Netuková; May Griffith; John V Forrester; Lucia Kuffová
      Pages: 346 - 356
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Vijayalakshmi Rajendran, Magdalena Netuková, May Griffith, John V Forrester, Lucia Kuffová
      Artificial corneas (keratoprostheses) and biosynthetic collagen-based corneal equivalents are surgical implants designed to ease the global burden of corneal blindness. However, keratoprostheses in many cases fail due to development of fibrous retro-corneal membranes (RCM). Fibrous membranes which develop in the anterior chamber after prosthesis implantation do so on a matrix of fibrin. This study investigated fibrin deposition and RCM formation after full-thickness collagen-based hydrogel implants and compared them with syngeneic and allogeneic corneal grafts in mice. Fibrin cleared from the anterior chamber within 14 days in both allo- and syn-grafts but, persisted in hydrogel implants and developed into dense retro-corneal membrane (RCM) which were heavily infiltrated by activated myofibroblasts. In contrast, the number of CD11b+ macrophages infiltrating the initial deposition of fibrin in the anterior chamber (AC) after hydrogel implantation was markedly reduced compared to syn- and allo-grafts. Inoculation of mesenchymal stem cells prior to collagen gel implant promoted clearance of gel-associated fibrin from the anterior chamber. We propose that a failure of macrophage-mediated clearance of fibrin may be the cause of RCM formation after collagen-based hydrogel implants and that mesenchymal stem cell therapy promotes clearance of fibrin and prevents RCM formation. Statement of Significance The manuscript addresses the potential value of bone marrow-derived mesenchymal stem cell therapy for retro-corneal membrane (RCM) formation in full-thickness transplantation of biosynthetic corneal equivalents. This work reports the pathophysiological changes in the anterior chamber of the mouse eye following full-thickness recombinant human cross-linked collagen-based hydrogel implants in which persistent fibrin promotes the development of dense RCM. Furthermore, pre-treatment with mesenchymal stem cells reduces RCM formation and enhances corneal transparency.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.011
      Issue No: Vol. 64 (2017)
       
  • Design, development and characterization of synthetic Bruch’s
           membranes
    • Authors: Denver C. Surrao; Ursula Greferath; Yu-Qian Chau; Stuart J. Skabo; Mario Huynh; Kinnari J. Shelat; Ioannis J. Limnios; Erica L. Fletcher; Qin Liu
      Pages: 357 - 376
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Denver C. Surrao, Ursula Greferath, Yu-Qian Chau, Stuart J. Skabo, Mario Huynh, Kinnari J. Shelat, Ioannis J. Limnios, Erica L. Fletcher, Qin Liu
      Age-related macular degeneration (AMD) is a leading cause of blindness, and dry AMD has no effective treatment. Retinal constructs comprising retinal pigment epithelium (RPE) cells supported by electrospun scaffolds have been investigated to treat dry AMD. However, electrospun scaffolds studied to-date do not mimic the structural microenvironment of human Bruch’s membrane (BM), essential for native-like RPE monolayers. The aim of this study was to develop a structurally biomimetic scaffold designed to support a functional RPE monolayer, comprising porous, electrospun nanofibrous membranes (ENMs), coated with laminin, mimicking the inner collagenous layer (ICL) and basal RPE lamina respectively, the cell supporting layers of the BM. In vitro evaluation showed 70nm PLLA ENMs adsorbed high amounts of laminin and supported functional RPE monolayers, exhibiting 3D polygonal-cobblestone morphology, apical microvilli, basal infoldings, high transepithelial resistance (TER), phagocytic activity and expression of signature RPE markers. 70nm PLLA ENMs were successfully implanted into the subretinal space of RCS-rdy+p+/LAV rats, also commonly know as rdy rats. At week 4, in the absence of immunosuppressants, implanted PLLA ENMs were surrounded by a significantly low number of activated microglial cells, compared to week 1, indicating no adverse long-term immune response. In conclusion, we successfully designed and tested ENMs emulating the RPE cell supporting layers of the BM, and found 70nm PLLA ENMs to be best suited as scaffolds for fabricating retinal constructs. Statement of Significance Age related macular degeneration (AMD) is a leading cause of vision loss in the developed world, with an increasing number of people suffering from blindness or severe visual impairment. Transplantation of retinal pigment epithelium (RPE) cells supported on a synthetic, biomimetic-like Bruch’s membrane (BM) is considered a promising treatment. However, the synthetic scaffolds used do not mimic the microenvironment of the RPE cell supporting layers, required for the development of a functional RPE monolayer. This study indicated that porous, laminin coated, 70nm PLLA ENMs supported functional RPE monolayers, exhibiting 3D polygonal-cobblestone morphology, apical microvilli, basal infoldings, high transepithelial resistance (TER), phagocytic activity and expression of signature RPE markers. These findings indicate the potential clinical use of porous, laminin coated, 70nm PLLA ENMs in fabricating retinal constructs aimed at treating dry AMD.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.032
      Issue No: Vol. 64 (2017)
       
