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Publisher: Elsevier   (Total: 3162 journals)

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Showing 1 - 200 of 3162 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 9)
AASRI Procedia     Open Access   (Followers: 14)
Academic Pediatrics     Hybrid Journal   (Followers: 30, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 88, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 35, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 396, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 27, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 245, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
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: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 6, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 6)
Acute Pain     Full-text available via subscription   (Followers: 15)
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: 8)
Additive Manufacturing     Hybrid Journal   (Followers: 9, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 22)
Advanced Cement Based Materials     Full-text available via subscription   (Followers: 3)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 137, 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: 12, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 10, 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: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 14, 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: 2, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 29, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 7, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 3)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, 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: 19, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 8)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 23)
Advances in Ecological Research     Full-text available via subscription   (Followers: 42, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 27, 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: 43, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 53, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
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: 8)
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: 21, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, 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: 37, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, 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: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 14, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 21)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, 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: 1)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 16, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 6, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 10)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 59)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.1, h-index: 2)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 388, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 9, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 29, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 17)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 46, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 336, 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: 6, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 10, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 437, 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: 31, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 43, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 1)
Agriculture and Natural Resources     Open Access   (Followers: 2)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 56, 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: 6, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 9)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access   (Followers: 1)
Algal Research     Partially Free   (Followers: 10, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
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)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 49, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 50, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 51, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 44, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 10, 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: 31, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 26, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 34, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 43, 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: 202, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 62, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 27, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 27, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 37, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 63, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 15)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 3, 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: 5, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 39, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 175, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 10, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 11)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1)

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Journal Cover Acta Biomaterialia
  Journal Prestige (SJR): 2.02
  Citation Impact (citeScore): 104
  Number of Followers: 27  
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1742-7061
   Published by Elsevier Homepage  [3162 journals]
  • Piezoelectric materials as stimulatory biomedical materials and scaffolds
           for bone repair
    • Authors: Biranche Tandon; Jonny J. Blaker; Sarah H. Cartmell
      Pages: 1 - 20
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Biranche Tandon, Jonny J. Blaker, Sarah H. Cartmell
      The process of bone repair and regeneration requires multiple physiological cues including biochemical, electrical and mechanical - that act together to ensure functional recovery. Myriad materials have been explored as bioactive scaffolds to deliver these cues locally to the damage site, amongst these piezoelectric materials have demonstrated significant potential for tissue engineering and regeneration, especially for bone repair. Piezoelectric materials have been widely explored for power generation and harvesting, structural health monitoring, and use in biomedical devices. They have the ability to deform with physiological movements and consequently deliver electrical stimulation to cells or damaged tissue without the need of an external power source. Bone itself is piezoelectric and the charges/potentials it generates in response to mechanical activity are capable of enhancing bone growth. Piezoelectric materials are capable of stimulating the physiological electrical microenvironment, and can play a vital role to stimulate regeneration and repair. This review gives an overview of the association of piezoelectric effect with bone repair, and focuses on state-of-the-art piezoelectric materials (polymers, ceramics and their composites), the fabrication routes to produce piezoelectric scaffolds, and their application in bone repair. Important characteristics of these materials from the perspective of bone tissue engineering are highlighted. Promising upcoming strategies and new piezoelectric materials for this application are presented. Statement of significance Electrical stimulation/electrical microenvironment are known effect the process of bone regeneration by altering the cellular response and are crucial in maintaining tissue functionality. Piezoelectric materials, owing to their capability of generating charges/potentials in response to mechanical deformations, have displayed great potential for fabricating smart stimulatory scaffolds for bone tissue engineering. The growing interest of the scientific community and compelling results of the published research articles has been the motivation of this review article. This article summarizes the significant progress in the field with a focus on the fabrication aspects of piezoelectric materials. The review of both material and cellular aspects on this topic ensures that this paper appeals to both material scientists and tissue engineers.
      Graphical abstract image

      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.026
      Issue No: Vol. 73 (2018)
       
