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Publisher: Elsevier   (Total: 3030 journals)

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Showing 1 - 200 of 3030 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 20, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 16, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 79, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 22, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 27, 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: 303, 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  
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: 196, 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: 9, 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: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 21, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 5, 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)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
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)
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: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 120, 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: 16, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 8, 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: 24, 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)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 21, 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: 26, 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 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: 24, 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: 8, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, 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 Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
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: 39, 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: 38, 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: 41, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
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: 18, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
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: 33, 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: 4)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 7, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
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: 5, 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: 21)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 6, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
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: 20, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 14)
Advances in Pharmacology     Full-text available via subscription   (Followers: 13, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, 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: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 56)
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: 1, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 332, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 7)
Advances in Surgery     Full-text available via subscription   (Followers: 6, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 28, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 14)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 12)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 42, 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: 304, 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: 4, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 7, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 390, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 29, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 36, 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: 48, 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: 3, 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: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 5)
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  
Algal Research     Partially Free   (Followers: 7, 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: 5, SJR: 0.776, h-index: 35)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 6, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 45, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 45, 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: 34, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, 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: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 31, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 48, 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: 174, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 51, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
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: 22, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 23, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 32, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 13, 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: 52, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 3)
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: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 154, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 7, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 10)
Anesthésie & Réanimation     Full-text available via subscription  
Anesthesiology Clinics     Full-text available via subscription   (Followers: 21, 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: 143, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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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  [3030 journals]
  • Topography of calcium phosphate ceramics regulates primary cilia length
           and TGF receptor recruitment associated with osteogenesis
    • Abstract: Publication date: Available online 27 April 2017
      Source:Acta Biomaterialia
      Author(s): Jingwei Zhang, Melis Dalbay, Xiaoman Luo, Erik Vrij, Davide Barbieri, Lorenzo Moroni, Joost D. de Bruijn, Clemens A. van Blitterswijk, Paul Chapple, Martin M. Knight, Huipin Yuan
      The surface topography of synthetic biomaterials is known to play a role in material-driven osteogenesis. Recent studies show that TGFβ signaling also initiates osteogenic differentiation. TGFβ signaling requires the recruitment of TGFβ receptors (TGFβR) to the primary cilia. In this study, we hypothesize that the surface topography of calcium phosphate ceramics regulates stem cell morphology, primary cilia structure and TGFβR recruitment to the cilium associated with osteogenic differentiation. We developed a 2D system using two types of tricalcium phosphate (TCP) ceramic discs with identical chemistry. One sample had a surface topography at micron-scale (TCP-B, with a bigger surface structure dimension) whilst the other had a surface topography at submicron scale (TCP-S, with a smaller surface structure dimension). In the absence of osteogenic differentiation factors, human bone marrow stromal cells (hBMSCs) were more spread on TCP-S than on TCP-B with alterations in actin organization and increased primary cilia prevalence and length. The cilia elongation on TCP-S was similar to that observed on glass in the presence of osteogenic media and was followed by recruitment of transforming growth factor-β RII (p-TGFβ RII) to the cilia axoneme. This was associated with enhanced osteogenic differentiation of hBMSCs on TCP-S, as shown by alkaline phosphatase activity and gene expression for key osteogenic markers in the absence of additional osteogenic growth factors. Similarly, in vivo after a 12-week intramuscular implantation in dogs, TCP-S induced bone formation while TCP-B did not. It is most likely that the surface topography of calcium phosphate ceramics regulates primary cilia length and ciliary recruitment of p-TGFβ RII associated with osteogenesis and bone formation. This bioengineering control of osteogenesis via primary cilia modulation may represent a new type of biomaterial-based ciliotherapy for orthopedic, dental and maxillofacial surgery applications Statement of significance The surface topography of synthetic biomaterials plays important roles in material-driven osteogenesis. The data presented herein have shown that the surface topography of calcium phosphate ceramics regulates mesenchymal stromal cells (e.g., human bone marrow mesenchymal stromal cells, hBMSCs) with respect to morphology, primary cilia structure and TGFβR recruitment to the cilium associated with osteogenic differentiation in vitro. Together with bone formation in vivo, our results suggested a new type of biomaterial-based ciliotherapy for orthopedic, dental and maxillofacial surgery by the bioengineering control of osteogenesis via primary cilia modulation.
      Graphical abstract image

      PubDate: 2017-04-28T10:17:10Z
       
  • Highly degradable porous melt-derived bioactive glass foam scaffolds for
           bone regeneration
    • Abstract: Publication date: Available online 27 April 2017
      Source:Acta Biomaterialia
      Author(s): Amy Nommeots-Nomm, Sheyda Labbaf, Aine Devlin, Naomi Todd, Hua Geng, Anu K. Solanki, Hok Man Tang, Polytimi Perdika, Alessandra Pinna, Fatemeh Ejeian, Olga Tsigkou, Peter D. Lee, Mohammad Hossein Nasr Esfahani, Christopher A. Mitchell, Julian R. Jones
      A challenge in using bioactive melt-derived glass in bone regeneration is to produce scaffolds with interconnected pores while maintaining the amorphous nature of the glass and its associated bioactivity. Here we introduce a method for creating porous melt-derived bioactive glass foam scaffolds with low silica content and report in vitro and preliminary in vivo data. The gel-cast foaming process was adapted, employing temperature controlled gelation of gelatin, rather than the in situ acrylic polymerisation used previously. To form a 3D construct from melt derived glasses, particles must be fused via thermal processing, termed sintering. The original Bioglass® 45S5 composition crystallises upon sintering, altering its bioactivity, due to the temperature difference between the glass transition temperature and the crystallisation onset being small. Here, we optimised and compared scaffolds from three glass compositions, ICIE16, PSrBG and 13-93, which were selected due to their widened sintering windows. Amorphous scaffolds with modal pore interconnect diameters between 100-150 µm and porosities of 75% had compressive strengths of 3.4 ± 0.3 MPa, 8.4 ± 0.8 MPa and 15.3 ± 1.8 MPa, for ICIE16, PSrBG and 13-93 respectively. These porosities and compressive strength values are within the range of cancellous bone, and greater than previously reported foamed scaffolds. Dental pulp stem cells attached to the scaffold surfaces during in vitro culture and were viable. In vivo, the scaffolds were found to regenerate bone in a rabbit model according to X-ray micro tomography imaging. Statement of Significance This manuscript describes a new method for making scaffolds from bioactive glasses using highly bioactive glass compositions. The glass compositions have lower silica content that those that have been previously made into amorphous scaffolds and they have been designed to have similar network connectivity to that of the original (and commercially used) 45S5 Bioglass. The aim was to match Bioglass’ bioactivity. The scaffolds retain the amorphous nature of bioactive glass while having an open pore structure and compressive strength similar to porous bone (the original 45S5 Bioglass crystallises during sintering, which can cause reduced bioactivity or instability). The new scaffolds showed unexpectedly rapid bone regeneration in a rabbit model.
      Graphical abstract image

      PubDate: 2017-04-28T10:17:10Z
       
  • Controlled release of GAG-binding Enhanced Transduction (GET) peptides for
           sustained and highly efficient intracellular delivery
    • Abstract: Publication date: Available online 27 April 2017
      Source:Acta Biomaterialia
      Author(s): Hosam Al-Deen M. Abu-Awwad, Lalitha Thiagarajan, James E. Dixon
      Controlled release systems for therapeutic molecules are vital to allow the sustained local delivery of their activities which direct cell behaviour and enable novel regenerative strategies. Direct programming of cells using exogenously delivered transcription factors can by-pass growth factor signalling but there is still a requirement to deliver such activity spatio-temporally. We previously developed a technology termed GAG-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding domains which promote cell targeting, and cell penetrating peptides (CPPs) which allow cell entry. Herein we demonstrate that GET system can be used in controlled release systems to mediate sustained intracellular transduction over one week. We assessed the stability and activity of GET peptides in poly(DL-lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) prepared using S/O/W double emulsion method. Efficient encapsulation (∼65%) and tailored protein release profiles could be achieved, however intracellular transduction was significantly inhibited post-release. To retain GET peptide activity we optimised a strategy of co-encapsulation of L-Histidine, which may form a complex with the PLGA degradation products under acidic conditions. Simulations of the polymer microclimate showed that hydrolytic acidic PLGA degradation products directly inhibited GET peptide transduction activity, and use of L-Histidine significantly enhanced released protein delivery. The ability to control the intracellular transduction of functional proteins into cells will facilitate new localised delivery methods and allow approaches to direct cellular behaviour for many regenerative medicine applications. Statement of significance The goal for regenerative medicine is to restore functional biological tissue by controlling and augmenting cellular behavior. Either Transcription (TFs) or growth factors (GFs) can be presented to cells in spatio-temporal gradients for programming cell fate and gene expression. Here, we have created a sustained and controlled release system for GET (Glycosaminoglycan-enhanced transducing)-tagged proteins using S/O/W PLGA microparticle fabrication. We demonstrated that PLGA and its acidic degradants inhibit GET-mediated transduction, which can be overcome by using pH-activated L-Histidine. L-Histidine inhibits the electrostatic interaction of GET/PLGA and allows enhanced intracellular transduction. GET could provide a powerful tool to program cell behaviour either in gradients or with sustained delivery. We believe that our controlled release systems will allow application of GET for tissue regeneration directly by TF cellular programming.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Development of a Local Anesthetic Lidocaine-loaded Redox-active Injectable
           Gel for Postoperative Pain Management
    • Abstract: Publication date: Available online 27 April 2017
      Source:Acta Biomaterialia
      Author(s): Yukio Nagasaki, Yutaro Mizukoshi, Zhenyu Gao, Chitho P. Feliciano, Kyungho Chang, Hiroshi Sekiyama, Hiroyuki Kimura
      Although local anesthesia is commonly applied for pain relief, there are several issues such as its short duration of action and low effectiveness at the areas of inflammation due to the acidic pH. The presence of excessive amount of reactive oxygen species (ROS) is known to induce inflammation and aggravate pain. To resolve these issues, we developed a redox-active injectable gel (RIG) with ROS-scavenging activity. RIG was prepared by mixing polyamine-b-poly(ethylene glycol)-b-polyamine with nitroxide radical moieties as side chains on the polyamine segments (PMNT-b-PEG-b-PMNT) with a polyanion, which formed a flower-type micelle via electrostatic complexation. Lidocaine could be stably incorporated in its core. When the temperature of the solution was increased to 37 °C, the PIC-type flower micelle transformed to gel. The continuous release of lidocaine from the gel was observed for more than three days, without remarkable initial burst, which is probably owing to the stable entrapment of lidocaine in the PIC core of the gel. We evaluated the analgesic effect of RIG in carrageenan-induced arthritis mouse model. Results showed that lidocaine-loaded RIG has stronger and longer analgesic effect when administered in inflamed areas. In contrast, while the use of non-complexed lidocaine did not show analgesic effect one day after its administration. Note that no effect was observed when PIC-type flower micelle without ROS-scavenging ability was used. These findings suggest that local anesthetic-loaded RIG can effectively reduce the number of injection times and limit the side effects associated with the use of anti-inflammatory drugs for postoperative pain management. Statement of Significance We have been working on nanomaterials, which effectively eliminate ROS, avoiding dysfunction of mitochondria in healthy cells. We designed redox injectable gel using polyion complexed flower type micelle, which can eliminates ROS locally. We could prepare local anesthesia-loaded trdox injectable gel (lido@RIG). Drug release could be extended by local administration of lido@RIG. Deprotonation of lidocaine improved anesthetic effect because ROS were eliminated locally by RIG. Local inflammation could be also suppressed by lido@RIG.
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      PubDate: 2017-04-28T10:17:10Z
       