  • 3D printing of hybrid biomaterials for bone tissue engineering:
           Calcium-polyphosphate microparticles encapsulated by polycaprolactone
    • Authors: Meik Neufurth; Xiaohong Wang; Shunfeng Wang; Renate Steffen; Maximilian Ackermann; Natalie D. Haep; Heinz C. Schröder; Werner E.G. Müller
      Pages: 377 - 388
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Meik Neufurth, Xiaohong Wang, Shunfeng Wang, Renate Steffen, Maximilian Ackermann, Natalie D. Haep, Heinz C. Schröder, Werner E.G. Müller
      Here we describe the formulation of a morphogenetically active bio-ink consisting of amorphous microparticles (MP) prepared from Ca2+ and the physiological inorganic polymer, polyphosphate (polyP). Those MP had been fortified by mixing with poly-ε-caprolactone (PCL) to allow 3D-bioprinting. The resulting granular PCL/Ca-polyP-MP hybrid material, liquefied by short-time heating to 100 °C, was used for the 3D-printing of tissue-like scaffolds formed by strands with a thickness of 400 µm and a stacked architecture leaving ≈0.5 mm2-sized open holes enabling cell migration. The printed composite scaffold turned out to combine suitable biomechanical properties (Young’s modulus of 1.60 ± 0.1 GPa; Martens hardness of 153 ± 28 MPa), matching those of cortical and trabecular bone, with morphogenetic activity. This scaffold was capable of attracting and promoting the growth of human bone-related SaOS-2 cells as demonstrated by staining for cell viability (Calcein AM), cell density (DRAQ5) and SEM studies. Furthermore, the hybrid material was demonstrated to upregulate the steady-state-expression of the cell migration-inducing chemokine SDF-1α. EDX analysis and FTIR measurements revealed the presence of hydroxyapatite in the mineral deposits formed on the scaffold surface. Based on the results we conclude that granular PCL/Ca-polyP-MP hybrid material is suitable for the fabrication of bioprintable scaffold which comprises not only biomechanical stability but also morphogenetic potential. Statement of Significance In present-day regenerative engineering efforts, biomaterial- and cell-based strategies are proposed that meet the required functional and spatial characteristics and variations, especially in the transition regions between soft (cartilage, tendon or ligament) and hard (bone) tissues. In a biomimetic approach we succeeded to fabricate amorphous Ca-polyP nanoparticles/microparticles which are highly biocompatible. Together with polycaprolactone (PCL), polyP can be bio-printed. This hybrid material attracts the cells, as documented optically as well as by a gene-expression studies. Since PCL is already a FDA-approved organic and inert polymer and polyP a physiological biologically active component this new bio-hybrid material has the potential to restore physiological functions, including bone remodelling and regeneration if used as implant.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.031
      Issue No: Vol. 64 (2017)
       
  • Nanocomposite hydrogels stabilized by self-assembled multivalent
           bisphosphonate-magnesium nanoparticles mediate sustained release of
           magnesium ion and promote in-situ bone regeneration
    • Authors: Kunyu Zhang; Sien Lin; Qian Feng; Chaoqun Dong; Yanhua Yang; Gang Li; Liming Bian
      Pages: 389 - 400
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Kunyu Zhang, Sien Lin, Qian Feng, Chaoqun Dong, Yanhua Yang, Gang Li, Liming Bian
      Hydrogels are appealing biomaterials for applications in regenerative medicine due to their tunable physical and bioactive properties. Meanwhile, therapeutic metal ions, such as magnesium ion (Mg2+), not only regulate the cellular behaviors but also stimulate local bone formation and healing. However, the effective delivery and tailored release of Mg2+ remains a challenge, with few reports on hydrogels being used for Mg2+ delivery. Bisphosphonate exhibits a variety of specific bioactivities and excellent binding affinity to multivalent cations such as Mg2+. Herein, we describe a nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. These nanoparticles bearing acrylate groups on the surface not only function as effective multivalent crosslinkers to strengthen the hydrogel network structure, but also promote the mineralization of hydrogels and mediate sustained release of Mg2+. The released Mg2+ ions facilitate stem cell adhesion and spreading on the hydrogel substrates in the absence of cell adhesion ligands, and promote osteogenesis of the seeded hMSCs in vitro. Furthermore, the acellular porous hydrogels alone can support in situ bone regeneration without using exogenous cells and inductive agents, thereby greatly simplifying the approaches of bone regeneration therapy. Statement of Significance In this study, we developed a novel bioactive nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. Such hydrogels are stabilized by the multivalent crosslinking domains formed by the aggregation of Ac-BP-Mg NPs, and therefore show enhanced mechanical properties, improved capacity for mineralization, and controlled release kinetics of Mg2+. Moreover, the released Mg2+ can enhance cell adhesion and spreading, and further promote the osteogenic differentiation of hMSCs. Owing to these unique properties, these acellular hydrogels alone can well facilitate the in vivo bone regeneration at the intended sites. We believe that the strategy reported in this work opens up a new route to develop biopolymer-based nanocomposite hydrogels with enhanced physical and biological functionalities for regenerative medicine.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.039
      Issue No: Vol. 64 (2017)
       
  • Delivery of the TLR ligand poly(I:C) to liver cells in vitro and in vivo
           by calcium phosphate nanoparticles leads to a pronounced immunostimulation
           