  • Combinatorial approaches in post-polymerization modification for rational
           development of therapeutic delivery systems
    • Authors: Yuanbo Zhong; Brian J. Zeberl; Xu Wang; Juntao Luo
      Pages: 21 - 37
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Yuanbo Zhong, Brian J. Zeberl, Xu Wang, Juntao Luo
      The combinatorial polymer library approach has been proven to be effective for the optimization of therapeutic delivery systems. The library of polymers with chemical diversity has been synthesized by (i) polymerization of functionalized monomers or (ii) post-polymerization modification of reactive polymers. Most scientists have followed the first approach so far, and the second method has emerged as a versatile approach for combinatorial biomaterials discovery. This review focuses on the second approach, especially discussing the post-modifications that employ reactive polymers as templates for combinatorial synthesis of a library of functional polymers with distinct structural diversity or a combination of different functionalities. In this way, the functional polymers have a consistent chain length and distribution, which allows for systematic optimization of therapeutic delivery polymers for the efficient delivery of genes, small-molecule drugs, and protein therapeutics. In this review, the modification of representative reactive polymers for the delivery of different therapeutic payloads are summarized. The recent advances in rational design and optimization of therapeutic delivery systems based on reactive polymers are highlighted. This review ends with a summary of the current achievements and the prospect on future directions in applying the approach of post-polymerization modification of polymers to accelerate the development of therapeutic delivery systems. Statement of significance A strategy to rationally design and systematically optimize polymers for the efficient delivery of specific therapeutics is highly needed. The combinatorial polymer library approach could be an effective way to this end. The post-polymerization modification of reactive polymer precursors is applicable for the combinatorial synthesis of a library of functional polymers with distinct structural diversity across a consistent degree of polymerization. This allows for parallel comparison and systematic evaluation/optimization of functional polymers for efficient therapeutic delivery. This review summarizes the key elements of this combinatorial polymer synthesis approach realized by post-polymerization modification of reactive polymer precursors towards the development and identification of optimal polymers for the efficient delivery of therapeutic agents.
      Graphical abstract image

      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.010
      Issue No: Vol. 73 (2018)
       
  • Customizing poly(lactic-co-glycolic acid) particles for biomedical
           applications
    • Authors: Edyta Swider; Olga Koshkina; Jurjen Tel; Luis J. Cruz; I. Jolanda M. de Vries; Mangala Srinivas
      Pages: 38 - 51
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Edyta Swider, Olga Koshkina, Jurjen Tel, Luis J. Cruz, I. Jolanda M. de Vries, Mangala Srinivas
      Nano- and microparticles have increasingly widespread applications in nanomedicine, ranging from drug delivery to imaging. Poly(lactic-co-glycolic acid) (PLGA) particles are the most widely-applied type of particles due to their biocompatibility and biodegradability. Here, we discuss the preparation of PLGA particles, and various modifications to tailor particles for applications in biological systems. We highlight new preparation approaches, including microfluidics and PRINT method, and modifications of PLGA particles resulting in novel or responsive properties, such as Janus or upconversion particles. Finally, we describe how the preparation methods can- and should-be adapted to tailor the properties of particles for the desired biomedical application. Our aim is to enable researchers who work with PLGA particles to better appreciate the effects of the selected preparation procedure on the final properties of the particles and its biological implications. Statement of Significance Nanoparticles are increasingly important in the field of biomedicine. Particles made of polymers are in the spotlight, due to their biodegradability, biocompatibility, versatility. In this review, we aim to discuss the range of formulation techniques, manipulations, and applications of poly(lactic-co-glycolic acid) (PLGA) particles, to enable a researcher to effectively select or design the optimal particles for their application. We describe the various techniques of PLGA particle synthesis and their impact on possible applications. We focus on recent developments in the field of PLGA particles, and new synthesis techniques that have emerged over the past years. Overall, we show how the chemistry of PLGA particles can be adapted to solve pressing biological needs.
      Graphical abstract image

      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.006
      Issue No: Vol. 73 (2018)
       