  • pH-sensitive polymeric nanoparticles for co-delivery of doxorubicin and
           curcumin to treat cancer via enhanced pro-apoptotic and anti-angiogenic
           activities
    • Abstract: Publication date: Available online 26 April 2017
      Source:Acta Biomaterialia
      Author(s): Jinming Zhang, Jingjing Li, Zhi Shi, Yang Yang, Xi Xie, Simon MingYuen Lee, Yitao Wang, Kam W. Leong, Meiwan Chen
      Co-delivery of multiple drugs with complementary anticancer mechanisms by nano-carriers offers an effective strategy to treat cancer. The combination of drugs with pro-apoptotic and anti-angiogenic activities is potentially effective in treating human hepatocellular carcinoma (HCC). Herein, we developed a co-delivery system for doxorubicin (Dox), a pro-apoptotic drug, and curcumin (Cur), a potent drug for antiangiogenesis, in pH-sensitive nanoparticles (NPs) constituted with amphiphilic poly(β-amino ester) copolymer. Dox & Cur co-loaded NPs ((D+C)/NPs) were prepared with optimized drug ratio, showing low polydispersity, high encapsulation efficiency, and enhanced release in the acidic environment of cancer cells. Furthermore, enhanced cellular internalization of cargoes delivered from (D+C)/NPs were observed in human liver cancer SMMC 7721 cells and human umbilical vein endothelial cells (HUVECs) compared to the use of free drugs. The (D+C)/NPs induced a high rate of apoptosis in SMMC 7721 cells through decreased mitochondrial membrane potential. Additionally, (D+C)/NPs exhibited stronger anti-angiogenic effects including inhibition of HUVEC proliferation, migration, invasion, and tube formation mediated VEGF pathway modulation in vitro and in vivo. Taken together, encapsulation of the pro-apoptotic drug Dox and antiangiogenic agent Cur in pH-sensitive NPs provides a promising strategy to effectively inhibit HCC progression in a synergistic manner. Statement of Significance The combination of multiple drugs has been demonstrated to be more effective than single treatment. However, the different physicochemical and pharmacokinetic profiles of each drug render optimal delivery challenging. In view of the great delivery advantage of nanocarriers to unify the multiple drugs in vivo, stimulus-responsive nano-carriers are more crucial to increase efficacy and reduce toxicity from off-target exposure. Therefore, herein the pH-sensitive nanoparticles, composed by D-α-tocopheryl polyethylene glycol 1000-block-poly (β-amino ester) (TPGS-PAE) polymers, have been fabricated for doxorubicin (Dox) and curcumin (Cur) co-delivery, which exhibited diverse anticancer approaches, i.e. pro-apoptosis and antiangiogenesis. The precise intracellular target site and effective drug combination concentration result in the enhanced antitumor efficiency and the reduced systematic toxicity of Dox. The co-encapsulation of the pro-apoptotic drug and antiangiogenic agent in pH-sensitive NPs provides a promising strategy to effectively inhibit malignant neoplasm progression in a synergistic manner.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Site-Specific Characterization of Beetle Horn Shell with Micromechanical
           Bending Test in Focused Ion Beam System
    • Abstract: Publication date: Available online 26 April 2017
      Source:Acta Biomaterialia
      Author(s): Hyun-Taek Lee, Ho-Jin Kim, Chung-Soo Kim, Kenji Gomi, Minoru Taya, Shûhei Nomura, Sung-Hoon Ahn
      Biological materials are the result of years of evolution and possess a number of efficient features and structures. Researchers have investigated the possibility of designing biomedical structures that take advantage of these structural features. Insect shells, such as beetle shells, are among the most promising types of biological material for biomimetic development. However, due to their intricate geometries and small sizes, it is challenging to measure the mechanical properties of these microscale structures. In this study, we developed an in-situ testing platform for site-specific experiments in a focused ion beam (FIB) system. Multi-axis nano-manipulators and a micro-force sensor were utilized in the testing platform to allow better results in the sample preparation and data acquisition. The entire test protocol, consisting of locating sample, ion beam milling and micro-mechanical bending tests, can be carried out without sample transfer or reattachment. We used our newly devised test platform to evaluate the micromechanical properties and structural features of each separated layer of the beetle horn shell. The Young’s modulus of both the exocuticle and endocuticle layers was measured. We carried out a bending test to characterize the layers mechanically. The exocuticle layer bent in a brick-like manner, while the endocuticle layer exhibited a crack blunting effect. Statement of Significance This paper proposed an in-situ manipulation/test method in focused ion beam for characterizing micromechanical properties of beetle horn shell. The challenge in precise and accurate fabrication for the samples with complex geometry was overcome by using nano-manipulators having multi-degree of freedom and a micro-gripper. With the aid of this specially designed test platform, bending tests were carried out on cantilever-shaped samples prepared by focused ion beam milling. Structural differences between exocuticle and endocuticle layers of beetle horn shell were explored and the results provided insight into the structural advantages of each biocomposite structure.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Age-dependent Functional Crosstalk Between Cardiac Fibroblasts and
           Cardiomyocytes in a 3D Engineered Cardiac Tissue
    • Abstract: Publication date: Available online 25 April 2017
      Source:Acta Biomaterialia
      Author(s): Yanzhen Li, Huda Asfour, Nenad Bursac
      Complex heterocellular interactions between cardiomyocytes and fibroblasts in the heart involve their bidirectional signaling via cell-cell contacts, paracrine factors, and extracellular matrix (ECM). These interactions vary with heart development and pathology leading to changes in cardiac structure and function. Whether cardiac fibroblasts of different ages interact differentially with cardiomyocytes to distinctly impact their function remains unknown. Here, we explored the direct structural and functional effects of fetal and adult cardiac fibroblasts on cardiomyocytes using a tissue-engineered 3D co-culture system. We show that the age of cardiac fibroblasts is a strong determinant of the structure, function, and molecular properties of co-cultured tissues. In particular, in vitro expanded adult, but not fetal, cardiac fibroblasts significantly deteriorated electrical and mechanical function of the co-cultured cardiomyocytes, as evidenced by slower action potential conduction, prolonged action potential duration, weaker contractions, higher tissue stiffness, and reduced calcium transient amplitude. This functional deficit was associated with structural and molecular signatures of pathological remodeling including fibroblast proliferation, interstitial collagen deposition, and upregulation of pro-fibrotic markers. Our studies imply critical roles of the age of supporting cells in engineering functional cardiac tissues and provide a new physiologically relevant in vitro platform to investigate influence of heterocellular interactions on cardiomyocyte function, development, and disease. Statement of Significance Previous studies have shown that cardiomyocytes and fibroblasts in the heart interact through direct contacts, paracrine factors, and matrix-mediated crosstalk. However, whether cardiac fibroblasts of different ages distinctly impact cardiomyocyte function remains elusive. We employed a tissue-engineered hydrogel-based co-culture system to study interactions of cardiomyocytes with fetal or adult cardiac fibroblasts. We show that the age of cardiac fibroblasts is a strong determinant of the structure, function, and molecular properties of engineered cardiac tissues and that key features of fibrotic myocardium are replicated by supplementing cardiomyocytes with adult but not fetal fibroblasts. These findings relate to implantation of stem cell-derived cardiomyocytes in adult myocardium and warrant further studies of how age and source of non-myocytes impact cardiac function and maturation.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Inhibition of Allogeneic Cytotoxic T Cell (CD8+) Proliferation Via
           Polymer-Induced Treg (CD4+) Cells
    • Abstract: Publication date: Available online 23 April 2017
      Source:Acta Biomaterialia
      Author(s): Ning Kang, Wendy M. Toyofuku, Xining Yang, Mark D. Scott
      T cell-mediated immune rejection remains a barrier to successful transplantation. Polymer-based bioengineering of cells may provide an effective means of preventing allorecognition and the proliferation of cytotoxic (CD8+) T lymphocytes (CTL). Using MHC-disparate murine splenocytes modified with succinimidyl valerate activated methoxypoly(ethylene glycol) [SVA-mPEG] polymers, the effects of leukocyte immunocamouflage on CD8+ and CD4+ alloproliferation and T regulatory (Treg) cell induction were assessed in a mixed lymphocyte reaction (MLR) model. Polymer-grafting effectively camouflaged multiple leukocyte markers (MHC class I and II, TCR and CD3) essential for effective allorecognition. Consequent to the polymer-induced immunocamouflage of the cell membrane, both CD8+ and CD4+ T cell alloproliferation were significantly inhibited in a polymer dose-dependent manner. The loss of alloproliferation correlated with the induction of Treg cells (CD4+CD25+Foxp3+). The Tregs, surprisingly, arose primarily via differentiation of naive, non-proliferating, CD4+ cells. Of biologic importance, the polymer-induced Treg were functional and exhibited potent immunosuppressive activity on allogeneic CTL proliferation. These results suggest that immunocamouflage-mediated attenuation of alloantigen-TCR recognition can prevent the tissue destructive allogeneic CD8+ T cell response, both directly and indirectly, through the generation/differentiation of functional Tregs. Immunocamouflage induced tolerance could be clinically valuable in attenuating T cell-mediated transplant rejection and in the treatment of autoimmune diseases. Statement of significance While our previous studies have demonstrated that polymer-grafting to MHC disparate leukocytes inhibits CD4+ cell proliferation, the effects of PEGylation of on the alloproliferation of CD8+ cytotoxic T cells (CTL) was not examined. As shown here, PEGylation of allogeneic leukocytes prevents the generation of the CTL response responsible for acute rejection. The loss of CTL proliferation is consequent to the polymer-based attenuation of allorecognition and the induction of T regulatory cells (Tregs). Interestingly, the Tregs are primarily generated via the differentiation of non-proliferating naive T cells. Importantly, the Tregs are functional and effectively induce a tolerogenic environment when transferred to an alloresponsive environment. The use of polymer-modified leukocytes provides a unique approach to effectively maximize the biologic production of functional Tregs both in vitro and in vivo. By using this approach it may be possible to attenuate unwanted alloresponses (e.g., graft rejection) or to While our previous studies have demonstrated that polymer-grafting to MHC disparate leukocytes inhibits CD4+ cell proliferation, the effects of PEGylation of on the alloproliferation of CD8+ cytotoxic T cells (CTL) was not examined. As shown here, PEGylation of allogeneic leukocytes prevents the generation of the CTL response responsible for acute rejection. The loss of CTL proliferation is consequent to the polymer-based attenuation of allorecognition and the induction of T regulatory cells (Tregs). Interestingly, the Tregs are primarily generated via the differentiation of non-proliferating naive T cells. Importantly, the Tregs are functional and effectively induce a tolerogenic environment when transferred to an alloresponsive environment. The use of polymer-modified leukocytes provides a unique approach to effectively maximize the biologic production of functional Tregs both in vitro and in vivo. By using this approach it may be possible to attenuate unwanted alloresponses (e.g., graft rejection) or to
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      PubDate: 2017-04-28T10:17:10Z
       