    • Authors: Viktoriya Sokolova; Zou Shi; Shunmei Huang; Yanqin Du; Mathis Kopp; Annika Frede; Torben Knuschke; Jan Buer; Dongliang Yang; Jun Wu; Astrid Maria Westendorf; Matthias Epple
      Pages: 401 - 410
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Viktoriya Sokolova, Zou Shi, Shunmei Huang, Yanqin Du, Mathis Kopp, Annika Frede, Torben Knuschke, Jan Buer, Dongliang Yang, Jun Wu, Astrid Maria Westendorf, Matthias Epple
      The selective activation of the immune system is a concurrent problem in the treatment of persistent diseases like viral infections (e.g. hepatitis). For the delivery of the toll-like receptor ligand poly(I:C), an immunostimulatory action was discovered earlier by hydrodynamic injection. However, this technique is not clinically transferable to human patients. A modular system where the immunoactive toll-like-receptor ligand 3 (TLR-3) poly(I:C) was incorporated into calcium phosphate nanoparticles was developed. The nanoparticles had a hydrodynamic diameter of 275nm and a zeta potential of +20mV, measured by dynamic light scattering. The diameter of the solid core was 120nm by scanning electron microscopy. In vitro, the nanoparticle uptake was investigated after 1 and 24h of incubation of THP-1 cells (macrophages) with nanoparticles by fluorescence microscopy. After intravenous injection into BALB/c and C57BL/6J mice, respectively, the in vivo uptake was especially prominent in lung and liver, 1 and 3h after the injection. Pronounced immunostimulatory effects of the nanoparticles were found in vitro with primary liver cells, i.e. Kupffer cells (KC) and liver sinusoidal endothelial cells (LSEC) from wild-type C57BL/6J mice. Thus, they represent a suitable alternative to hydrodynamic injection treatments for future vaccination concepts. Statement of Significance The selective activation of the immune system is a concurrent problem in the treatment of persistent diseases like viral infections (e.g. hepatitis). For the delivery of the toll-like receptor ligand poly(I:C), an immunostimulatory action has been discovered earlier by hydrodynamic injection. However, this technique is not clinically transferable to human patients. We have developed a modular system where poly(I:C) was incorporated into calcium phosphate nanoparticles. The uptake into relevant liver cells was studied both in vitro and in vivo. After intravenous injection into mice, the in vivo uptake was especially prominent in lung and liver, 1 and 3h after the injection. The corresponding strong immune reaction proves their high potential to turn up the immune system, e.g. against viral infections, without adverse side reactions.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.037
      Issue No: Vol. 64 (2017)
       
  • Human osteoblasts grow transitional Si/N apatite in quickly
           osteointegrated Si3N4 cervical insert
    • Authors: Giuseppe Pezzotti; Naoki Oba; Wenliang Zhu; Elia Marin; Alfredo Rondinella; Francesco Boschetto; Bryan McEntire; Kengo Yamamoto; B. Sonny Bal
      Pages: 411 - 420
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Giuseppe Pezzotti, Naoki Oba, Wenliang Zhu, Elia Marin, Alfredo Rondinella, Francesco Boschetto, Bryan McEntire, Kengo Yamamoto, B. Sonny Bal
      Silicon nitride (Si3N4) ceramics possesses surface chemistry that accelerates bone repair, as previously established by in vitro experiments using both osteosarcoma and mesenchymal cells. The release of silicic acid and nitrogen compounds from the surface Si3N4 enhanced in vitro cellular activity. The results of this study demonstrate for the first time that the osseointegration behavior previously observed is operative with a peculiar chemistry within the human milieu. Si and N elements stimulated progenitor cell differentiation and osteoblastic activity, which ultimately resulted in accelerated bone ingrowth. At the molecular scale, insight into the effect of silicon and nitrogen ions released from the Si3N4 surface was obtained through combined histomorphometric analyses, Raman, Fourier-transform-infrared, and X-ray photoelectron spectroscopies. Identical analyses conducted on a polyetheretherketone (PEEK) spinal explant showed no chemical changes and a lower propensity for osteogenic activity. Silicon and nitrogen are key elements in stimulating cells to generate bony apatite with crystallographic imperfections, leading to enhanced bioactivity of Si3N4 biomedical devices. Statement of Significance This research studies osseointegration processes comparing results from explanted PEEK and Si3N4 spinal spacers. Data show that the formation of hydroxyapatite on silicon nitride bio-ceramic surfaces happens with a peculiar mechanism inside the human body. Silicon and nitrogen were incorporated inside the bony tissue structure allowing the developing of off-stoichiometric bony apatite and stimulating progenitor cell differentiation/osteoblastic activity. Silicon and nitrogen ions released from the Si3N4 surface were detected through combined histologic analyses, Raman microspectroscopy, Fourier-transform-infrared, and X-ray photoelectron spectroscopies.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.09.038
      Issue No: Vol. 64 (2017)
       