  • Towards tailored management of malignant brain tumors with
           nanotheranostics
    • Authors: Juan Aparicio-Blanco; Ana-Isabel Torres-Suárez
      Pages: 52 - 63
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Juan Aparicio-Blanco, Ana-Isabel Torres-Suárez
      Malignant brain tumors still represent an unmet medical need given their rapid progression and often fatal outcome within months of diagnosis. Given their extremely heterogeneous nature, the assumption that a single therapy could be beneficial for all patients is no longer plausible. Hence, early feedback on drug accumulation at the tumor site and on tumor response to treatment would help tailor therapies to each patient’s individual needs for personalized medicine. In this context, at the intersection between imaging and therapy, theranostic nanomedicine is a promising new technique for individualized management of malignant brain tumors. Although brain nanotheranostics has yet to be translated into clinical practice, this field is now a research hotspot due to the growing demand for personalized therapies. In this review, the barriers to the clinical implementation of theranostic nanomedicine for tracking tumor responses to treatment and for guiding stimulus-activated therapies and surgical resection of malignant brain tumors are discussed. Likewise, the criteria that nanotheranostic systems need to fulfil to become clinically relevant formulations are analyzed in depth, focusing on theranostic agents already tested in vivo. Currently, magnetic nanoparticles exploiting brain targeting strategies represent the first generation of preclinical theranostic nanomedicines for the management of malignant brain tumors. Statement of Significance The development of nanocarriers that can be used both in imaging studies and the treatment of brain tumors could help identify which patients are most and least likely to respond to a given treatment. This will enable clinicians to adapt the therapy to the needs of the patient and avoid overdosing non-responders. Given the many different approaches to non-invasive techniques for imaging and treating brain tumors, it is important to focus on the strategies most likely to be implemented and to design the most feasible theranostic biomaterials that will bring nanotheranostics one step closer to clinical practice.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.029
      Issue No: Vol. 73 (2018)
       
  • Therapeutics incorporating blood constituents
    • Authors: Phapanin Charoenphol; Katie Oswalt; Corey J. Bishop
      Pages: 64 - 80
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Phapanin Charoenphol, Katie Oswalt, Corey J. Bishop
      Blood deficiency and dysfunctionality can result in adverse events, which can primarily be treated by transfusion of blood or the re-introduction of properly functioning sub-components. Blood constituents can be engineered on the sub-cellular (i.e., DNA recombinant technology) and cellular level (i.e., cellular hitchhiking for drug delivery) for supplementing and enhancing therapeutic efficacy, in addition to rectifying dysfunctioning mechanisms (i.e., clotting). Herein, we report the progress of blood-based therapeutics, with an emphasis on recent applications of blood transfusion, blood cell-based therapies and biomimetic carriers. Clinically translated technologies and commercial products of blood-based therapeutics are subsequently highlighted and perspectives on challenges and future prospects are discussed. Statement of significance Blood-based therapeutics is a burgeoning field and has advanced considerably in recent years. Blood and its constituents, with and without modification (i.e., combinatorial), have been utilized in a broad spectrum of pre-clinical and clinically-translated treatments. This review article summarizes the most up-to-date progress of blood-based therapeutics in the following contexts: synthetic blood substitutes, acellular/non-recombinant therapies, cell-based therapies, and therapeutic sub-components. The article subsequently discusses clinically-translated technologies and future prospects thereof.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.03.046
      Issue No: Vol. 73 (2018)
       
  • Hyperspectral chemical imaging reveals spatially varied degradation of
           polycarbonate urethane (PCU) biomaterials
    • Authors: Ronan M. Dorrepaal; Bernard M. Lawless; Hanna E. Burton; Daniel M. Espino; Duncan E.T. Shepherd; Aoife A. Gowen
      Pages: 81 - 89
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Ronan M. Dorrepaal, Bernard M. Lawless, Hanna E. Burton, Daniel M. Espino, Duncan E.T. Shepherd, Aoife A. Gowen
      Hyperspectral chemical imaging (HCI) is an emerging technique which combines spectroscopy with imaging. Unlike traditional point spectroscopy, which is used in the majority of polymer biomaterial degradation studies, HCI enables the acquisition of spatially localised spectra across the surface of a material in an objective manner. Here, we demonstrate that attenuated total reflectance Fourier transform infra-red (ATR-FTIR) HCI reveals spatial variation in the degradation of implantable polycarbonate urethane (PCU) biomaterials. It is also shown that HCI can detect possible defects in biomaterial formulation or specimen production; these spatially resolved images reveal regional or scattered spatial heterogeneity. Further, we demonstrate a map sampling method, which can be used in time-sensitive scenarios, allowing for the investigation of degradation across a larger component or component area. Unlike imaging, mapping does not produce a contiguous image, yet grants an insight into the spatial heterogeneity of the biomaterial across a larger area. These novel applications of HCI demonstrate its ability to assist in the detection of defective manufacturing components and lead to a deeper understanding of how a biomaterial’s chemical structure changes due to implantation. Statement of significance The human body is an aggressive environment for implantable devices and their biomaterial components. Polycarbonate urethane (PCU) biomaterials in particular were investigated in this study. Traditionally one or a few points on the PCU surface are analysed using ATR-FTIR spectroscopy. However the selection of acquisition points is susceptible to operator bias and critical information can be lost. This study utilises hyperspectral chemical imaging (HCI) to demonstrate that the degradation of a biomaterial varies spatially. Further, HCI revealed spatial variations of biomaterials that were not subjected to oxidative degradation leading to the possibility of HCI being used in the assessment of biomaterial formulation and/or component production.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.03.045
      Issue No: Vol. 73 (2018)
       