  • Folic Acid-Decorated Polyamidoamine Dendrimer Exhibits High Tumor Uptake
           and Sustained Highly Localized Retention in Solid Tumors: Its Utility for
           Local siRNA Delivery
    • Abstract: Publication date: Available online 22 April 2017
      Source:Acta Biomaterialia
      Author(s): Leyuan Xu, W. Andrew Yeudall, Hu Yang
      The utility of folic acid (FA)-decorated polyamidoamine dendrimer G4 (G4-FA) as a vector was investigated for local delivery of siRNA. In a xenograft HN12 (or HN12-YFP) tumor mouse model of head and neck squamous cell carcinomas (HNSCC), intratumorally (i.t.) injected G4-FA exhibited high tumor uptake and sustained highly localized retention in the tumors according to near infrared (NIR) imaging assessment. siRNA against vascular endothelial growth factor A (siVEGFA) was chosen as a therapeutic modality. Compared to the nontherapeutic treatment groups (PBS solution or dendrimer complexed with nontherapeutic green fluorescent protein siRNA [siGFP]), G4-FA/siVEGFA showed tumor inhibition effects in single-dose and two-dose regimen studies. In particular, two doses of G4-FA/siVEGFA i.t. administered eight days apart resulted in a more profound inhibition of tumor growth, accompanied with significant reduction in angiogenesis, as judged by CD31 staining and microvessel counts. Tumor size reduction in the two-dose regimen study was ascertained semi-quantitatively by live fluorescence imaging of YFP tumors and independently supported antitumor effects of G4-FA/siVEGFA. Taken together, G4-FA shows high tumor uptake and sustained retention properties, making it a suitable platform for local delivery of siRNAs to treat cancers that are readily accessible such as HNSCC. Statement of Significance Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is difficult to transfect for gene therapy. We developed folate receptor (FA)-targeted polyamidoamine (PAMAM) dendrimer for enhanced delivery of genes to HNSCC and gained in-depth understanding of how gene delivery and transfection in head and neck squamous cancer cells can be enhanced via FR-targeted PAMAM dendrimers. The results we report here are encouraging and present latest advances in using dendrimers for cancer therapies, in particular for HNSCC. Our work has demonstrated that localized delivery of FR-targeted PAMAM dendrimer G4 complexed with siVEGFA resulted in pronounced tumor suppression in an HN12 xenograft tumor model. Tumor suppression was attributed to enhanced tumor uptake of siRNA and prolonged nanoparticle retention and infiltration in the tumor. Taken together, G4-FA shows high tumor uptake and sustained highly localized retention properties, making it a suitable platform for local delivery of siRNAs to treat cancers that are readily accessible for injection of therapeutics such as HNSCC.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Retro-inverso D-peptide-modified HA/RHB/pDNA core-shell ternary
           nanoparticles for the dual-targeted delivery of short hairpin RNA-encoding
           plasmids
    • Abstract: Publication date: Available online 22 April 2017
      Source:Acta Biomaterialia
      Author(s): Jijin Gu, Xinyi Chen, Xiaoling Fang, Xianyi Sha
      The active targeting of gene carriers is a powerful strategy for improving tumour-specific delivery and therapy. Although numerous L-peptide ligands play significant roles in the active targeting of nanomedicine, retro-inverso D-peptides have been explored as targeting ligands due to their superior stability and bioactivity in vivo. In this study, retro-inverso D-peptide (RIF7)-modified hyaluronic acid (HA)/bioreducible hyperbranched poly(amido amine) (RHB)/plasmid DNA (pDNA) ternary nanoparticles were successfully developed using the layer-by-layer method for the CD44-positive tumour-specific delivery of short hairpin RNA-encoding pDNA through the synergistic reaction of the Anxa1 (tumour vasculature) and CD44 (tumour cell-surface) receptors, which mediated the dual targeting. The potential of these newly designed nanoparticles was evaluated by examining the efficacy of their cellular uptake and transfection in cell monolayers, tumour spheroids, and malignant xenograft animal models. With negligible cytotoxicity, the spherical-shaped RIF7-HA/RHB/pDNA nanoparticles were the direct result of an electrostatic complex that had efficiently targeted CD44-positive tumour delivery, penetration, and cellular uptake in vitro. The nanoparticles showed excellent target-specific gene transfection even in the presence of serum. The in vivo therapeutic effect of RIF7-HA/RHB/pDNA-shRNA nanoparticle-mediated shRNA targeting of the Cyclin gene (shCyclin) was evaluated in tumour-bearing mice. The RIF7-HA/RHB/pDNA-shCyclin nanoparticles significantly increased the survival time of tumour-bearing mice and substantially reduced tumour growth due to their extremely specific tumour-targeting activity. These results suggested that the combination of HA and retro-inverso peptide RIF7 significantly increased the therapeutic effect of pDNA-shCyclin-loaded nanoparticles for CD44-positive tumours. Thus, RIF7-HA-mediated multi-target ternary gene vectors are an efficient and promising strategy for the delivery of pDNA-shRNA in the targeted treatment of malignant and metastatic cancers. Statement of Significance Although L-peptides ligands play significant roles in active targeting of nanomedicine, retro-inverso D-peptides have been explored as targeting ligands due to their superior stability and bioactivity in vivo. Retro-inverso peptide RIF7 was designed as a ligand of Anxa1 receptor. The resultant peptide, RIF7, displayed high binding efficiency within Anxa1 receptor highly expressed tumor vasculature cells and some tumor cells such as B16F10 and U87MG cells. The most important feature of RIF7 is its high stability in the blood which is suitable and promising for application in vivo. Multifunctional RIF7-HA was then synthesized by conjugated RIF7 peptide to HA, which was used to modify the surface of RHB/pDNA nanoparticles to prepare RIF7-HA/RHB/pDNA dual-targeting core/shell ternary nanoparticles for delivery plasmid expressing shRNA in vitro and in vivo.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Multilayered Membranes with Tuned Well Arrays to Be Used as Regenerative
           Patches
    • Abstract: Publication date: Available online 21 April 2017
      Source:Acta Biomaterialia
      Author(s): Nádia I. Martins, Maria P. Sousa, Catarina A. Custódio, Vânia C. Pinto, Paulo J. Sousa, Graça Minas, Franck Cleymand, João F. Mano
      Membranes have been explored as patches in tissue repair and regeneration, most of them presenting a flat geometry or a patterned texture at the nano/micrometer scale. Herein, a new concept of a flexible membrane featuring well arrays forming pore-like environments to accommodate cell culture is proposed. The processing of such membranes using polysaccharides is based on the production of multilayers using the layer-by-layer methodology over a patterned PDMS substrate. The detached multilayered membrane exhibits a layer of open pores at one side and a total thickness of 38 ± 2.2 µm. The photolithography technology used to produce the molds allows obtaining wells on the final membranes with a tuned shape and micro-scale precision. The influence of post-processing procedures over chitosan/alginate films with 100 double layers, including crosslinking with genipin or fibronectin immobilization, on the adhesion and proliferation of human osteoblast-like cells is also investigated. The results suggest that the presence of patterned wells affects positively cell adhesion, morphology and proliferation. In particular, it is seen that cells colonized preferentially the well regions. The geometrical features with micro to sub-millimeter patterned wells, together with the nano-scale organization of the polymeric components along the thickness of the film will allow to engineer highly versatile multilayered membranes exhibiting a pore-like microstructure in just one of the sides, that could be adaptable in the regeneration of multiple tissues. Statement of significance Flexible multilayered membranes containing multiple micro-reservoirs are found as potential regenerative patches. Layer-by-layer (LbL) methodology over a featured PDMS substrate is used to produce patterned membranes, composed only by natural-based polymers, that can be easily detached from the PDMS substrate. The combination of nano-scale control of the polymeric organization along the thickness of the chitosan/alginate (CHT/ALG) membranes, provided by LbL, together with the geometrical micro-scale features of the patterned membranes offers a uniqueness system that allows cells to colonize 3-dimensionally. This study provides a promising strategy to control cellular spatial organization that can face the region of the tissue to regenerate.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Biphasic calcium phosphate ceramics for bone reconstruction: A review of
           biological response
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): J.M. Bouler, P. Pilet, O. Gauthier, E. Verron
      Autologous bone graft is considered as the gold standard in bone reconstructive surgery. However, the quantity of bone available is limited and the harvesting procedure requires a second surgical site resulting in severe complications. Due to these limits, scientists and clinicians have considered alternatives to autologous bone graft. Calcium phosphates (CaPs) biomaterials including biphasic calcium phosphate (BCP) ceramics have proven efficacy in numerous clinical indications. Their specific physico-chemical properties (HA/TCP ratio, dual porosity and subsequent interconnected architecture) control (regulate/condition) the progressive resorption and the bone substitution process. By describing the most significant biological responses reported in the last 30years, we review the main events that made their clinical success. We also discuss about their exciting future applications as osteoconductive scaffold for delivering various bioactive molecules or bone cells in bone tissue engineering and regenerative medicine. Statement of Significance Nowadays, BCPs are definitely considered as the gold standard of bone substitutes in bone reconstructive surgery. Among the numerous clinical studies in literature demonstrating the performance of BCP, Passuti et al. and Randsford et al. studies largely contributed to the emergence of the BCPs. It could be interesting to come back to the main events that made their success and could explain their large adhesion from scientists to clinicians. This paper aims to review the most significant biological responses reported in the last 30years, of these BCP-based materials. We also discuss about their exciting future applications as osteoconductive scaffold for delivering various bioactive molecules or bone cells in bone tissue engineering and regenerative medicine.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Promoting tissue regeneration by modulating the immune system
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Ziad Julier, Anthony J. Park, Priscilla S. Briquez, Mikaël M. Martino
      The immune system plays a central role in tissue repair and regeneration. Indeed, the immune response to tissue injury is crucial in determining the speed and the outcome of the healing process, including the extent of scarring and the restoration of organ function. Therefore, controlling immune components via biomaterials and drug delivery systems is becoming an attractive approach in regenerative medicine, since therapies based on stem cells and growth factors have not yet proven to be broadly effective in the clinic. To integrate the immune system into regenerative strategies, one of the first challenges is to understand the precise functions of the different immune components during the tissue healing process. While remarkable progress has been made, the immune mechanisms involved are still elusive, and there is indication for both negative and positive roles depending on the tissue type or organ and life stage. It is well recognized that the innate immune response comprising danger signals, neutrophils and macrophages modulates tissue healing. In addition, it is becoming evident that the adaptive immune response, in particular T cell subset activities, plays a critical role. In this review, we first present an overview of the basic immune mechanisms involved in tissue repair and regeneration. Then, we highlight various approaches based on biomaterials and drug delivery systems that aim at modulating these mechanisms to limit fibrosis and promote regeneration. We propose that the next generation of regenerative therapies may evolve from typical biomaterial-, stem cell-, or growth factor-centric approaches to an immune-centric approach. Statement of Significance Most regenerative strategies have not yet proven to be safe or reasonably efficient in the clinic. In addition to stem cells and growth factors, the immune system plays a crucial role in the tissue healing process. Here, we propose that controlling the immune-mediated mechanisms of tissue repair and regeneration may support existing regenerative strategies or could be an alternative to using stem cells and growth factors. The first part of this review we highlight key immune mechanisms involved in the tissue healing process and marks them as potential target for designing regenerative strategies. In the second part, we discuss various approaches using biomaterials and drug delivery systems that aim at modulating the components of the immune system to promote tissue regeneration.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Cellular self-assembly and biomaterials-based organoid models of
           development and diseases
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Shivem B. Shah, Ankur Singh
      Organogenesis and morphogenesis have informed our understanding of physiology, pathophysiology, and avenues to create new curative and regenerative therapies. Thus far, this understanding has been hindered by the lack of a physiologically relevant yet accessible model that affords biological control. Recently, three-dimensional ex vivo cellular cultures created through cellular self-assembly under natural extracellular matrix cues or through biomaterial-based directed assembly have been shown to physically resemble and recapture some functionality of target organs. These “organoids” have garnered momentum for their applications in modeling human development and disease, drug screening, and future therapy design or even organ replacement. This review first discusses the self-organizing organoids as materials with emergent properties and their advantages and limitations. We subsequently describe biomaterials-based strategies used to afford more control of the organoid’s microenvironment and ensuing cellular composition and organization. In this review, we also offer our perspective on how multifunctional biomaterials with precise spatial and temporal control could ultimately bridge the gap between in vitro organoid platforms and their in vivo counterparts. Statement of Significance Several notable reviews have highlighted PSC-derived organoids and 3D aggregates, including embryoid bodies, from a development and cellular assembly perspective. The focus of this review is to highlight the materials-based approaches that cells, including PSCs and others, adopt for self-assembly and the controlled development of complex tissues, such as that of the brain, gut, and immune system.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Ultrasoft microwire neural electrodes improve chronic tissue integration
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Zhanhong Jeff Du, Christi L. Kolarcik, Takashi D.Y. Kozai, Silvia D. Luebben, Shawn A. Sapp, Xin Sally Zheng, James A. Nabity, X. Tracy Cui
      Chronically implanted neural multi-electrode arrays (MEA) are an essential technology for recording electrical signals from neurons and/or modulating neural activity through stimulation. However, current MEAs, regardless of the type, elicit an inflammatory response that ultimately leads to device failure. Traditionally, rigid materials like tungsten and silicon have been employed to interface with the relatively soft neural tissue. The large stiffness mismatch is thought to exacerbate the inflammatory response. In order to minimize the disparity between the device and the brain, we fabricated novel ultrasoft electrodes consisting of elastomers and conducting polymers with mechanical properties much more similar to those of brain tissue than previous neural implants. In this study, these ultrasoft microelectrodes were inserted and released using a stainless steel shuttle with polyethyleneglycol (PEG) glue. The implanted microwires showed functionality in acute neural stimulation. When implanted for 1 or 8weeks, the novel soft implants demonstrated significantly reduced inflammatory tissue response at week 8 compared to tungsten wires of similar dimension and surface chemistry. Furthermore, a higher degree of cell body distortion was found next to the tungsten implants compared to the polymer implants. Our results support the use of these novel ultrasoft electrodes for long term neural implants. Statement of Significance One critical challenge to the translation of neural recording/stimulation electrode technology to clinically viable devices for brain computer interface (BCI) or deep brain stimulation (DBS) applications is the chronic degradation of device performance due to the inflammatory tissue reaction. While many hypothesize that soft and flexible devices elicit reduced inflammatory tissue responses, there has yet to be a rigorous comparison between soft and stiff implants. We have developed an ultra-soft microelectrode with Young’s modulus lower than 1MPa, closely mimicking the brain tissue modulus. Here, we present a rigorous histological comparison of this novel ultrasoft electrode and conventional stiff electrode with the same size, shape and surface chemistry, implanted in rat brains for 1-week and 8-weeks. Significant improvement was observed for ultrasoft electrodes, including inflammatory tissue reaction, electrode-tissue integration as well as mechanical disturbance to nearby neurons. A full spectrum of new techniques were developed in this study, from insertion shuttle to in situ sectioning of the microelectrode to automated cell shape analysis, all of which should contribute new methods to the field. Finally, we showed the electrical functionality of the ultrasoft electrode, demonstrating the potential of flexible neural implant devices for future research and clinical use.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Identification of the mechanisms by which age alters the
           mechanosensitivity of mesenchymal stromal cells on substrates of differing
           stiffness: Implications for osteogenesis and angiogenesis
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Sara Barreto, Arlyng Gonzalez-Vazquez, Andrew R. Cameron, Brenton Cavanagh, Dylan J. Murray, Fergal J. O'Brien
      In order to identify the mechanisms by which skeletal maturity alters the mechanosensitivity of mesenchymal stromal cells (MSCs) and, the implications for osteogenesis and angiogenesis during bone formation, we compared the response of MSCs derived from children and skeletally-mature healthy adults cultured on soft and stiff collagen-coated polyacrylamide substrates. MSCs from children were more mechanosensitive, showing enhanced angiogenesis and osteogenesis on stiff substrates as indicated by increased endothelial tubule formation, PGF production, nuclear-translocation of YAP, ALP activity and mineralisation. To examine these mechanisms in more detail, a customised PCR array identified an age-dependent, stiffness-induced upregulation of NOX1, VEGFR1, VEGFR2, WIF1 and, of particular interest, JNK3 in cells from children compared to adults. When JNK3 activity was inhibited, a reduction in stiffness-induced driven osteogenesis was observed – suggesting that JNK3 might serve as a novel target for recapitulating the enhanced regenerative potential of children in adults suffering from bone degeneration. Statement of Significance We investigated the age-associated changes in the capacity of MSCs for bone regeneration involving the mechanosensitive signalling pathways, which reduce the ability of adult cells to respond to biophysical cues in comparison to cells from children, who are still undergoing bone development. Our results offer new insights into the mechanobiology of MSCs and sheds new light on age-altered mechanosensitivity and, on why children have such an immense capacity to regenerate their skeletal system. We have identified the mechanisms by which skeletal maturity alters the mechanosensitivity of mesenchymal stromal cells and an age-dependent, stiffness-induced upregulation of a number of prominent genes including, most notably, JNK3 in children cells, thus suggesting its potential to promote enhanced bone repair.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Cell-instructive starPEG-heparin-collagen composite matrices
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Marcus Binner, Laura J. Bray, Jens Friedrichs, Uwe Freudenberg, Mikhail V. Tsurkan, Carsten Werner
      Polymer hydrogels can be readily modulated with regard to their physical properties and functionalized to recapitulate molecular cues of the extracellular matrix (ECM). However, they remain structurally different from the hierarchical supramolecular assemblies of natural ECM. Accordingly, we herein report a set of hydrogel composite materials made from starPEG-peptide conjugates, maleimide-functionalized heparin and collagen type I that combine semisynthetic and ECM-derived components. Collagen fibrillogenesis was controlled by temperature and collagen concentration to form collagen microstructures which were then homogeneously distributed within the 3D composite matrix during hydrogel formation. The collagen-laden hydrogel materials showed a heterogeneous local variation of the stiffness and adhesion ligand density. Composite gels functionalized with growth factors and cell adhesive peptides (RGDSP) supported the growth of embedded human umbilical cord vein endothelial cells (HUVECs) and induced the alignment of embedded bone marrow–derived human mesenchymal stem cells (MSCs) to the collagen microstructures in vitro. The introduced composite hydrogel material is concluded to faithfully mimic cell-instructive features of the ECM. Statement of Significance Cell-instructive materials play an important role in the generation of both regenerative therapies and advanced tissue and disease models. For that purpose, biofunctional polymer hydrogels recapitulating molecular cues of the extracellular matrix (ECM) were successfully applied in various different studies. However, hydrogels generally lack the hierarchical supramolecular structure of natural ECM. We have therefore developed a hydrogel composite material made from starPEG-peptide conjugates, maleimide-functionalized heparin and collagen type I fibrils. The collagen-laden scaffolds showed a heterogeneous local variation in the stiffness of the material. The composite gels were successfully tested in culture experiments with human umbilical cord vein endothelial cells and bone marrow–derived human mesenchymal stem cells. It was concluded that the composite scaffold was able to faithfully mimic important cell-instructive features of the ECM.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Thermoresponsive polymer-modified microfibers for cell separations
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Kenichi Nagase, Yoichi Sakurada, Satoru Onizuka, Takanori Iwata, Masayuki Yamato, Naoya Takeda, Teruo Okano
      Thermoresponsive polymer-modified microfibers were prepared through electrospinning of poly(4-vinylbenzyl chloride) (PVBC) and subsequent surface-initiated atom transfer radical polymerization for grafting poly(N-isopropylacrylamide) (PIPAAm). Electrospinning conditions were optimized to produce large-diameter (20μm) PVBC microfibers. The amount of PIPAAm grafted on the microfibers was controlled via the IPAAm monomer concentration. The microfibers exhibited thermally controlled cell separation by selective adhesion of normal human dermal fibroblasts in a mixed cell suspension that also contained human umbilical vein endothelial cells. In addition, adipose-derived stem cells (ADSCs) exhibited thermally modulated cell adhesion and detachment, while adhesion of other ADSC-related cells was low. Thus, ADSCs could be separated from a mixture of adipose tissue-derived cells simply by changing the temperature. Overall, the PIPAAm-modified microfibers are potentially applicable as temperature-modulated cell separation materials. Statement of Significance Thermoresponsive poly(N-isopropylacrylamide) (PIPAAm) polymer-modified poly(4-vinylbenzyl chloride) (PVBC) microfibers were prepared via electrospinning of PVBC, followed by surface-initiated ATRP. They formed effective thermally-modulated cell separation materials with large surface areas. Cells adhered and extended along the modified microfibers; this was not observed on previously reported PIPAAm-modified flat substrates. The cellular adhesion enabled separation of fibroblast cells, as well as that of adipose-derived mesenchymal stem cells, from mixtures of similar cells. Thus, the temperature-controlled thermoresponsive microfibers would be potentially useful as cell separation materials.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Strong tissue glue with tunable elasticity
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Regina Kelmansky, Brian J. McAlvin, Abraham Nyska, Jenny C. Dohlman, Homer H. Chiang, Michinao Hashimoto, Daniel S. Kohane, Boaz Mizrahi
      Many bio-adhesive materials adhere weakly to tissue due to their high water content and weak structural integrity. Others provide desirable adhesive strength but suffer from rigid structure and lack of elasticity after administration. We have developed two water-free, liquid four-armed PEG pre-polymers modified with NHS or with NH2 end groups which upon mixing changed from liquids to an elastic solid. The sealant and adhesive properties increased with the amount of the %v/v PEG4-NHS pre-polymer, and achieved adhesive properties comparable to those of cyanoacrylate glues. All mixtures showed minimal cytotoxicity in vitro. Mixtures of 90%v/v PEG4-NHS were retained in the subcutaneous space in vivo for up to 14days with minimal inflammation. This material’s combination of desirable mechanical properties and biocompatibility has potential in numerous biomedical applications. Statement of Significance Many bio-adhesive materials adhere weakly to tissue (e.g. hydrogels) due to their high water content and weak structural integrity. Others provide desirable mechanical properties but suffer from poor biocompatibility (e.g. cyanoacrylates). This study proposes a new concept for the formation of super strong and tunable tissue glues. Our bio-materials’ enhanced performance is the product of new neat (without water or other solvents) liquid polymers that solidify after administration while allowing interactions with the tissue. Moreover, the elastic modulus of these materials could easily be tuned without compromising biocompatibility. This system could be an attractive alternative to sutures and staples since it can be applied more quickly, causes less pain and may require less equipment while maintaining the desired adhesion strength.
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      PubDate: 2017-04-28T10:17:10Z
       