  • Development of magnesium-based biodegradable metals with dietary trace
           element germanium as orthopaedic implant applications
    • Authors: Dong Bian; Weirui Zhou; Jiuxu Deng; Yang Liu; Wenting Li; Xiao Chu; Peng Xiu; Hong Cai; Yuhui Kou; Baoguo Jiang; Yufeng Zheng
      Pages: 421 - 436
      Abstract: Publication date: December 2017
      Source:Acta Biomaterialia, Volume 64
      Author(s): Dong Bian, Weirui Zhou, Jiuxu Deng, Yang Liu, Wenting Li, Xiao Chu, Peng Xiu, Hong Cai, Yuhui Kou, Baoguo Jiang, Yufeng Zheng
      From the perspective of element biosafety and dietetics, the ideal alloying elements for magnesium should be those which are essential to or naturally presented in human body. Element germanium is a unique metalloid in the carbon group, chemically similar to its group neighbors, Si and Sn. It is a dietary trace element that naturally presents in human body. Physiological role of Ge is still unanswered, but it might be necessary to ensure normal functioning of the body. In present study, novel magnesium alloys with dietary trace element Ge were developed. Feasibility of those alloys to be used as orthopaedic implant applications was systematically evaluated. Mg-Ge alloys consisted of α-Mg matrix and eutectic phases (α-Mg + Mg2Ge). Mechanical properties of Mg-Ge alloys were comparable to current Mg-Ca, Mg-Zn and Mg-Sr biodegradable metals. As-rolled Mg-3Ge alloy exhibited outstanding corrosion resistance in vitro (0.02 mm/y, electrochemical) with decent corrosion rate in vivo (0.6 mm/y, in rabbit tibia). New bone could directly lay down onto the implant and grew along its surface. After 3 months, bone and implant were closely integrated, indicating well osseointegration being obtained. Generally, this is a pioneering study on the in vitro and in vivo performances of novel Mg-Ge based biodegradable metals, and will benefit the future development of this alloy system. Statement of Significance The ideal alloying elements for magnesium-based biodegradable metals should be those which are essential to or naturally presented in human body. Element germanium is a unique metalloid in the carbon group. It is a dietary trace element that naturally presents in human body. In present study, feasibility of Mg-Ge alloys to be utilized as orthopedic applications was systematically investigated, mainly focusing on the microstructure, mechanical property, corrosion behavior and biocompatibility. Our findings showed that Mg-3Ge alloy exhibited superior corrosion resistance to current Mg-Ca, Mg-Zn and Mg-Sr alloys with favorable biocompatibility. This is a pioneering study on the in vitro & in vivo performances of Mg-Ge biodegradable metals, and will benefit the future development of this alloy system.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.004
      Issue No: Vol. 64 (2017)
       
  • Corrigendum to “One step fabrication of hydrogel microcapsules with
           hollow core for assembly and cultivation of hepatocyte spheroids” [Acta
           Biomater. 50 (2017) 428–436]
    • Authors: Christian Siltanen; Michalitsa Diakatou; Jeremy Lowen; Amranul Haque; Ali Rahimian; Gulnaz Stybayeva; Alexander Revzin
      Abstract: Publication date: Available online 11 November 2017
      Source:Acta Biomaterialia
      Author(s): Christian Siltanen, Michalitsa Diakatou, Jeremy Lowen, Amranul Haque, Ali Rahimian, Gulnaz Stybayeva, Alexander Revzin


      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.10.023
       
  • Dual pH-responsive multifunctional nanoparticles for targeted treatment of
           breast cancer by combining immunotherapy and chemotherapy
    • Authors: Yuanyuan Liu; Linan Qiao; Sipei Zhang; Guoyun Wan; Bowei Chen; Ping Zhou; Ning Zhang; Yinsong Wang
      Abstract: Publication date: Available online 10 November 2017
      Source:Acta Biomaterialia
      Author(s): Yuanyuan Liu, Linan Qiao, Sipei Zhang, Guoyun Wan, Bowei Chen, Ping Zhou, Ning Zhang, Yinsong Wang
      In the present study, a dual pH-responsive multifunctional nanoparticle system was designed for combining immunotherapy and chemotherapy to treat breast cancer through targeting immune cells and cancer cells. A proven anti-tumor immune regulator, R848, was encapsulated with poly(L-histidine) (PHIS) to form PHIS/R848 nanocores. Doxorubicin (DOX) was conjugated to hyaluronic acid (HA) through an acid-cleavable hydrazone bond linkage to synthesize polymeric prodrug HA-DOX, which was subsequently coated outside PHIS/R848 nanocores to form HA-DOX/PHIS/R848 nanoparticles. Ionization of PHIS around pH 6.5 (a pH value close to that of tumor microenvironment) switched the nature of this material from hydrophobic to hydrophilic, and thus triggered the release of R848 to exert immunoregulatory action. The rupture of hydrazone bond in HA-DOX at about pH 5.5 (pH of endo/lysosomes) accelerated the release of DOX to exert cytotoxic effects. In immune cells, PHIS/R848 nanocores exhibited strong immunoregulatory activities similar to those induced by free R848. In breast cancer cells overexpressing CD44, HA-DOX was specially internalized by CD44-mediated endocytosis and significantly inhibited the cell growth. In 4T1 tumor-bearing mice, HA-DOX/PHIS/R848 nanoparticles showed excellent tumor-targeting ability and remarkably inhibited the tumor growth by regulating tumor immunity and killing tumor cells. In summary, this multifunctional nanoparticle system could deliver R848 and DOX respectively to tumor microenvironment and breast cancer cells to achieve synergistic effects of immunotherapy and chemotherapy against breast cancer. Statement of Significance Combination of immunotherapy and chemotherapy is becoming a promising new treatment for cancer. The major challenge is to target cancer and immune cells simultaneously and specifically. In this study, a dual pH-responsive multifunctional nanoparticle system based on poly(L-histidine) and hyaluronic acid was designed for co-loading R848 (immune-regulator) and doxorubicin (chemotherapeutic drug) through different encapsulation modes. By responding to the acidic pHs of tumor microenvironment and intracellular organelles, this multifunctional nanoparticle system could release R848 extracellularly and deliver DOX targetedly to breast cancer cells, thus achieving synergistic effects of immunotherapy and chemotherapy against breast cancer.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.010
       