  • Injectable drug depot engineered to release multiple ophthalmic
           therapeutic agents with precise time profiles for postoperative treatment
           following ocular surgery
    • Authors: Maziar Mohammadi; Kisha Patel; Seyedeh P. Alaie; Ron B. Shmueli; Cagri G. Besirli; Ronald G. Larson; Jordan J. Green
      Pages: 90 - 102
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Maziar Mohammadi, Kisha Patel, Seyedeh P. Alaie, Ron B. Shmueli, Cagri G. Besirli, Ronald G. Larson, Jordan J. Green
      A multi-drug delivery platform is developed to address current shortcomings of post-operative ocular drug delivery. The sustained biodegradable drug release system is composed of biodegradable polymeric microparticles (MPs) incorporated into a bulk biodegradable hydrogel made from triblock copolymers with poly(ethylene glycol) (PEG) center blocks and hydrophobic biodegradable polyester blocks such as poly(lactide-co-glycolide) (PLGA), Poly(lactic acid) (PLA), or Poly(lactide-co-caprolactone) (PLCL) blocks. This system is engineered to flow as a liquid solution at room temperature for facile injection into the eye and then quickly gel as it warms to physiological body temperatures (approximately 37 °C). The hydrogel acts as an ocular depot that can release three different drug molecules at programmed rates and times to provide optimal release of each species. In this manuscript, the hydrogel is configured to release a broad-spectrum antibiotic, a potent corticosteroid, and an ocular hypotensive, three ophthalmic therapeutic agents that are essential for post-operative management after ocular surgery, each drug released at its own timescale. The delivery platform is designed to mimic current topical application of postoperative ocular formulations, releasing the antibiotic for up to a week, and the corticosteroid and the ocular hypotensive agents for at least a month. Hydrophobic blocks, such as PLCL, were utilized to prolong the release duration of the biomolecules. This system also enables customization by being able to vary the initial drug loading to linearly tune the drug dose released, while maintaining a constant drug release profile over time. This minimally invasive biodegradable multi-drug delivery system is capable of replacing a complex ocular treatment regimen with a simple injection. Such a depot system has the potential to increase patient medication compliance and reduce both the immediate and late term complications following ophthalmic surgery. Statement of Significance After ocular surgery, patients routinely receive multiple medications including antibiotics, steroids and ocular hypotensives to ensure optimal surgical outcomes. The current standard of care for postoperative treatment after ocular surgery involves using eye drops daily, which has limited effectiveness mainly due to poor patient adherence. To improve patient experience and outcomes, this article presents the first thermoresponsive hydrogel able to release multiple drug molecules for the application of post-operative treatment following ocular surgery. By varying the parameters such as hydrogel type and polymer hydrophobicity, the drug release profile, duration and dosage can finely be tuned. The approach presented in this article can readily be applied to other applications by simply changing the drug loaded in the drug delivery system.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.037
      Issue No: Vol. 73 (2018)
       