  • High-water-content and resilient PEG-containing hydrogels with low
           fibrotic response
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Yu Zhang, Duo An, Yehudah Pardo, Alan Chiu, Wei Song, Qingsheng Liu, Fang Zhou, Sean P. McDonough, Minglin Ma
      Hydrogels such as those based on polyethylene glycol (PEG) are broadly used in biomedicine where high water contents, robust mechanical properties such as resilience and favorable interactions with the body are often simultaneously desirable. However, the mechanical properties of conventional hydrogels often degrade rapidly after swelling or with increasing water content, limiting their potential in many applications. Here we describe a new class of PEG-containing hydrogels that remain highly resilient after maximum swelling. We achieved the hydrogels by incorporating reversible “dual” hydrogen bonding into highly coiled, elastic PEG networks. These hydrogels, due to their high water content and high mechanical resilience, can form highly permeable, yet durable and easy-to-handle cell delivery devices without any additional structural support. In addition, optimization of chemical composition resulted in hydrogels with superior bio-inertness, inducing much less fibrosis upon subcutaneous implantation in mice than a polyhydroxyethylmethacrylate (PHEMA) hydrogel control. Statement of Significance Hydrogels such as polyethylene glycol (PEG)-based ones are broadly used in the biomedical world. Examples include wound dressings, tissue scaffolds, medical implants, biosensors and drug or cell delivery devices. In many of these applications, robust mechanical property, high water content (or facile mass transfer) and favorable interactions with the body are often simultaneously desirable. However, the mechanical property of hydrogels often degrades rapidly after swelling or with increasing water content. Here we report a new class of PEG-based hydrogels that simultaneously possess high water content, high mechanical resilience and low fibrotic response upon subcutaneous implantation in mice. These hydrogels may therefore find broad applications in biomedicine.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Aspirin-Triggered Resolvin D1-modified materials promote the accumulation
           of pro-regenerative immune cell subsets and enhance vascular remodeling
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Mary Caitlin P. Sok, Maxianne C. Tria, Claire E. Olingy, Cheryl L. San Emeterio, Edward A. Botchwey
      Many goals in tissue engineering rely on modulating cellular localization and polarization of cell signaling, including the inhibition of inflammatory infiltrate, facilitation of inflammatory cell egress, and clearance of apoptotic cells. Omega-3 polyunsaturated fatty acid-derived resolvins are gaining increasing recognition for their essential roles in inhibition of neutrophil invasion into inflamed tissue and promotion of macrophage phagocytosis of cellular debris as well as their egress to the lymphatics. Biomaterial-based release of lipid mediators is a largely under-explored approach that provides a method to manipulate local lipid signaling gradients in vivo and direct the recruitment and/or polarization of anti-inflammatory cell subsets to suppress inflammatory signaling and enhance angiogenesis and tissue regeneration. The goal of this study was to encapsulate Aspirin-Triggered Resolvin D1 (AT-RvD1) into a degradable biomaterial in order to elucidate the effects of sustained, localized delivery in a model of sterile inflammation. Flow cytometric and imaging analysis at both 1 and 3days after injury showed that localized AT-RvD1 delivery was able significantly increase the accumulation of anti-inflammatory monocytes and M2 macrophages while limiting the infiltration of neutrophils. Additionally, cytokine profiling and longitudinal vascular analysis revealed a shift towards a pro-angiogenic profile with increased concentrations of VEGF and SDF-1α, and increased arteriolar diameter and tortuosity. These results demonstrate the ability of locally-delivered AT-RvD1 to increase pro-regenerative immune subpopulations and promote vascular remodeling. Statement of Significance This work is motivated by our efforts to explore the underlying mechanisms of inflammation resolution after injury and to develop biomaterial-based approaches to amplify endogenous mechanisms of resolution and repair. Though specific lipid mediators have been identified that actively promote the resolution of inflammation, biomaterial-based localized delivery of these mediators has been largely unexplored. We loaded Aspirin-Triggered Resolvin D1 into a PLGA scaffold and examined the effects of sustained, localized delivery on the innate immune response. We found that biomaterial delivery of resolvin was able to enhance the accumulation of pro-regenerative populations of immune cells, including anti-inflammatory monocytes, population that has never before been shown to respond to resolvin treatment, and also enhance vascular remodeling in response to tissue injury.
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      PubDate: 2017-04-28T10:17:10Z
       
  • The pressure-induced deformation response of the human lamina cribrosa:
           Analysis of regional variations
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Dan E. Midgett, Mary E. Pease, Joan L. Jefferys, Mohak Patel, Christian Franck, Harry A. Quigley, Thao D. Nguyen
      The objective of this study was to measure the pressure-induced deformation response of the human lamina cribrosa (LC) and analyze for variations with age and anatomical region. The posterior scleral cup of 8 eyes from 6 human donors was mounted onto a custom inflation chamber. A laser-scanning microscope was used for second harmonic generation (SHG) imaging of the collagen structure in the posterior volume of the LC at pressures from 5mmHg to 45mmHg. The SHG volumes were analyzed by the Fast-Fourier Iterative Digital Volume Correlation (DVC) algorithm for the three dimensional (3D) displacement field. The components of the Green–Lagrange strain tensor and the in-plane principal and maximum shear strains were evaluated from the DVC displacement field for the central and peripheral regions of the LC and the nasal, temporal, inferior, and superior quadrants surrounding the central retinal artery and vein. Among the major findings were that older age was associated with lower strains, the maximum shear strain was larger in the peripheral than central region, and the maximum principal strain was lower in the nasal quadrant. The elliptical shape of the LC was also predictive of the biaxial strain ratio. Age-related and structure-related variations in the pressure-induced strains of the LC may contribute to the susceptibility and severity of optic nerve damage in glaucoma, and regional variations may explain the progression of axonal damage and tissue remodeling observed in the LC in glaucoma. Statement of Significance Glaucoma causes vision loss through progressive damage of the retinal ganglion axons at the lamina cribrosa (LC), the connective tissue structure that supports the axons as they leave the eye. Mechanical characterization of the LC is challenging because of the complex 3D shape and inaccessibility of the tissue. We present a new method using digital volume correlation to map the 3D displacement and strain fields in the LC under inflation. We report for the first time significant regional variations in the strains that are consistent with the pattern of optic nerve damage in early glaucoma. Thus regional strain variations may be predictive of the progression of axonal damage in glaucoma.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Covalent growth factor tethering to direct neural stem cell
           differentiation and self-organization
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Trevor R. Ham, Mahmoud Farrag, Nic D. Leipzig
      Tethered growth factors offer exciting new possibilities for guiding stem cell behavior. However, many of the current methods present substantial drawbacks which can limit their application and confound results. In this work, we developed a new method for the site-specific covalent immobilization of azide-tagged growth factors and investigated its utility in a model system for guiding neural stem cell (NSC) behavior. An engineered interferon- γ (IFN- γ ) fusion protein was tagged with an N-terminal azide group, and immobilized to two different dibenzocyclooctyne-functionalized biomimetic polysaccharides (chitosan and hyaluronan). We successfully immobilized azide-tagged IFN- γ under a wide variety of reaction conditions, both in solution and to bulk hydrogels. To understand the interplay between surface chemistry and protein immobilization, we cultured primary rat NSCs on both materials and showed pronounced biological effects. Expectedly, immobilized IFN- γ increased neuronal differentiation on both materials. Expression of other lineage markers varied depending on the material, suggesting that the interplay of surface chemistry and protein immobilization plays a large role in nuanced cell behavior. We also investigated the bioactivity of immobilized IFN- γ in a 3D environment in vivo and found that it sparked the robust formation of neural tube-like structures from encapsulated NSCs. These findings support a wide range of potential uses for this approach and provide further evidence that adult NSCs are capable of self-organization when exposed to the proper microenvironment. Statement of Significance For stem cells to be used effectively in regenerative medicine applications, they must be provided with the appropriate cues and microenvironment so that they integrate with existing tissue. This study explores a new method for guiding stem cell behavior: covalent growth factor tethering. We found that adding an N-terminal azide-tag to interferon-γ enabled stable and robust Cu-free ‘click’ immobilization under a variety of physiologic conditions. We showed that the tagged growth factors retained their bioactivity when immobilized and were able to guide neural stem cell lineage commitment in vitro. We also showed self-organization and neurulation from neural stem cells in vivo. This approach will provide another tool for the orchestration of the complex signaling events required to guide stem cell integration.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Improvement of osteogenesis in dental pulp pluripotent-like stem cells by
           oligopeptide-modified poly(β-amino ester)s
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Raquel Núñez-Toldrà, Pere Dosta, Sheyla Montori, Víctor Ramos, Maher Atari, Salvador Borrós
      Controlling pluripotent stem cell differentiation via genetic manipulation is a promising technique in regenerative medicine. However, the lack of safe and efficient delivery vehicles limits this application. Recently, a new family of poly(β-amino ester)s (pBAEs) with oligopeptide-modified termini showing high transfection efficiency of both siRNA and DNA plasmid has been developed. In this study, oligopeptide-modified pBAEs were used to simultaneously deliver anti-OCT3/4 siRNA, anti-NANOG siRNA, and RUNX2 plasmid to cells from the dental pulp with pluripotent-like characteristics (DPPSC) in order to promote their osteogenic differentiation. Results indicate that transient inhibition of the pluripotency marker OCT3/4 and the overexpression of RUNX2 at day 7 of differentiation markedly increased and accelerated the expression of osteogenic markers. Furthermore, terminally-differentiated cells exhibited higher matrix mineralization and alkaline phosphatase activity. Finally, cell viability and genetic stability assays indicate that this co-delivery system has high chromosomal stability and minimal cytotoxicity. Therefore, we conclude that such co-delivery strategy is a safe and a quick option for the improvement of DPPSC osteogenic differentiation. Statement of Significance Controlling pluripotent stem cell differentiation via genetic manipulation is a promising technique in regenerative medicine. However, the lack of safe and efficient delivery vehicles limits this application. In this study, we propose the use of a new family of oligopeptide-modified pBAEs developed in our group to control the differentiation of dental pulp pluripotential stem cells (DPPSC). In order to promote their osteogenic differentiation. The strategy proposed markedly increased and accelerated the expression of osteogenic markers, cell mineralization and alkaline phosphatase activity. Finally, cell viability and genetic stability assays indicated that this co-delivery system has high chromosomal stability and minimal cytotoxicity. These findings open a new interesting path in the usage of non-viral gene delivery systems for the control of pluripotential stem cell differentiation.
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      PubDate: 2017-04-28T10:17:10Z
       