  • In vitro osteogenesis by intracellular uptake of strontium containing
           bioactive glass nanoparticles
    • Authors: Parichart Naruphontjirakul; Alexandra E. Porter; Julian R. Jones
      Abstract: Publication date: Available online 10 November 2017
      Source:Acta Biomaterialia
      Author(s): Parichart Naruphontjirakul, Alexandra E. Porter, Julian R. Jones
      Monodispersed strontium containing bioactive glass nanoparticles (Sr-BGNPs) with two compositions were synthesised, through a modified sol-gel Stöber process, wherein silica nanoparticles (SiO2-NPs) were formed prior to incorporation of calcium and strontium, with diameters of 90 ± 10 nm. The osteogenic response of a murine preosteoblast cell line, MC3T3-E1, was investigated in vitro for a nanoparticle concentration of 250 µg/mL with compositions of 87 mol% SiO2, 7 mol% CaO, 6 mol% SrO and 83 mol% SiO2, 3 mol% CaO, 14 mol% SrO. Dissolution studies in minimum essential media (α-MEM) at pH 7.4 and artificial lysosomal fluid (ALF) at pH 4.5 showed that the particles dissolved and that Sr2+ ions were released from Sr-BGNPs in both environments. Both particle compositions and their ionic dissolution products enhanced the alkaline phosphatase (ALP) activity of the cells and calcium deposition. Immunohistochemistry (IHC) staining of Col1a1, osteocalcin (OSC) and osteopontin (OSP) showed that these proteins were expressed in the MC3T3-E1 cells following three weeks of culture. In the basal condition, the late osteogenic differentiation markers, OSC and OSP, were more overtly expressed by cells cultured with Sr-BGNPs with 14 mol% SrO and their ionic release products than in the control condition. Col1a1 expression was only slightly enhanced in the basal condition, but was enhanced further by the osteogenic supplements. These data demonstrate that Sr-BGNPs accelerate mineralisation without osteogenic supplements. Sr-BGNPs were internalised into MC3T3-E1 cells by endocytosis and stimulated osteogenic differentiation of the pre-osteoblast cell line. Sr-BGNPs are likely to be beneficial for bone regeneration and the observed osteogenic effects of these particles can be attributed to their ionic release products. Significance We report, for the first time, that monodispersed bioactive glass nanoparticles (∼90 nm) are internalised into preosteoblast cells by endocytosis but by unspecific mechanisms. The bioactive nanoparticles and their dissolution products (without the particles present) stimulated the expression of osteogenic markers from preosteoblast cells without the addition of other osteogenic supplements. Incorporating Sr into the bioactive glass nanoparticle composition, in addition to Ca, increased the total cation content (and therefore dissolution rate) of the nanoparticles, even though nominal total cation addition was constant, without changing size or morphology. Increasing Sr content in the nanoparticles and in their dissolution products enhanced osteogenesis in vitro. The particles therefore have great potential as an injectable therapeutic for bone regeneration, particularly in patients with osteoporosis, for which Sr is known to be therapeutic agent.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.008
       
  • A new formulation of poly(MAOTIB) nanoparticles as an efficient contrast
           agent for in vivo X-ray imaging
    • Authors: Justine Wallyn; Nicolas Anton; Christophe Serra; Michel Bouquey; Mayeul Collot; Halina Anton; Jean-Luc Weickert; Nadia Messaddeq; Thierry F. Vandamme
      Abstract: Publication date: Available online 9 November 2017
      Source:Acta Biomaterialia
      Author(s): Justine Wallyn, Nicolas Anton, Christophe Serra, Michel Bouquey, Mayeul Collot, Halina Anton, Jean-Luc Weickert, Nadia Messaddeq, Thierry F. Vandamme
      Polymeric nanoparticles (PNPs) are gaining increasing importance as nanocarriers or contrasting material for preclinical diagnosis by micro-CT scanner. Here, we investigated a straightforward approach to produce a biocompatible, radiopaque, and stable polymer-based nanoparticle contrast agent, which was evaluated on mice. To this end, we used a nanoprecipitation dropping technique to obtain PEGylated PNPs from a preformed iodinated homopolymer, poly(MAOTIB), synthesized by radical polymerization of 2-methacryloyloxyethyl(2,3,5-triiodobenzoate) monomer (MAOTIB). The process developed allows an accurate control of the nanoparticle properties (mean size can range from 140 nm to 200 nm, tuned according to the formulation parameters) along with unprecedented important X-ray attenuation properties (concentration of iodine around 59 mg I/mL) compatible with a follow-up in vivo study. Routine characterizations such as FTIR, DSC, GPC, TGA, 1H and 13C NMR, and finally SEM were accomplished to obtain the main properties of the optimal contrast agent. Owing to excellent colloidal stability against physiological conditions evaluated in the presence of fetal bovine serum, the selected PNPs suspension was administered to mice. Monitoring and quantification by micro-CT showed that iodinated PNPs are endowed strong X-ray attenuation capacity toward blood pool and underwent a rapid and passive accumulation in the liver and spleen. Statement of Significance The design of X-ray contrast agents for preclinical imaging is still highly challenging. To date, the best contrast agents reported are based on iodinated lipids or inorganic materials such as gold. In literature, several attempts were undertaken to create polymer-based X-ray contrast agents, but their applicability in vivo was limited to their low contrasting properties. Polymer-based contrast agents present the advantages of an easy surface modification for future application in targeting. Herein, we develop a novel approach to design polymer-based nanoparticle X-ray contrast agent (polymerization of a highly iodine-loaded monomer (MAOTIB)), leading to an iodine concentration of 59 mg/mL. We showed their high efficiency in vivo in mice, in terms of providing a strong signal in blood and then accumulating in the liver and spleen.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.011
       