  • Component effect of stem cell-loaded thermosensitive polypeptide hydrogels
           on cartilage repair
    • Authors: He Liu; Yilong Cheng; Jinjin Chen; Fei Chang; Jincheng Wang; Jianxun Ding; Xuesi Chen
      Pages: 103 - 111
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): He Liu, Yilong Cheng, Jinjin Chen, Fei Chang, Jincheng Wang, Jianxun Ding, Xuesi Chen
      Biophysical properties of the desired biomimetic scaffolds, such as porosity and elasticity, have been proven associated with the efficacy of cartilage regeneration. In this work, the copolymers of poly(l-alanine)-block-poly(ethylene glycol)-block-poly(l-alanine) (PA-PEG-PA) and poly(l-alanine-co-l-phenylalanine)-block-poly(ethylene glycol)-block-poly(l-alanine-co-l-phenylalanine) (PAF-PEG-PAF) with different ratios of alanine to phenylalanine were synthesized. The introduction of a hydrophobic amino acid, i.e., phenylalanine, into polyalanine-based thermosensitive hydrogel led to the enhanced gelation behaviors and upregulated mechanical properties. Moreover, the increase of phenylalanine content resulted in the enlarged pore size and enhanced mechanical strength of PAF-PEG-PAF thermogel, followed by the regeneration of hyaline-like cartilage with reduced fibrous tissue formation in vivo. The findings indicated the great potential of thermosensitive polypeptide hydrogels in cartilage tissue engineering. Statement of Significance Articular cartilage defect has limited self-repair ability due to the lack of blood supply and innervation, which may lead to knee osteoarthritis afterwards. Injectable hydrogels are demonstrated possessing outstanding properties as biomimetic scaffolds in cartilage tissue engineering, while the effect of biophysical properties on the efficacy of cartilage regeneration has not been revealed. Herein, the poly(ethylene glycol)-polypeptide triblock copolymers with different ratios of alanine to phenylalanine were synthesized. The sol-to-gel transition temperature and the critical gelation concentration decreased as the increased amount of phenylalanine unit, resulting in the enlarged pore size and enhanced mechanical strength. These features lead to better regeneration of hyaline-like cartilage with reduced fibrous tissue formation, indicating great potential of thermosensitive polypeptide hydrogels for efficient cartilage repair.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.035
      Issue No: Vol. 73 (2018)
       
  • Injectable, porous, biohybrid hydrogels incorporating decellularized
           tissue components for soft tissue applications
    • Authors: Yang Zhu; Sato Hideyoshi; Hongbin Jiang; Yasumoto Matsumura; Jenna L. Dziki; Samuel T. LoPresti; Luai Huleihel; Gabriela N.F. Faria; Leah C. Fuhrman; Ricardo Lodono; Stephen F. Badylak; William R. Wagner
      Pages: 112 - 126
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Yang Zhu, Sato Hideyoshi, Hongbin Jiang, Yasumoto Matsumura, Jenna L. Dziki, Samuel T. LoPresti, Luai Huleihel, Gabriela N.F. Faria, Leah C. Fuhrman, Ricardo Lodono, Stephen F. Badylak, William R. Wagner
      Biodegradable injectable hydrogels have been extensively studied and evaluated in various medical applications such as for bulking agents, drug delivery reservoirs, temporary barriers, adhesives, and cell delivery matrices. Where injectable hydrogels are intended to facilitate a healing response, it may be desirable to encourage rapid cellular infiltration into the hydrogel volume from the tissue surrounding the injection site. In this study, we developed a platform technique to rapidly form pores in a thermally responsive injectable hydrogel, poly(NIPAAm-co-VP-co-MAPLA) by using mannitol particles as porogens. In a rat hindlimb muscle injection model, hydrogels incorporating porosity had significantly accelerated cellular infiltration. To influence the inflammatory response to the injected hydrogel, enzymatically digested urinary bladder matrix (UBM) was mixed with the solubilized hydrogel. The presence of UBM was associated with greater polarization of the recruited macrophage population to the M2 phenotype, indicating a more constructive foreign body response. The hybrid hydrogel positively affected the wound healing outcomes of defects in rabbit adipose tissue with negligible inflammation and fibrosis, whereas scar formation and chronic inflammation were observed with autotransplantation and in saline injected groups. These results demonstrate the value of combining the effects of promoting cell infiltration and mediating the foreign body response for improved biomaterials options soft tissue defect filling applications. Statement of Significance Our objective was to develop a fabrication process to create porous injectable hydrogels incorporating decellularized tissue digest material. This new hydrogel material was expected to exhibit faster cellular infiltration and a greater extent of pro-M2 macrophage polarization compared to control groups not incorporating each of the functional components. Poly(NIPAAm-co-VP-co-MAPLA) was chosen as the representative thermoresponsive hydrogel, and mannitol particles and digested urinary bladder matrix (UBM) were selected as the porogen and the bioactive decellularized material components respectively. In rat hindlimb intramuscular injection models, this new hydrogel material induced more rapid cellular infiltration and a greater extent of M2 macrophage polarization compared to control groups not incorporating all of the functional components. The hybrid hydrogel positively affected the wound healing outcomes of defects in rabbit adipose tissue with negligible inflammation and fibrosis, whereas scar formation and chronic inflammation were observed with autotransplantation and in saline injected groups. The methodology of this report provides a straightforward and convenient mechanism to promote cell infiltration and mediate foreign body response in injectable hydrogels for soft tissue applications. We believe that the readership of Acta Biomaterialia will find the work of interest both for its specific results and general translatability of the findings.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.003
      Issue No: Vol. 73 (2018)
       