  • TGF-β1 activation in human hamstring cells through growth factor binding
           peptides on polycaprolactone surfaces
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): J. Crispim, H.A.M. Fernandes, S.C. Fu, Y.W. Lee, P. Jonkheijm, D.B.F. Saris
      The administration of soluble growth factors (GFs) to injured tendons and ligaments (T/L) is known to promote and enhance the healing process. However, the administration of GFs is a complex, expensive and heavily-regulated process and only achieved by employing supraphysiological GF concentrations. In addition, for proper healing, specific and spatial immobilization of the GFs (s) is critical. We hypothesized that biomaterials functionalized with GF-binding peptides can be employed to capture endogenous GFs in a spatially-controlled manner, thus overcoming the need for the exogenous administration of supraphysiological doses of GFs. Here we demonstrate that the modification of films of polycaprolactone (PCL) with transforming growth factor β1 (TGF-β1)-binding peptides allows GFs to be captured and presented to the target cells. Moreover, using a TGF-β reporter cell line and immunocytochemistry, we show that the GFs retained their biological activity. In human primary tendon cells, the immobilized TGF-β1 activated TGF-β target genes ultimately lead to a 2.5-fold increase in total collagen matrix production. In vivo implantation in rats clearly shows an accumulation of TGF-β1 on the polymer films functionalized with the TGF-β1-binding peptide when compared with the native films. This accumulation leads to an increase in the recruitment of inflammatory cells at day 3 and an increase in the fibrogenic response and vascularization around the implant at day 7. The results herein presented will endow current and future medical devices with novel biological properties and by doing so will accelerate T/L healing. Statement of Significance Our study describes the possibility to deliver hTGF-β1 to human derived hamstring cells using a non-covalent bioactive strategy. The significance of our results in vivo with our functionalized biomaterial with TGF-β1-binding peptides lies in the fact that these materials can now be employed to capture endogenous TGF-β1 in a spatially-controlled manner, overcoming the need for exogenous administration of supra-physiological TGF-β1 doses. Our method is different from current solutions that rely on global TGF-β1 administration, soaking the devices with TGF-β1, etc. Therefore we believe that our method is a significant change from current state-of-the-art in the types of devices that are used for ligament/tendon repair and that following our method can endow current and future medical devices with TGF-β1 binding properties.
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      PubDate: 2017-04-28T10:17:10Z
       