  • Fatigue performance of additively manufactured meta-biomaterials: the
           effects of topology and material type
    • Authors: S.M. Ahmadi; R. Hedayati; Y. Li; K. Lietaert; N. Tümer; A. Fatemi; C.D. Rans; B. Pouran; H. Weinans; A.A. Zadpoor
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): S.M. Ahmadi, R. Hedayati, Y. Li, K. Lietaert, N. Tümer, A. Fatemi, C.D. Rans, B. Pouran, H. Weinans, A.A. Zadpoor
      Additive manufacturing (AM) techniques enable fabrication of bone-mimicking meta-biomaterials with unprecedented combinations of topological, mechanical, and mass transport properties. The mechanical performance of AM meta-biomaterials is a direct function of their topological design. It is, however, not clear to what extent the material type is important in determining the fatigue behavior of such biomaterials. We therefore aimed to determine the isolated and modulated effects of topological design and material type on the fatigue response of metallic meta-biomaterials fabricated with selective laser melting. Towards that end, we designed and additively manufactured Co-Cr meta-biomaterials with three types of repeating unit cells and three to four porosities per type of repeating unit cell. The AM meta-biomaterials were then mechanically tested to obtain their normalized S-N curves. The obtained S-N curves of Co-Cr meta-biomaterials were compared to those of meta-biomaterials with same topological designs but made from other materials, i.e. Ti-6Al-4V, tantalum, and pure titanium, available from our previous studies. We found the material type to be far more important than the topological design in determining the normalized fatigue strength of our AM metallic meta-biomaterials. This is the opposite of what we have found for the quasi-static mechanical properties of the same meta-biomaterials. The effects of material type, manufacturing imperfections, and topological design were different in the high and low cycle fatigue regions. That is likely because the cyclic response of meta-biomaterials depends not only on the static and fatigue strengths of the bulk material but also on other factors that may include strut roughness, distribution of the micro-pores created inside the struts during the AM process, and plasticity. Statement of Significance Meta-biomaterials are a special class of metamaterials with unusual or unprecedented combinations of mechanical, physical (e.g. mass transport), and biological properties. Topologically complex and additively manufactured meta-biomaterials have been shown to improve bone regeneration and osseointegration. The mechanical properties of such biomaterials are directly related to their topological design and material type. However, previous studies of such biomaterials have largely neglected the effects of material type, instead focusing on topological design. We show here that neglecting the effects of material type is unjustified. We studied the isolated and combined effects of topological design and material type on the normalized S-N curves of metallic bone-mimicking biomaterials and found them to be more strongly dependent on the material type than topological design.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.014
       