  • An electrospun fiber reinforced scaffold promotes total meniscus
           regeneration in rabbit meniscectomy model
    • Authors: Shuang Gao; Mingxue Chen; Pei Wang; Yan Li; Zhiguo Yuan; Weimin Guo; Zengzeng Zhang; Xueliang Zhang; Xiaoguang Jing; Xu Li; Shuyun Liu; Xiang Sui; Tingfei Xi; Quanyi Guo
      Pages: 127 - 140
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Shuang Gao, Mingxue Chen, Pei Wang, Yan Li, Zhiguo Yuan, Weimin Guo, Zengzeng Zhang, Xueliang Zhang, Xiaoguang Jing, Xu Li, Shuyun Liu, Xiang Sui, Tingfei Xi, Quanyi Guo
      Low vascularization in meniscus limits its regeneration ability after injury, and tissue engineering is the most promising method to achieve meniscus regeneration. In this study, we fabricated a kind of composite scaffold by decellularized meniscus extracellular matrix/polycaprolactone (DMECM/PCL) electrospinning fibers and porous DMECM, in which DMECM/PCL fibers were used as reinforcing component. The tensile modulus of the composite scaffold in longitudinal and crosswise directions were 8.5 ± 1.9 and 2.3 ± 0.3 MPa, respectively. Besides that, the DMECM/PCL electrospinning fibers enhanced suture resistance of the composite scaffold more than 5 times than DMECM scaffold effectively. In vitro cytocompatibility showed that the porous structure provided by DMECM component facilitated meniscus cells’ proliferation. DMECM was also the main component to regulate cell behaviors, which promoted meniscus cells expressing extracellular matrix related genes such as COL I, COL II, SOX9 and AGG. Rabbits with total meniscectomy were used as animal model to evaluated the composited scaffolds performance in vivo at 3 and 6 months. Results showed that rabbits with scaffold implanting could regenerate neo-menisci in both time points. The neo-menisci had similar histology structure and biochemical content with native menisci. Although neo-menisci had inferior tensile modulus than native ones, its modulus was improved with implanting time prolonging. MRI imaging showed the signal of neo-meniscus in the body is clear, and X-ray imaging of knee joints demonstrated the implantation of scaffolds could relief joint space narrowing. Moreover, rabbits with neo-menisci had better cartilage condition in femoral condyle and tibial plateau compared than meniscectomy group. Statement of Significance We fabricated the meniscus scaffold by combining porous decellularized meniscus extracellular matrix (DMECM) and DMECM/PCL electrospinning fibers together, which used the porous structure of DMECM, and the good tensile property of electrospinning fibers. We believe single material cannot satisfy increasing needs of scaffold. Therefore, we combined not only materials but also fabrication methods together to develop scaffold to make good use of each part. DMECM in electrospinning fibers also made these two components possible to be integrated through crosslinking. Compared to existing meniscus scaffold, the composite scaffold had (1) soft structure and extrusion would not happen after implantation, (2) ability to be trimmed to suitable shape during surgery, and (3) good resistance to suture.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.012
      Issue No: Vol. 73 (2018)
       