  • A poly(l-glutamic acid)-combretastatin A4 conjugate for solid tumor
           therapy: Markedly improved therapeutic efficiency through its low tissue
           penetration in solid tumor
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Tianzhou Liu, Dawei Zhang, Wantong Song, Zhaohui Tang, Jiaming Zhu, Zhiming Ma, Xudong Wang, Xuesi Chen, Ti Tong
      Combretastatin A4 (CA4) is a leading agent in vascular disrupting strategies for tumor therapy. Although many small-molecule prodrugs of CA4 have been developed to improve its solubility, the overall therapeutic efficiency is moderate. A key reason for this is the reversible effect that CA4 has on tubulin as well as its rapid clearance from plasma and tissues. In this study, we proposed a poly(l-glutamic acid)-CA4 conjugate (PLG-CA4) nanomedicine to fulfill the requirements for fully liberating the potential of CA4 on tumor therapy. Enhanced accumulation and retention of CA4 in tumor tissue, especially, high distribution and gradual release around tumor blood vessels resulted in prolonged vascular disruption and markedly enhanced therapeutic efficiency. We examined and compared the therapeutic effect of PLG-CA4 and commercial combretastatin-A4 phosphate (CA4P) in a murine colon C26 tumor. PLG-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, the PLG-CA4 was mainly distributed around the tumor vessels because of its low tissue penetration in solid tumor. Pathology tests showed that PLG-CA4 treatment resulted in persistent vascular disruption and tumor damage 72h after a single injection, this in contrast to CA4P treatment, which showed quick relapse at an equal dose. Tumor suppression tests showed that PLG-CA4 treatment resulted in a tumor suppression rate of 74%, which indicates a significant advantage when compared to tumor suppression rate of the CA4P group, which was 24%. This is the first time that an advantage of the polymeric CA4 nanomedicine with low tissue penetration for solid tumor therapy has been shown. Thus, the results presented in this study provide a new idea for enhancing the tumor therapeutic effect of vascular disrupting agents. Statement of Significance Nanomedicine usually has low tissue penetration in solid tumors, which limits the efficacy of nanomedicine in most cases. But herein, we demonstrate a nanosized vascular disruptive agent (VDA) PLG-CA4 has supper advantages over small molecular combretastatin-A4 phosphate (CA4P) because the PLG-CA4 was mainly distributed around the tumor vessels due to its low tissue penetration in solid tumor.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Unusual behaviour induced by phase separation in hydrogel microspheres
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Clare L. Heaysman, Gary J. Philips, Andrew W. Lloyd, Andrew L. Lewis
      Hydrogel microspheres with the capability to interact with charged species such as various drugs by ion-exchange processes are useful in a variety of biomedical applications. Such systems have been developed to allow active loading of the microsphere with chemotherapeutic agents in the hospital pharmacy for subsequent locoregional therapy of tumours in the liver by drug-eluting bead chemoembolization (DEB-TACE). A variety of microspherical embolisation systems have been described, all based upon hydrogels bearing anionic functionalities to allow interaction with cationically charged drugs. We have recently prepared a series of microspheres bearing cationic functionality and have observed some unusual behaviour induced by phase-separation that occurs during the synthesis of the microspheres. The phase-separation results in the core of the microsphere being enriched in cationic polymer component compared to the outer polyvinyl alcohol (PVA)-based phase. For certain formulations, subsequent swelling in water results in the PVA-rich skins separating from the charged cores. Ion-exchange interactions with model compounds bearing multi-anionic groups create differential contraction of the charged core relative to the skin, resulting in an unusual “golf-ball” appearance to the surface of the microspheres. Statement of Significance The authors believe that the unusual behaviour of the microspheres reported in this paper is the first observation of its kind resulting from phase-separation during synthesis. This could have novel applications in drug delivery for systems that can respond by shedding their skin or altering the surface area to volume ratio upon loading a drug.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Polymeric nanoparticles loaded with dexamethasone or α-tocopheryl
           succinate to prevent cisplatin-induced ototoxicity
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Sergio Martín-Saldaña, Raquel Palao-Suay, María Rosa Aguilar, Rafael Ramírez-Camacho, Julio San Román
      The aim of this work is the development of highly protective agents to be administered locally within the middle ear to avoid cisplatin-induced ototoxicity, which affects to 100% of the clinical patients at ultra-high concentrations (16mg/kg). The protective agents are based on polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate as anti-inflammarory and anti-apoptotic molecules. Dexamethasone and α-tocopheryl succinate are poorly soluble in water and present severe side effects when systemic administered during long periods of time. Their incorporation in the hydrophobic core of nanoparticles with the appropriate hydrodynamic properties provides the desired effects in vitro (lower cisplatin-induced toxicity, decreasing of caspase 3/7 activity, and lower IL-1β release) and in vivo (reducing the hearing loss at the local level). The local administration of the nanoparticles by bullostomy provides an adequate dose of drug without systemic interference with the chemotherapeutic effect of cisplatin. Statement of Significance 100% of the cancer patients receiving ultra-high doses of CDDP (16mg/kg) suffer severe hearing loss, being a limiting factor in antineoplastic treatments. In this paper we describe the application of polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate to palliate the cisplatin ototoxicity derived from chemotherapy treatment. These new nanoparticles, that encapsulate, transport, and deliver dexamethasone or α-tocopheryl succinate in the middle ear, are able to partially prevent ototoxicity derived from high doses of CDDP. This is an interdisciplinary study in which in vitro and in vivo experiments are described and extensively discussed. The importance of the results opens an excellent opportunity to the translation to the clinic.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Design and optimization of a novel implantation technology in contact
           lenses for the treatment of dry eye syndrome: In vitro and in vivo
           evaluation
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Furqan A. Maulvi, Anjum A. Shaikh, Dhara H. Lakdawala, Ankita R. Desai, Mihir M. Pandya, Sulabh S. Singhania, Rutvi J. Vaidya, Ketan M. Ranch, Bhavin A. Vyas, Dinesh O. Shah
      Contact lenses are widely used for ophthalmic drug delivery, but incorporation of drug or formulation in the contact lenses affects its optical and physical property. In the present study, we have designed a novel hyaluronic acid (HA)-laden ring implant contact lenses (modified cast moulding method), to circumvent the changes in critical lens property. The objective was to improve the ocular residence time of HA, by providing sustained ocular HA delivery through implant contact lenses for the treatment of dry eye syndrome. Optimization of HA-implant was carried out using 32 factorial design by tailoring the amount of cross linker and thickness of implant, to achieve sustained HA release with constraint on effective ion diffusivity. The in vivo pharmacokinetic study in rabbit tear fluid showed sustained HA release up to 15days, by fabricating implant (80μgHA loading) with 78.4μm thickness (total thickness of lens=100μm) using 0.925% of cross linker, with effective ion diffusivity>1.5×10−6 mm2/min. In vivo efficacy study in benzalkonium chloride induced dry eye syndrome rabbits showed faster healing with implant contact lenses in comparison to positive control group. The study demonstrated the promising potential of implantation technology to deliver hyaluronic acid without compromising optical and physical properties of contact lens. Statement of Significance The limitation of contact lenses to be used as therapeutic device for controlled drug delivery is focused in this study. Incorporation of drug or formulation in the biomaterial affects the optical and physical property of contact lenses. The significance of project was to design a novel hyaluronic acid-laden ring implant contact lenses, to by-pass the changes in critical property of biomaterial.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Cyclodextrin modified PLLA parietal reinforcement implant with prolonged
           antibacterial activity
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): G. Vermet, S. Degoutin, F. Chai, M. Maton, C. Flores, C. Neut, P.E. Danjou, B. Martel, N. Blanchemain
      The use of textile meshes in hernia repair is widespread in visceral surgery. Though, mesh infection is a complication that may prolong the patient recovery period and consequently presents an impact on public health economy. Such concern can be avoided thanks to a local and extended antibiotic release on the operative site. In recent developments, poly-l-lactic acid (PLLA) has been used in complement of polyethyleneterephthalate (Dacron®) (PET) or polypropylene (PP) yarns in the manufacture of semi-resorbable parietal implants. The goal of the present study consisted in assigning drug reservoir properties and prolonged antibacterial effect to a 100% PLLA knit through its functionalization with a cyclodextrin polymer (polyCD) and activation with ciprofloxacin. The study focused i) on the control of degree of polyCD functionalization of the PLLA support and on its physical and biological characterization by Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC) and cell viability, ii) on the understanding of drug/meshes interaction using mathematic model and iii) on the correlation between drug release studies in phosphate buffer saline (PBS) and microbiological evaluation of meshes and release medium against E. coli and S. aureus. All above mentioned tests highlighted the contribution of polyCD on the improved performances of the resulting antibacterial implantable material. Statement of Significance 1. We managed for the first time, with well-defined parameters in terms of temperature and time of treatment, to functionalize a bio-absorbable synthetic material to improve drug sorption and drug release properties without affecting its mechanical properties. 2. We analyzed for the first time the degradation of our coating products by mass spectroscopy to show that only citrate and cyclodextrin residues (and glucose units) without any cytotoxicity are formed. 3. We managed to improve the mechanical properties of the PLA with the cyclodextrin polymer to form a composite. The assembly (cyclodextrin polymer and PLLA) remains biodegradable.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Nanosized sustained-release drug depots fabricated using modified
           tri-axial electrospinning
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Guang-Zhi Yang, Jiao-Jiao Li, Deng-Guang Yu, Mei-Feng He, Jun-He Yang, Gareth R. Williams
      Nanoscale drug depots, comprising a drug reservoir surrounded by a carrier membrane, are much sought after in contemporary pharmaceutical research. Using cellulose acetate (CA) as a filament-forming polymeric matrix and ferulic acid (FA) as a model drug, nanoscale drug depots in the form of core-shell fibers were designed and fabricated using a modified tri-axial electrospinning process. This employed a solvent mixture as the outer working fluid, as a result of which a robust and continuous preparation process could be achieved. The fiber-based depots had a linear morphology, smooth surfaces, and an average diameter of 0.62±0.07μm. Electron microscopy data showed them to have clear core-shell structures, with the FA encapsulated inside a CA shell. X-ray diffraction and IR spectroscopy results verified that FA was present in the crystalline physical form. In vitro dissolution tests revealed that the fibers were able to provide close to zero-order release over 36h, with no initial burst release and minimal tailing-off. The release properties of the depot systems were much improved over monolithic CA/FA fibers, which exhibited a significant burst release and also considerable tailing-off at the end of the release experiment. Here we thus demonstrate the concept of using modified tri-axial electrospinning to design and develop new types of heterogeneous nanoscale biomaterials. Statement of Significance Nanoscale drug depots with a drug reservoir surrounded by a carrier are highly attractive in biomedicine. A cellulose acetate based drug depot was investigated in detail, starting with the design of the nanostructure, and moving through its fabrication using a modified tri-axial electrospinning process and a series of characterizations. The core-shell fiber-based drug depots can provide a more sustained release profile with no initial burst effect and less tailing-off than equivalent monolithic drug-loaded fibers. The drug release mechanisms are also distinct in the two systems. This proof-of-concept work can be further expanded to conceive a series of new structural biomaterials with improved or new functional performance.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Long-term antimicrobial effect of nisin released from electrospun triaxial
           fiber membranes
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Daewoo Han, Shalli Sherman, Shaun Filocamo, Andrew J. Steckl
      Electrospun membranes encapsulating nisin in the core of multi-layer coaxial fibers, with a hydrophobic PCL intermediate layer and a hygroscopic cellulose acetate sheath, have been demonstrated to provide long-term antimicrobial activity combined with a hygroscopic outer layer. Antimicrobial performance has been evaluated using modified versions of the antimicrobial textile test AATCC 100 and AATCC 147 against Staphylococcus aureus. The AATCC 147 tests indicate that antimicrobial activity persists up to 7days. The quantitative analysis from the AATCC 100 test indicates that tri-layer coaxial (“triaxial”) electrospun fiber membranes provide >99.99% bacteria kill (4logkill) for up to five days. This indicates that the nisin-incorporated triaxial fibers have excellent biocidal activities for up to 5days and then provide biostatic activity for 2 or more days. Compared with other types of electrospun membranes, such as core-sheath coaxial (“coaxial”) and single homogenous fibers, triaxial fiber membranes provided more robust and more sustained antimicrobial activity. Single fibers with nisin showed relatively weak activity and only for one day. Coaxial fiber membranes exhibited antimicrobial activity for a long period, but their biocidal activity was much weaker than that of triaxial fiber membranes, and only exhibited >99% bacteria kill (2logkill) after 1day of exposure. Statement of Significance The increase in drug resistant pathogens has driven the need for alternative treatments that are effective against resistant bacteria and do not contribute to drug resistance. Nisin is an excellent model bacteriocin for antimicrobials because of its size and mode of action, and has been extensively used as FDA-approved food preservatives without any problematic resistance growth in bacteria during past decades. Nisin-containing fibers have been previously reported using conventional electrospinning but sustained antimicrobial effect has not been obtained. Here, we report the encapsulation of nisin into a multi-layered nanofiber construct using triaxial electrospinning in order to obtain a long-term antimicrobial activity. This will be highly beneficial in many applications, such as protective textiles, food packaging and cancer therapy.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Electrospun nanofiber sheets incorporating methylcobalamin promote nerve
           regeneration and functional recovery in a rat sciatic nerve crush injury
           model
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Koji Suzuki, Hiroyuki Tanaka, Mitsuhiro Ebara, Koichiro Uto, Hozo Matsuoka, Shunsuke Nishimoto, Kiyoshi Okada, Tsuyoshi Murase, Hideki Yoshikawa
      Peripheral nerve injury is one of common traumas. Although injured peripheral nerves have the capacity to regenerate, axon regeneration proceeds slowly and functional outcomes are often poor. Pharmacological enhancement of regeneration can play an important role in increasing functional recovery. In this study, we developed a novel electrospun nanofiber sheet incorporating methylcobalamin (MeCbl), one of the active forms of vitamin B12 homologues, to deliver it enough locally to the peripheral nerve injury site. We evaluated whether local administration of MeCbl at the nerve injury site was effective in promoting nerve regeneration. Electrospun nanofiber sheets gradually released MeCbl for at least 8weeks when tested in vitro. There was no adverse effect of nanofiber sheets on function in vivo of the peripheral nervous system. Local implantation of nanofiber sheets incorporating MeCbl contributed to the recovery of the motor and sensory function, the recovery of nerve conduction velocity, and the promotion of myelination after sciatic nerve injury, without affecting plasma concentration of MeCbl. Statement of Significance Methylcobalamin (MeCbl) is a vitamin B12 analog and we previously reported its effectiveness in axonal outgrowth of neurons and differentiation of Schwann cells both in vitro and in vivo. Here we estimated the effect of local administered MeCbl with an electrospun nanofiber sheet on peripheral nerve injury. Local administration of MeCbl promoted functional recovery in a rat sciatic nerve crush injury model. These sheets are useful for nerve injury in continuity differently from artificial nerve conduits, which are useful only for nerve defects. We believe that the findings of this study are relevant to the scope of your journal and will be of interest to its readership.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Customized biomaterials to augment chondrocyte gene therapy
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Izath Nizeet Aguilar, Stephen Trippel, Shuiliang Shi, Lawrence J. Bonassar
      A persistent challenge in enhancing gene therapy is the transient availability of the target gene product. This is particularly true in tissue engineering applications. The transient exposure of cells to the product could be insufficient to promote tissue regeneration. Here we report the development of a new material engineered to have a high affinity for a therapeutic gene product. We focus on insulin-like growth factor-I (IGF-I) for its highly anabolic effects on many tissues such as spinal cord, heart, brain and cartilage. One of the ways that tissues store IGF-I is through a group of insulin like growth factor binding proteins (IGFBPs), such as IGFBP-5. We grafted the IGF-I binding peptide sequence from IGFBP-5 onto alginate in order to retain the endogenous IGF-I produced by transfected chondrocytes. This novel material bound IGF-I and released the growth factor for at least 30days in culture. We found that this binding enhanced the biosynthesis of transfected cells up to 19-fold. These data demonstrate the coordinated engineering of cell behavior and material chemistry to greatly enhance extracellular matrix synthesis and tissue assembly, and can serve as a template for the enhanced performance of other therapeutic proteins. Statement of Significance The present manuscript focuses on the enhancement of chondrocyte gene therapy through the modification of scaffold materials to enhance the retention of targeted gene products. This study combined tissue engineering and gene therapy, where customized biomaterials augmented the action of IGF-I by enhancing the retention of protein produced by transfection of the IGF-I gene. This approach enabled tuning of binding of IGF-I to alginate, which increased GAG and HYPRO production by transfected chondrocytes. To our knowledge, peptide-based modification of materials to augment growth factor-targeted gene therapy has not been reported previously.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Molecular assessment of collagen denaturation in decellularized tissues
           using a collagen hybridizing peptide
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Jeongmin Hwang, Boi Hoa San, Neill J. Turner, Lisa J. White, Denver M. Faulk, Stephen F. Badylak, Yang Li, S. Michael Yu
      Decellularized extracellular matrix (ECM) derived from tissues and organs are emerging as important scaffold materials for regenerative medicine. Many believe that preservation of the native ECM structure during decellularization is highly desirable. However, because effective techniques to assess the structural damage in ECM are lacking, the disruptive effects of a decellularization method and the impact of the associated structural damage upon the scaffold’s regenerative capacity are often debated. Using a novel collagen hybridizing peptide (CHP) that specifically binds to unfolded collagen chains, we investigated the molecular denaturation of collagen in the ECM decellularized by four commonly used cell-removing detergents: sodium dodecyl sulfate (SDS), 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), sodium deoxycholate (SD), and Triton X-100. Staining of the detergent-treated porcine ligament and urinary bladder matrix with carboxyfluorescein-labeled CHP demonstrated that SDS and Triton X-100 denature the triple helical collagen molecule while CHAPS and SD do not, although second harmonic generation imaging and transmission electron microscopy (TEM) revealed that all four detergents disrupt collagen fibrils. Our findings from the CHP staining were further confirmed by the circular dichroism spectra of intact triple helical collagen molecules in CHAPS and SD solutions, and the TEM images of CHP-conjugated gold nanoparticles binding only to the SDS and Triton X-100 treated collagen fibrils. CHP is a powerful new tool for direct and reliable measurement of denatured collagen molecules in decellularized tissues. It is expected to have wide applications in the development and standardization of the tissue/organ decellularization technology. Statement of Significance Preservation of the native ECM structure in decellularized tissues is highly desirable, since denaturation of ECM molecules (e.g., collagen) during decellularization can strongly influence the cellular response. Unfortunately, conventional techniques (SEM, SHG) are not conducive to identifying denatured collagen molecules in tissues. We demonstrate the first investigation into the molecular denaturation of collagen in decellularized ECM enabled by a novel Collagen Hybridizing Peptide (CHP) that specifically binds to unfolded collagen chains. We show that SDS and Triton X-100 denature collagen molecules while CHAPS and SD cannot. Such detection has been nearly impossible with other existing techniques. The CHP technique will advance our understanding about the effect of the cell-removing process on ECM, and lead to development of the decellularization technology.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Microfracture combined with functional pig peritoneum-derived acellular
           matrix for cartilage repair in rabbit models
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Qingyang Meng, Xiaoqing Hu, Hongjie Huang, Zhenlong Liu, Lan Yuan, Zhenxing Shao, Yanfang Jiang, Jiying Zhang, Xin Fu, Xiaoning Duan, Yingfang Ao
      Due to avascular and hypocellular nature of cartilage, repair of articular cartilage defects within synovial joints still poses a significant clinical challenge. To promote neocartilage properties, we established a functional scaffold named APM-E7 by conjugating a bone marrow-derived mesenchymal stem cell (BM-MSC) affinity peptide (E7) onto the acellular peritoneum matrix (APM). During in vitro culture, the APM-E7 scaffold can support better proliferation as well as better differentiation into chondrocytes of BM-MSCs. After implanting into cartilage defects in rabbits for 24weeks, compared with microfracture and APM groups, the APM-E7 scaffolds exhibited superior quality of neocartilage without transplant rejection, according to general observations, histological assessment, synovial fluid analysis, magnetic resonance imaging (MRI) and nanomechanical properties. This APM-E7 scaffold provided a scaffold for cell attachment, which was crucial for cartilage regeneration. Overall, the APM-E7 is a promising biomaterial with low immunogenicity for one-step cartilage repair by promoting autologous connective tissue progenitor (CTP) attachment. Statement of Significance We report the one-step transplantation of functional acellular peritoneum matrix (APM-E7) with specific mesenchymal stem cell recruitment to repair rabbit cartilage injury. The experimental results illustrated that the APM-E7 scaffold was successfully fabricated, which could specifically recruit MSCs and fill the cartilage defects in the femoral trochlear of rabbits at 24weeks post-surgery. The repaired tissue was hyaline cartilage, which exhibited ideal mechanical stability. The APM-E7 biomaterial could provide scaffold for MSCs and improve cell homing, which are two key factors required for cartilage tissue engineering, thereby providing new insights into cartilage tissue engineering.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Gelatin-based 3D conduits for transdifferentiation of mesenchymal stem
           cells into Schwann cell-like phenotypes
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Metin Uz, Melda Büyüköz, Anup D. Sharma, Donald S. Sakaguchi, Sacide Alsoy Altinkaya, Surya K. Mallapragada
      In this study, gelatin-based 3D conduits with three different microstructures (nanofibrous, macroporous and ladder-like) were fabricated for the first time via combined molding and thermally induced phase separation (TIPS) technique for peripheral nerve regeneration. The effects of conduit microstructure and mechanical properties on the transdifferentiation of bone marrow-derived mesenchymal stem cells (MSCs) into Schwann cell (SC) like phenotypes were examined to help facilitate neuroregeneration and understand material-cell interfaces. Results indicated that 3D macroporous and ladder-like structures enhanced MSC attachment, proliferation and spreading, creating interconnected cellular networks with large numbers of viable cells compared to nanofibrous and 2D-tissue culture plate counterparts. 3D-ladder-like conduit structure with complex modulus of ∼0.4×106 Pa and pore size of ∼150μm provided the most favorable microenvironment for MSC transdifferentiation leading to ∼85% immunolabeling of all SC markers. On the other hand, the macroporous conduits with complex modulus of ∼4×106 Pa and pore size of ∼100μm showed slightly lower (∼65% for p75, ∼75% for S100 and ∼85% for S100β markers) immunolabeling. Transdifferentiated MSCs within 3D-ladder-like conduits secreted significant amounts (∼2.5pg/mL NGF and ∼0.7pg/mL GDNF per cell) of neurotrophic factors, while MSCs in macroporous conduits released slightly lower (∼1.5pg/mL NGF and 0.7pg/mL GDNF per cell) levels. PC12 cells displayed enhanced neurite outgrowth in media conditioned by conduits with transdifferentiated MSCs. Overall, conduits with macroporous and ladder-like 3D structures are promising platforms in transdifferentiation of MSCs for neuroregeneration and should be further tested in vivo. Statement of Significance This manuscript focuses on the effect of microstructure and mechanical properties of gelatin-based 3D conduits on the transdifferentiation of mesenchymal stem cells to Schwann cell-like phenotypes. This work builds on our recently accepted manuscript in Acta Biomaterialia focused on multifunctional 2D films, and focuses on 3D microstructured conduits designed to overcome limitations of current strategies to facilitate peripheral nerve regeneration. The comparison between conduits fabricated with nanofibrous, macroporous and ladder-like microstructures showed that the ladder-like conduits showed the most favorable environment for MSC transdifferentiation to Schwann-cell like phenotypes, as seen by both immunolabeling as well as secretion of neurotrophic factors. This work demonstrates the importance of controlling the 3D microstructure to facilitate tissue engineering strategies involving stem cells that can serve as promising approaches for peripheral nerve regeneration.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Ectopic tissue engineered ligament with silk collagen scaffold for ACL
           regeneration: A preliminary study
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Jisheng Ran, Yejun Hu, Huihui Le, Yangwu Chen, Zefeng Zheng, Xiao Chen, Zi Yin, Ruijian Yan, Zhangchu Jin, Chenqi Tang, Jiayun Huang, Yanjia Gu, Langhai Xu, Shengjun Qian, Wei Zhang, Boon Chin Heng, Pioletti Dominique, Weishan Chen, Lidong Wu, Weiliang Shen, Hongwei Ouyang
      Anterior cruciate ligament (ACL) reconstruction remains a formidable clinical challenge because of the lack of vascularization and adequate cell numbers in the joint cavity. In this study, we developed a novel strategy to mimic the early stage of repair in vivo, which recapitulated extra-articular inflammatory response to facilitate the early ingrowth of blood vessels and cells. A vascularized ectopic tissue engineered ligament (ETEL) with silk collagen scaffold was developed and then transferred to reconstruct the ACL in rabbits without interruption of perfusion. At 2weeks after ACL reconstruction, more well-perfused cells and vessels were found in the regenerated ACL with ETEL, which decreased dramatically at the 4 and 12week time points with collagen deposition and maturation. ACL treated with ETEL exhibited more mature ligament structure and enhanced ligament-bone healing post-reconstructive surgery at 4 and 12weeks, as compared with the control group. In addition, the ETEL group was demonstrated to have higher modulus and stiffness than the control group significantly at 12weeks post-reconstructive surgery. In conclusion, our results demonstrated that the ETEL can provide sufficient vascularity and cellularity during the early stages of healing, and subsequently promote ACL regeneration and ligament-bone healing, suggesting its clinic use as a promising therapeutic modality. Statement of Significance Early inflammatory cell infiltration, tissue and vessels ingrowth were significantly higher in the extra-articular implanted scaffolds than theses in the joint cavity. By mimicking the early stages of wound repair, which provided extra-articular inflammatory stimulation to facilitate the early ingrowth of blood vessels and cells, a vascularized ectopic tissue engineered ligament (ETEL) with silk collagen scaffold was constructed by subcutaneous implantation for 2weeks. The fully vascularized TE ligament was then transferred to rebuild ACL without blood perfusion interruption, and was demonstrated to exhibit improved ACL regeneration, bone tunnel healing and mechanical properties.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Chondrogenically primed tonsil-derived mesenchymal stem cells encapsulated
           in riboflavin-induced photocrosslinking collagen-hyaluronic acid hydrogel
           for meniscus tissue repairs
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Rachel H. Koh, Yinji Jin, Byung-Jae Kang, Nathaniel S. Hwang
      Current meniscus tissue repairing strategies involve partial or total meniscectomy, followed by allograft transplantation or synthetic material implantation. However, allografts and synthetic implants have major drawbacks such as the limited supply of grafts and lack of integration into host tissue, respectively. In this study, we investigated the effects of conditioned medium (CM) from meniscal fibrochondrocytes and TGF-β3 on tonsil-derived mesenchymal stem cells (T-MSCs) for meniscus tissue engineering. CM-expanded T-MSCs were encapsulated in riboflavin-induced photocrosslinked collagen-hyaluronic acid (COL-RF-HA) hydrogels and cultured in chondrogenic medium containing TGF-β3. In vitro results indicate that CM-expanded cells followed by TGF-β3 exposure stimulated the expression of fibrocartilage-related genes (COL2, SOX9, ACAN, COL1) and production of extracellular matrix components. Histological assessment of in vitro and subcutaneously implanted in vivo constructs demonstrated that CM-expanded cells followed by TGF-β3 exposure resulted in highest cell proliferation, GAG accumulation, and collagen deposition. Furthermore, when implanted into meniscus defect model, CM treatment amplified the potential of TGF-β3 and induced complete regeneration. Statement of Significance Conditioned medium derived from chondrocytes have been reported to effectively prime mesenchymal stem cells toward chondrogenic lineage. Type I collagen is the main component of meniscus extracellular matrix and hyaluronic acid is known to promote meniscus regeneration. In this manuscript, we investigated the effects of conditioned medium (CM) and transforming growth factor-β3 (TGF-β3) on tonsil-derived mesenchymal stem cells (T-MSCs) encapsulated in riboflavin-induced photocrosslinked collagen-hyaluronic acid (COL-RF-HA) hydrogel. We employed a novel source of conditioned medium, derived from meniscal fibrochondrocytes. Our in vitro and in vivo results collectively illustrate that CM-expanded cells followed by TGF-β3 exposure have the best potential for meniscus regeneration. This manuscript highlights a novel stem cell commitment strategy combined with biomaterials designs for meniscus regeneration.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Sulfated hyaluronic acid hydrogels with retarded degradation and enhanced
           growth factor retention promote hMSC chondrogenesis and articular
           cartilage integrity with reduced hypertrophy
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Qian Feng, Sien Lin, Kunyu Zhang, Chaoqun Dong, Tianyi Wu, Heqin Huang, Xiaohui Yan, Li Zhang, Gang Li, Liming Bian
      Recently, hyaluronic acid (HA) hydrogels have been extensively researched for delivering cells and drugs to repair damaged tissues, particularly articular cartilage. However, the in vivo degradation of HA is fast, thus limiting the clinical translation of HA hydrogels. Furthermore, HA cannot bind proteins with high affinity because of the lack of negatively charged sulfate groups. In this study, we conjugated tunable amount of sulfate groups to HA. The sulfated HA exhibits significantly slower degradation by hyaluronidase compared to the wild type HA. We hypothesize that the sulfation reduces the available HA octasaccharide substrate needed for the effective catalytic action of hyaluronidase. Moreover, the sulfated HA hydrogels significantly improve the protein sequestration, thereby effectively extending the availability of the proteinaceous drugs in the hydrogels. In the following in vitro study, we demonstrate that the HA hydrogel sulfation exerts no negative effect on the viability of encapsulated human mesenchymal stem cells (hMSCs). Furthermore, the sulfated HA hydrogels promote the chondrogenesis and suppresses the hypertrophy of encapsulated hMSCs both in vitro and in vivo. Moreover, intra-articular injections of the sulfated HA hydrogels avert the cartilage abrasion and hypertrophy in the animal osteoarthritic joints. Collectively, our findings demonstrate that the sulfated HA is a promising biomaterial for the delivery of therapeutic agents to aid the regeneration of injured or diseased tissues and organs. Statement of Significance In this paper, we conjugated sulfate groups to hyaluronic acid (HA) and demonstrated the slow degradation and growth factor delivery of sulfated HA. Furthermore, the in vitro and in vivo culture of hMSCs laden HA hydrogels proved that the sulfation of HA hydrogels not only promotes the chondrogenesis of hMSCs but also suppresses hypertrophic differentiation of the chondrogenically induced hMSCs. The animal OA model study showed that the injected sulfated HA hydrogels significantly reduced the cartilage abrasion and hypertrophy in the animal OA joints. We believe that this study will provide important insights into the design and optimization of the HA-based hydrogels as the scaffold materials for cartilage regeneration and OA treatment in clinical setting.
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      PubDate: 2017-04-28T10:17:10Z
       