  • Laponite nanoparticle-associated silated hydroxypropylmethyl cellulose as
           an injectable reinforced interpenetrating network hydrogel for cartilage
           tissue engineering
    • Authors: Cécile Boyer; Lara Figueiredo; Richard Pace; Julie Lesoeur; Thierry Rouillon; Catherine Le Visage; Jean-François Tassin; Pierre Weiss; Jérôme Guicheux; Gildas Rethore
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): Cécile Boyer, Lara Figueiredo, Richard Pace, Julie Lesoeur, Thierry Rouillon, Catherine Le Visage, Jean-François Tassin, Pierre Weiss, Jérôme Guicheux, Gildas Rethore
      Articular cartilage is a connective tissue which does not spontaneously heal. To address this issue, biomaterial-assisted cell therapy has been researched with promising advances. The lack of strong mechanical properties is still a concern despite significant progress in three-dimensional scaffolds. This article’s objective was to develop a composite hydrogel using a small amount of nano-reinforcement clay known as laponites. These laponites were capable of self-setting within the gel structure of the silated hydroxylpropylmethyl cellulose (Si-HPMC) hydrogel. Laponites (XLG) were mixed with Si-HPMC to prepare composite hydrogels leading to the development of a hybrid interpenetrating network. This interpenetrating network increases the mechanical properties of the hydrogel. The in vitro investigations showed no side effects from the XLG regarding cytocompatibility or oxygen diffusion within the composite after cross-linking. The ability of the hybrid scaffold containing the composite hydrogel and chondrogenic cells to form a cartilaginous tissue in vivo was investigated during a 6-week implantation in subcutaneous pockets of nude mice. Histological analysis of the composite constructs revealed the formation of a cartilage-like tissue with an extracellular matrix containing glycosaminoglycans and collagens. Overall, this new hybrid construct demonstrates an interpenetrating network which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, oxygen diffusion, or the ability of chondrogenic cells to self-organize in the cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects in a large animal model of articular cartilage defects. Significance Articular Cartilage is a tissue that fails to heal spontaneously. To address this clinically relevant issue, biomaterial-assisted cell therapy is considered promising but they are often lacking in mechanical properties. Our objective was to develop a composite hydrogel using a small amount of nano reinforcement (laponite) capable of gelling within polysaccharide based self-crosslinking hydrogel. This new hybrid construct demonstrates an interpenetrating network (IPN) which enhances the hydrogel mechanical properties without interfering with its cytocompatibility, O2 diffusion and the ability of chondrogenic cells to self-organize in cluster and produce extracellular matrix components. This composite hydrogel may be of relevance for the treatment of cartilage defects will now be considered in a large animal model of articular cartilage defects.
      Graphical abstract image

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

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

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.018
       
  • Branched peptides integrate into self-assembled nanostructures and enhance
           biomechanics of peptidic hydrogels
    • Authors: Raffaele Pugliese; Federico Fontana; Amanda Marchini; Fabrizio Gelain
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): Raffaele Pugliese, Federico Fontana, Amanda Marchini, Fabrizio Gelain
      Self-assembling peptides (SAP) have drawn an increasing interest in the tissue engineering community. They display unquestionable biomimetic properties, tailorability and promising biocompatibility. However their use has been hampered by poor mechanical properties making them fragile soft scaffolds. To increase SAP hydrogel stiffness we introduced a novel strategy based on multiple ramifications of (LDLK)3, a well-known linear SAP, connected with one or multiple “lysine knots”. Differently branched SAPs were tested by increasing the number of (LDLK)3-like branches and by adding the neuro-regenerative functional motif BMHP1 as a single branch. While pure branched peptides did not have appealing self-assembling propensity, when mixed with the corresponding linear SAP they increased the stiffness of the overall hydrogel of multiple times. Notably, optimal results (or peak) were obtained 1) at similar molar ratio (between linear and branched peptides) for all tested sequences and 2) for the branched SAPs featuring the highest number of branches made of (LDLK)3. The functional motif BMHP1, as expected, seemed not to contribute to the increase of the storage modulus as efficiently as (LDLK)3. Interestingly, branched SAPs improved the β-sheet self-arrangement of (LDLK)3 and allowed for the formation of assembled nanofibers. Indeed in coarse-grained molecular dynamics we showed they readily integrate in the assembled aggregates providing “molecular connections” among otherwise weakly paired β-structures. Lastly, branched SAPs did not affect the usual response of human neural stem cells cultured on (LDLK)3-like scaffolds in vitro. Hence, branched SAPs may be a valuable new tool to enhance mechanical properties of self-assembling peptide biomaterials harmlessly; as neither chemical nor enzymatic cross-linking reactions are involved. As a consequence, branched SAPs may enlarge the field of application of SAPs in tissue engineering and beyond. Significance Self-assembling peptides stand at the forefront of regenerative medicine because they feature biomimetic nano-architectures that mimic the complexity of natural peptide-based extracellular matrices of living tissues. Their superior biocompatibility and ease of scale-up production are hampered by weak mechanical properties due to transient non-covalent interactions among and within the self-assembled peptide chains, thus limiting their potential applications. We introduced new branched self-assembling peptides to be used as “molecular connectors” among self-assembled nanostructures made of linear SAPs. Branched SAPs could be mixed with linear SAPs before self-assembling in order to have them intermingled with different β-sheets of linear SAPs after gelation. This strategy caused a manifold increase of the stiffness of the assembled hydrogels (proportional to the number of self-assembling branches), did not affect SAP propensity to form β-sheet but, instead, further stimulated their secondary structure rearrangements. It is now possible to modularly improve SAP scaffold mechanical properties without using harmful chemical reactions. Therefore, branched SAPs represent an additional tool to be adopted for efficient and harmless SAP scaffold customization in tissue engineering.
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      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.026
       