  • A novel injectable tissue adhesive based on oxidized dextran and chitosan
    • Abstract: Publication date: 15 April 2017
      Source:Acta Biomaterialia, Volume 53
      Author(s): Biji Balakrishnan, Dawlee Soman, Umashanker Payanam, Alexandre Laurent, Denis Labarre, Athipettah Jayakrishnan
      A surgical adhesive that can be used in different surgical situations with or without sutures is a surgeons’ dream and yet none has been able to fulfill many such demanding requirements. It was therefore a major challenge to develop an adhesive biomaterial that stops bleeding and bond tissues well, which at the same time is non-toxic, biocompatible and yet biodegradable, economically viable and appealing to the surgeon in terms of the simplicity of application in complex surgical situations. With this aim, we developed an in situ setting adhesive based on biopolymers such as chitosan and dextran. Dextran was oxidized using periodate to generate aldehyde functions on the biopolymer and then reacted with chitosan hydrochloride. Gelation occurred instantaneously upon mixing these components and the resulting gel showed good tissue adhesive properties with negligible cytotoxicity and minimal swelling in phosphate buffered saline (PBS). Rheology analysis confirmed the gelation process by demonstrating storage modulus having value higher than loss modulus. Adhesive strength was in the range 200–400gf/cm2 which is about 4–5 times more than that of fibrin glue at comparable setting times. The adhesive showed burst strength in the range of 400–410mm of Hg which should make the same suitable as a sealant for controlling bleeding in many surgical situations even at high blood pressure. Efficacy of the adhesive as a hemostat was demonstrated in a rabbit liver injury model. Histological features after two weeks were comparable to that of commercially available BioGlue®. The adhesive also demonstrated its efficacy as a drug delivery vehicle. The present adhesive could function without the many toxicity and biocompatibility issues associated with such products. Statement of Significance Though there are many tissue adhesives available in market, none are free of shortcomings. The newly developed surgical adhesive is a 2-component adhesive system based on time-tested, naturally occurring polysaccharides such as chitosan and dextran which are both biocompatible and biodegradable. Simple polymer modification has been carried out on both polysaccharides so that when aqueous solutions of both are mixed, the solutions gel in less than 10s and forms an adhesive that seals a variety of incisions. The strength of the adhesive is over 5-times the strength of commercially available Fibrin glue and is more tissue compliant than BioGlue®. This adhesive biomaterial showed excellent tissue bonding, was hemostatic, biocompatible and biodegradable. The significance of this work lies on the features of the developed tissue adhesive that it stops bleeding, bond the tissues well, can act as a drug delivery vehicle and would appeal to the surgeon in terms of the simplicity of application in complex surgical situations. There is no need for special delivery systems for application of this adhesive. The two-component adhesive can be applied one over the other using syringes. There is also no need for light curing with UV or visible light and the gelation between the two components spontaneously takes place on application leading to excellent tissue bonding.
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      PubDate: 2017-04-28T10:17:10Z
       
  • Polyurethane Acrylates as Effective Substrates for Sustained In Vitro
           Culture of Human Myotubes
    • Authors: Yosephine Andriani; Jason Chua Min-Wen; Benjamin Chua Yan-Jiang; Phang In Yee; Ng Shyh-Chang; Tan Wui Siew
      Abstract: Publication date: Available online 21 April 2017
      Source:Acta Biomaterialia
      Author(s): Yosephine Andriani, Jason Chua Min-Wen, Benjamin Chua Yan-Jiang, Phang In Yee, Ng Shyh-Chang, Tan Wui Siew
      Muscular disease has debilitating effects with severe damage leading to death. Our knowledge of muscle biology, disease and treatment is largely derived from non human cell models, even though non human cells are known to differ from human cells in their biochemical responses. Attempts to develop highly sought after in vitro human cell models have been plagued by early cell delamination and difficulties in achieving human myotube culture in vitro. In this work, we developed polyurethane acrylate (PUA) materials to support long term in vitro culture of human skeletal muscle tissue. Using a constant base with modulated crosslink density we were able to vary the material modulus while keeping surface chemistry and roughness constant. While previous studies have focused on materials that mimic soft muscle tissue with stiffness ca. 12 kPa, we investigated materials with tendon like surface moduli in the higher 150 MPa to 2.4 GPa range, which has remained unexplored. We found that PUA of an optimal modulus within this range can support human myoblast proliferation, terminal differentiation and sustenance beyond 35 days, without use of any extracellular protein coating. Results show that PUA materials can serve as effective substrates for successful development of human skeletal muscle cell models and are suitable for long term in vitro studies. Statement of Significance We developed polyurethane acrylates (PUA) to modulate the human skeletal muscle cell growth and maturation in vitro by controlling surface chemistry, morphology and tuning material’s stiffness. PUA was able to maintain muscle cell viability for over a month without any detectable signs of material degradation. The best performing PUA prevented premature cell detachment from the substrate which often hampered long term muscle cell studies. It also supported muscle cell maturation up to the late state of differentiation. The significance of these findings lies in the possibility to advance studies on muscle cell biology, disease and therapy by using human muscle cells instead of relying on the widely used animal based in vitro models.
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      PubDate: 2017-04-21T13:47:56Z
      DOI: 10.1016/j.actbio.2017.04.022
       
  • Investigating Mechanisms of Tendon Damage by Measuring Multi-scale
           Recovery Following Tensile Loading
    • Authors: Andrea H. Lee; Spencer E. Szczesny; Michael H. Santare; Dawn M. Elliott
      Abstract: Publication date: Available online 21 April 2017
      Source:Acta Biomaterialia
      Author(s): Andrea H. Lee, Spencer E. Szczesny, Michael H. Santare, Dawn M. Elliott
      Tendon pathology is associated with damage. While tendon damage is likely initiated by mechanical loading, little is known about the specific etiology. Damage is defined as an irreversible change in the microstructure that alters the macroscopic mechanical parameters. In tendon, the link between mechanical loading and microstructural damage, resulting in macroscopic changes, is not fully elucidated. In addition, tendon damage at the macroscale has been proposed to initiate when tendon is loaded beyond a strain threshold, yet the metrics to define the damage threshold are not determined. We conducted multiscale mechanical testing to investigate the mechanism of tendon damage by simultaneously quantifying macroscale mechanical and microstructural changes. At the microscale, we observe full recovery of the fibril stretch and only partial recovery of, the interfibrillar sliding, indicating that the damage initiates at the interfibrillar structures. We show that non-recoverable sliding is a mechanism for tendon damage and is responsible for the macroscale decreased linear modulus and elongated toe-region observed at the fascicle-level, and these macroscale properties are appropriate metrics that reflect tendon damage. We concluded that the inflection point of the stress-strain curve represents the damage threshold and, therefore, may be a useful parameter for future studies. Establishing the mechanism of damage at multiple length scales can improve prevention and rehabilitation strategies for tendon pathology. Statement of Significance Tendon pathology is associated with mechanically induced damage. Damage, as defined in engineering, is an irreversible change in microstructure that alters the macroscopic mechanical properties. Although microstructural damage and changes to macroscale mechanics are likely, this link to microstructural change was not yet established. We conducted multiscale mechanical testing to investigate the mechanism of tendon damage by simultaneously quantifying macroscale mechanical and microstructural changes. We showed that non-recoverable sliding between collagen fibrils is a mechanism for tendon damage. Establishing the mechanism of damage at multiple length scales can improve prevention and rehabilitation strategies for tendon pathology.
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      PubDate: 2017-04-21T13:47:56Z
      DOI: 10.1016/j.actbio.2017.04.011
       
  • Regulation of Human Nucleus Pulposus Cells by Peptide-Coupled Substrates
    • Authors: Devin T. Bridgen; Bailey V. Fearing; Liufang Jing; Johannah Sanchez-Adams; Megan C. Cohan; Farshid Guilak; Jun Chen; Lori A. Setton
      Abstract: Publication date: Available online 20 April 2017
      Source:Acta Biomaterialia
      Author(s): Devin T. Bridgen, Bailey V. Fearing, Liufang Jing, Johannah Sanchez-Adams, Megan C. Cohan, Farshid Guilak, Jun Chen, Lori A. Setton
      Nucleus pulposus (NP) cells are derived from the notochord and differ from neighboring cells of the intervertebral disc in phenotypic marker expression and morphology. Adult human NP cells lose this phenotype and morphology with age in a pattern that contributes to progressive disc degeneration and pathology. Select laminin-mimetic peptide ligands and substrate stiffnesses were examined for their ability to regulate human NP cell phenotype and biosynthesis through the expression of NP-specific markers aggrecan, N-cadherin, collagen types I and II, and GLUT1. Peptide-conjugated substrates demonstrated an ability to promote expression of healthy NP-specific markers, as well as increased biosynthetic activity. We show an ability to re-express markers of the juvenile NP cell and morphology through control of peptide presentation and stiffness on well-characterized polyacrylamide substrates. NP cells cultured on surfaces conjugated with α3 integrin receptor peptides P4 and P678, and on α2, α5, α6, β1 integrin-recognizing peptide AG10, show increased expression of aggrecan, N-cadherin, and types I and II collagen, suggesting a healthier, more juvenile-like phenotype. Multi-cell cluster formation was also observed to be more prominent on peptide-conjugated substrates. These findings indicate a critical role for cell-matrix interactions with specific ECM-mimetic peptides in supporting and maintaining a healthy NP cell phenotype and bioactivity. Statement of Significance NP cells reside in a laminin-rich environment that deteriorates with age, including a loss of water content and changes in the extracellular matrix (ECM) structure that may lead to the development of a degenerated IVD. There is great interest in methods to re-express healthy, biosynthetically active NP cells using laminin-derived biomimetic peptides toward the goal of using autologous cell sources for tissue regeneration. Here, we describe a novel study utilizing several laminin mimetic peptides conjugated to polyacrylamide gels that are able to support an immature, healthy NP phenotype after culture on “soft” peptide gels. These findings can support future studies in tissue regeneration where cells may be directed to a desired regenerative phenotype using niche-specific ECM peptides.
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      PubDate: 2017-04-21T13:47:56Z
      DOI: 10.1016/j.actbio.2017.04.019
       
  • Macromolecular crowding for tailoring tissue-derived fibrillated matrices
    • Authors: Valentina Magno; Jens Friedrichs; Heather M. Weber; Marina C. Prewitz; Mikhail V. Tsurkan; Carsten Werner
      Abstract: Publication date: Available online 20 April 2017
      Source:Acta Biomaterialia
      Author(s): Valentina Magno, Jens Friedrichs, Heather M. Weber, Marina C. Prewitz, Mikhail V. Tsurkan, Carsten Werner
      Tissue-derived fibrillated matrices can be instrumental for the in vitro reconstitution of multiphasic extracellular microenvironments. However, despite of several advantages, the obtained scaffolds so far offer a rather narrow range of materials characteristics only. In this work, we demonstrate how macromolecular crowding (MMC) - the supplementation of matrix reconstitution media with synthetic or natural macromolecules in ways to create excluded volume effects (EVE) - can be employed for tailoring important structural and biophysical characteristics of kidney-derived fibrillated matrices. Porcine kidneys were decellularized, ground and the obtained extracellular matrix (ECM) preparations were reconstituted under varied MMC conditions. We show that MMC strongly influences the fibrillogenesis kinetics and impacts the architecture and the elastic modulus of the reconstituted matrices, with diameters and relative alignment of fibrils increasing at elevated concentrations of the crowding agent Ficoll400, a nonionic synthetic polymer of sucrose. Furthermore, we demonstrate how MMC modulates the distribution of key ECM molecules within the reconstituted matrix scaffolds. As a proof of concept, we compared different variants of kidney-derived fibrillated matrices in cell culture experiments referring to specific requirements of kidney tissue engineering approaches. The results revealed that MMC-tailored matrices support the morphogenesis of human umbilical vein endothelial cells (HUVECs) into capillary networks and of murine kidney stem cells (KSCs) into highly branched aggregates. The established methodology is concluded to provide generally applicable new options for tailoring tissue-specific multiphasic matrices in vitro. Statement of Significance Tissue-derived fibrillated matrices can be instrumental for the in vitro reconstitution of multiphasic extracellular microenvironments. However, despite of several advantages, the obtained scaffolds so far offer a rather narrow range of materials characteristics only. Using the kidney matrix as a model, we herein report a new approach for tailoring tissue-derived fibrillated matrices by means of macromolecular crowding (MMC), the supplementation of reconstitution media with synthetic or natural macromolecules. MMC-modulation of matrix reconstitution is demonstrated to allow for the adjustment of fibrillation kinetics and nano-architecture, fiber diameter, alignment, and matrix elasticity. Primary human umbilical vein endothelial cells (HUVEC) and murine kidney stem cells (KSC) were cultured within different variants of fibrillated kidney matrix scaffolds. The results showed that MMC-tailored matrices were superior in supporting desired morphogenesis phenomena of both cell types.
      Graphical abstract image

      PubDate: 2017-04-21T13:47:56Z
      DOI: 10.1016/j.actbio.2017.04.018
       
  • Facile encapsulation of hydroxycamptothecin nanocrystals into zein-based
           nanocomplexes for active targeting drug delivery and cell imaging
    • Authors: Hongdi Wang; Wei Zhu; Yunna Huang; Zhixian Li; Yanbin Jiang; Qiuling Xie
      Abstract: Publication date: Available online 19 April 2017
      Source:Acta Biomaterialia
      Author(s): Hongdi Wang, Wei Zhu, Yunna Huang, Zhixian Li, Yanbin Jiang, Qiuling Xie
      Nano-drug delivery systems that integrate inorganic and organic or even bioactive components into a single nanoscale platform are playing a greatly important role in cancer treatment. Here, the fabrication of a versatile nanocarrier based on self-assembled structures of gold nanoparticles (AuNPs)-zein is reported, which displays high drug-loading efficiency for needle-shaped hydroxycamptothecin (HCPT) nanocrystals. The surface modification with folate-conjugated polydopamine (PFA) renders them stable and also facilitates their selective cellular internalization and enhancement of endocytosis. The release of payloads from nanocomplexes (NCs) was shown to be limited at physiological pH (17.1 ± 2.8%) but significantly elevated at endosomal/lysosomal pH (58.4 ± 3.0%) and at enzymatic environment (81.4 ± 4.2%). Compared to free HCPT and its non-targeting equivalent, HCPT@AuNPs-Zein-PFA, exerted a superior tumor suppression capacity as well as low side effects due to their active and passive targeting delivery both in vitro and in vivo. These results suggest that the NCs with well-defined core@shell nanostructures encapsulated with HCPT nanocrystals hold great promise to improve cancer therapy with a high efficiency in the clinic. Statement of significance A novel nanocomplex encapsulated HCPT nanocrystals was designed to achieve selective cellular uptake by endocytosis, acid responsive release in the tumour microenvironment and excellent tumour suppression without toxicity. This nanocomplex with conjugation of folate was stable in the bloodstream, with minimal drug release in extracellular conditions, leading to prolonged blood circulation and high accumulation in tumour tissues. The entrapment of nanocrystal drug into nanomaterials might be capable of delivering drugs in a predictable and controllable manner.
      Graphical abstract image

      PubDate: 2017-04-21T13:47:56Z
      DOI: 10.1016/j.actbio.2017.04.017
       
  • A strain-mediated corrosion model for bioabsorbable metallic stents
    • Authors: E. Galvin; D. O'Brien; C. Cummins; B.J. Mac Donald; C. Lally
      Abstract: Publication date: Available online 19 April 2017
      Source:Acta Biomaterialia
      Author(s): E. Galvin, D. O'Brien, C. Cummins, B.J. Mac Donald, C. Lally
      This paper presents a strain-mediated phenomenological corrosion model, based on the discrete finite element modelling method which was developed for use with the ANSYS Implicit finite element code. The corrosion model was calibrated from experimental data and used to simulate the corrosion performance of a WE43 magnesium alloy stent. The model was found to be capable of predicting the experimentally observed plastic strain-mediated mass loss profile. The non-linear plastic strain model, extrapolated from the experimental data, was also found to adequately capture the corrosion-induced reduction in the radial stiffness of the stent over time. The model developed will help direct future design efforts towards the minimisation of plastic strain during device manufacture, deployment and in-service, in order to reduce corrosion rates and prolong the mechanical integrity of magnesium devices. Statement of Significance The need for corrosion models that explore the interaction of strain with corrosion damage has been recognised as one of the current challenges in degradable material modelling (Gastaldi et al., 2011). A FE based plastic strain mediated phenomenological corrosion model was developed in this work and was calibrated based on the results of the corrosion experiments. It was found to be capable of predicting the experimentally observed plastic strain mediated mass loss profile and the corrosion-induced reduction in the radial stiffness of the stent over time. To the author’s knowledge, the results presented here represent the first experimental calibration of a plastic strain mediated corrosion model of a corroding magnesium stent.
      Graphical abstract image

      PubDate: 2017-04-21T13:47:56Z
      DOI: 10.1016/j.actbio.2017.04.020
       
  • Synergistic effects of BMP-2, BMP-6 or BMP-7 with human plasma fibronectin
           onto hydroxyapatite coatings: a comparative study
    • Authors: Isabelle Brigaud; Rémy Agniel; Johanne Leroy Dudal; Sabrina Kellouche; Arnaud Ponche; Tahar Bouceba; Natalia Mihailescu; Mihai Sopronyi; Eric Viguier; Carmen Ristoscu; Felix Sima; Ion N. Mihailescu; Ana Claudia O. Carreira; Mari Cleide Sogayar; Olivier Gallet; Karine Anselme
      Abstract: Publication date: Available online 19 April 2017
      Source:Acta Biomaterialia
      Author(s): Isabelle Brigaud, Rémy Agniel, Johanne Leroy Dudal, Sabrina Kellouche, Arnaud Ponche, Tahar Bouceba, Natalia Mihailescu, Mihai Sopronyi, Eric Viguier, Carmen Ristoscu, Felix Sima, Ion N. Mihailescu, Ana Claudia O. Carreira, Mari Cleide Sogayar, Olivier Gallet, Karine Anselme
      Design of new osteoinductive biomaterials to reproduce an optimized physiological environment capable of recruiting stem cells and instructing their fate towards the osteoblastic lineage has become a priority in orthopedic surgery. This work aims at evaluating the bioactivity of BMP combined with human plasma fibronectin (FN/BMP) delivered in solution or coated onto titanium-hydroxyapatite (TiHA) surfaces. Herein, we focus on the comparison of in vitro osteogenic efficacy in mouse C2C12 pre-osteoblasts of three BMP members, namely: BMP-2, BMP-6 and BMP-7. In parallel, we evaluated the molecular binding strength between each BMP with FN using the Surface Plasmon Resonance (SPR) technology. The affinity of BMPs for FN was found totally different and dependent on BMP type. Indeed, the combination of FN with BMP-2 on TiHA surfaces potentiates the burst of gene-mediated osteogenic induction, while it prolongs the osteogenic activity of BMP-6 and surprisingly annihilates the BMP-7 one. These results correlate with FN/BMP affinity for TiHA, since BMP-6 > BMP-2 > BMP-7. In addition, by analyzing the osteogenic activity in the peri-implant environment, we showed that osteoinductive paracrine effects were significantly decreased upon (FN/BMP-6), as opposed to (FN/BMP-2) coatings. Altogether, our results support the use of FN/BMP-6 to develop a biomimetic microenvironment capable to induce osteogenic activity under physiological conditions, with minimum paracrine signalization. Statement of significance The originality of our paper relies on the first direct comparison of the in vitro osteogenic potential of three osteogenic BMPs (BMP-2, -6 and -7) combined with native human plasma fibronectin delivered in solution or coated by laser transfer onto titanium hydroxyapatite surfaces. We confirm that BMP association with fibronectin enhances the osteogenic activity of BMP-2, -6 and -7, but with essential discrepancies, depending on the BMP member, and in agreement with the affinity of BMPs for fibronectin. Moreover, we bring elements to explain the origin of the BMP-2 medical life-threatening side-effects by analyzing in vitro paracrine effects. Finally, this work supports the alternative use of FN/BMP-6 to induce osteogenic activity under physiological conditions, with minimum side effects.
      Graphical abstract image

      PubDate: 2017-04-21T13:47:56Z
      DOI: 10.1016/j.actbio.2017.04.013
       
  • Non-Invasive Tracking of Hydrogel Degradation Using Upconversion
           Nanoparticles
    • Authors: Yuqing Dong; Guorui Jin; Changchun Ji; Rongyan He; Min Lin; Xin Zhao; Ang Li; Tian Jian Lu; Feng Xu
      Abstract: Publication date: Available online 17 April 2017
      Source:Acta Biomaterialia
      Author(s): Yuqing Dong, Guorui Jin, Changchun Ji, Rongyan He, Min Lin, Xin Zhao, Ang Li, Tian Jian Lu, Feng Xu
      Tracking the distribution and degradation of hydrogels in vivo is important for various applications including tissue engineering and drug delivery. Among various imaging modalities, fluorescence imaging has attracted intensive attention due to their high sensitivity, low cost and easy operation. Particularly, upconversion nanoparticles (UCNPs) that emit visible lights upon near-infrared (NIR) light excitation as tracking probes are promising in deciphering the fate of hydrogels after transplantation. Herein, we reported a facile and non-invasive in vivo hydrogel tracking method using UCNPs, where the degradation of hydrogels was determined using the decrease in fluorescence intensity from the UCNPs encapsulated in the hydrogels. We found that the change in the fluorescence intensity from the UCNPs was well consistent with that of the fluorescein isothiocyanate (FITC) covalently conjugated to hydrogels and also with the weight change of the hydrogels, suggesting the accuracy of the UCNPs in tracking the degradation of hydrogels. Furthermore, the in vivo fluorescence signals were only observed from the UCNPs instead of FITC after implantation for 7 days due to the deep tissue penetration of UCNPs, demonstrating the capability of UCNPs in longitudinal, consecutive and non-invasive monitoring the in vivo degradation of hydrogels without causing any damage to the major organs (heart, lung, liver and kidney) of model rats. This study thus paves the way for monitoring the in vivo behaviors of biomimetic materials via deep tissue imaging with great clinical translation potentials. Statement of Significance Long-term noninvasive in vivo tracking of the distribution and degradation of biodegradable hydrogels using fluorescent probes is important in tissue regeneration and drug delivery. Unlike the widely used fluorescent dyes and quantum dots (QDs) that suffer from photobleaching and undesired toxicity, upconversion nanoparticles (UCNPs) with high stability, deep tissue penetration as tracking probes are promising in deciphering the fate of hydrogels after transplantation. Herein, we reported a noninvasive in vivo hydrogel tracking method using UCNPs and found that the fluorescence intensity change from the UCNPs was well consistent with the weight change of the hydrogels, suggesting the accuracy of UCNPs in tracking hydrogel degradation. This study provides inspirations on developing advanced NIR light regulated probes with great clinical translation potentials.
      Graphical abstract image

      PubDate: 2017-04-21T13:47:56Z
      DOI: 10.1016/j.actbio.2017.04.016
       
 
 
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