  • Hyaluronan size alters chondrogenesis of adipose-derived stem cells via
           the CD44/ERK/SOX-9 pathway
    • Authors: Shun-Cheng Wu; Chung-Hwan Chen; Jyun-Ya Wang; Yi-Shan Lin; Je-Ken Chang; Mei-Ling Ho
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): Shun-Cheng Wu, Chung-Hwan Chen, Jyun-Ya Wang, Yi-Shan Lin, Je-Ken Chang, Mei-Ling Ho
      Hyaluronan (HA) is a natural linear polymer that is one of the main types of extracellular matrix during the early stage of chondrogenesis. We found that the chondrogenesis of adipose-derived stem cells (ADSCs) can be initiated and promoted by the application of HA to mimic the chondrogenic niche. The aim of this study is to investigate the optimal HA molecular weight (Mw) for chondrogenesis of ADSCs and the detailed mechanism. In this study, we investigated the relationships among HA Mw, CD44 clustering, and the extracellular signal-regulated kinase (ERK)/SOX-9 pathway during chondrogenesis of ADSCs. Human ADSCs (hADSCs) and rabbit ADSCs (rADSCs) were isolated and expanded. Chondrogenesis was induced in rADSCs by culturing cells in HA-coated wells (HA Mw: 80 kDa, 600 kDa and 2000 kDa) and evaluated by examining cell aggregation, chondrogenic gene expression (collagen type II and aggrecan) and sulfated glycosaminoglycan (sGAG) deposition in vitro. Cartilaginous tissue formation in vivo was confirmed by implanting HA/rADSCs into joint cavities. CD44 clustering, ERK phosphorylation, SOX-9 expression and SOX-9 phosphorylation in cultured hADSCs were further evaluated. Isolated and expanded rADSCs showed multilineage potential and anchorage-independent growth properties. Cell aggregation, chondrogenic gene expression, and sGAG deposition increased with increasing HA Mw in rADSCs. The 2000 kDa HA had the most pronounced chondrogenic effect on rADSCs in vitro, and implanted 2000 kDa HA/rADSCs exhibited marked cartilaginous tissue formation in vivo. CD44 clustering and cell aggregation of hADSCs were enhanced by an increase in HA Mw. In addition, higher HA Mws further enhanced CD44 clustering, ERK phosphorylation, and SOX-9 expression and phosphorylation in hADSCs. Inhibiting CD44 clustering in hADSCs reduced HA-induced chondrogenic gene expression. Inhibiting ERK phosphorylation also simultaneously attenuated HA-induced SOX-9 expression and phosphorylation and chondrogenic gene expression in hADSCs. Our results indicate that HA initiates ADSC chondrogenesis and that higher Mw HAs exhibit stronger effects, with 2000 kDa HA having the strongest effect. These effects may be mediated through increased CD44 clustering and the ERK/SOX-9 signaling pathway.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.025
       
  • Injectable nanocomposite cryogels for versatile protein drug delivery
    • Authors: Sandeep T. Koshy; David K.Y. Zhang; Joshua M. Grolman; Alexander G. Stafford; David J. Mooney
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): Sandeep T. Koshy, David K.Y. Zhang, Joshua M. Grolman, Alexander G. Stafford, David J. Mooney
      Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems. Statement of Significance Here we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein’s activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.024
       
  • Mono vs multilayer Fibronectin coatings on polar/hydrophobic/ionic
           polyurethanes: Altering surface interactions with human monocytes
    • Authors: Audrey Gossart; Kyle G. Battiston; Adeline Gand; Emmanuel Pauthe; J Paul Santerre
      Abstract: Publication date: Available online 8 November 2017
      Source:Acta Biomaterialia
      Author(s): Audrey Gossart, Kyle G. Battiston, Adeline Gand, Emmanuel Pauthe, J Paul Santerre
      Monocyte interactions with materials that are biofunctionalized with fibronectin (Fn) are of interest because of the documented literature which associates this protein with white blood cell function at implant sites. A degradable-polar hydrophobic ionic polyurethane (D-PHI), has been reported to promote an anti-inflammatory response from human monocytes. The aim of the current work was to study the influence of intrinsic D-PHI material chemistry on Fn adsorption (mono and multi-layer structures), and to investigate the influence of such chemistry on the structural state of the Fn, as well as the latter’s influence on the activity of human monocytes on the protein coated substrates. Significant differences in Fn adsorption, surface hydrophobicity and the availability of defined peptide sequences (N terminal, C terminal or Cell Binding Domain) for the Fn in mono vs multilayer structures were observed as a function of the changes in intrinsic material chemistry. A D-PHI-formulated polyurethane substrate with subtle changes in anionic and hydrophobic domain content relative to the polar non-ionic urethane/carbonate groups within the polymer matrix promoted the lowest activation of monocytes, in the presence of multi-layer Fn constructs. These results highlight the importance of chemical heterogeneity as a design parameter for biomaterial surfaces, and establishes a desired strategy for controlling human monocyte activity at the surface of devices, when these are coated with multi-layer Fn structures. The latter is an important step towards functionalizing the materials with multi-layer protein drug carriers as interventional therapeutic agents. Statement of Significance The control of the behavior of monocytes, especially migration and activation, is of crucial interest to modulate the inflammatory response at the site of implanted biomaterial. Several studies report the influence of adsorbed serum proteins on the behavior of monocytes on biomaterials. However, few studies show the influence of surface chemical group distribution on the controlled adsorption and the subsequent induced conformation- of mono versus multi-layer assembled structures generated from specific proteins implicated in wound repair. The current research considered the role of Fn adsorption and conformation in thin films while interacting with the intrinsic chemistry of segmented block polyurethanes; and the influence of the former on modulation and activation of human monocytes.
      Graphical abstract image

      PubDate: 2017-11-11T11:42:31Z
      DOI: 10.1016/j.actbio.2017.11.013
       
 
 
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