  • Exploring the potential of polyurethane-based soft foam as cell-free
           scaffold for soft tissue regeneration
    • Authors: Irini Gerges; Margherita Tamplenizza; Federico Martello; Camilla Recordati; Cristina Martelli; Luisa Ottobrini; Mariacaterina Tamplenizza; Scott A. Guelcher; Alessandro Tocchio; Cristina Lenardi
      Pages: 141 - 153
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Irini Gerges, Margherita Tamplenizza, Federico Martello, Camilla Recordati, Cristina Martelli, Luisa Ottobrini, Mariacaterina Tamplenizza, Scott A. Guelcher, Alessandro Tocchio, Cristina Lenardi
      Reconstructive treatment after trauma and tumor resection would greatly benefit from an effective soft tissue regeneration. The use of cell-free scaffolds for adipose tissue regeneration in vivo is emerging as an attractive alternative to tissue-engineered constructs, since this approach avoids complications due to cell manipulation and lack of synchronous vascularization. In this study, we developed a biodegradable polyurethane-based scaffold for soft tissue regeneration, characterized by an exceptional combination between softness and resilience. Exploring the potential as a cell-free scaffold required profound understanding of the impact of its intrinsic physico-chemical properties on the biological performance in vivo. We investigated the effect of the scaffold’s hydrophilic character, degradation kinetics, and internal morphology on (i) the local inflammatory response and activation of MGCs (foreign body response); (ii) its ability to promote rapid vascularisation, cell infiltration and migration through the scaffold over time; and (iii) the grade of maturation of the newly formed tissue into vascularized soft tissue in a murine model. The study revealed that soft tissue regeneration in vivo proceeded by gradual infiltration of undifferentiated mesenchymal cells though the periphery toward the center of the scaffold, where the rapid formation of a functional and well-formed vascular network supported cell viability overtime. Statement of significance Exploring the potential of polyurethane-based soft foam as cell-free scaffold for soft tissue regeneration. In this work, we address the unmet need for synthetic functional soft tissue substitutes that provide adequate biological and mechanical support to soft tissue. We developed a series of flexible cross-linked polyurethane copolymer scaffolds with remarkable fatigue-resistance and tunable physico-chemical properties for soft tissue regeneration in vivo. Accordingly, we could extend the potential of this class of biomaterials, which was so far confined for bone and osteochondral tissue regeneration, to other types of connective tissue.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.011
      Issue No: Vol. 73 (2018)
       
  • Decoration of RGD-mimetic porous scaffolds with engineered and devitalized
           extracellular matrix for adipose tissue regeneration
    • Authors: Eleonora Rossi; Julien Guerrero; Paola Aprile; Alessandro Tocchio; Elisabeth A. Kappos; Irini Gerges; Cristina Lenardi; Ivan Martin; Arnaud Scherberich
      Pages: 154 - 166
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Eleonora Rossi, Julien Guerrero, Paola Aprile, Alessandro Tocchio, Elisabeth A. Kappos, Irini Gerges, Cristina Lenardi, Ivan Martin, Arnaud Scherberich
      Fat grafting is emerging as a promising alternative to silicon implants in breast reconstruction surgery. Unfortunately, this approach does not provide a proper mechanical support and is affected by drawbacks such as tissue resorption and donor site morbidity. Synthetic scaffolds can offer a valuable alternative to address these challenges, but poorly recapitulate the biochemical stimuli needed for tissue regeneration. Here, we aim at combining the positive features of a structural, synthetic polymer to an engineered, devitalized extracellular matrix (ECM) to generate a hybrid construct that can provide a mix of structural and biological stimuli needed for adipose tissue regeneration. A RGD-mimetic synthetic scaffold OPAAF, designed for soft tissue engineering, was decorated with ECM deposited by human adipose stromal cells (hASCs). The adipoinductive potential of the hybrid ECM-OPAAF construct was validated in vitro, by culture with hASC in a perfusion bioreactor system, and in vivo, by subcutaneous implantation in nude mouse. Our findings demonstrate that the hybrid ECM-OPAAF provides proper mechanical support and adipoinductive stimuli, with potential applicability as off-the-shelf material for adipose tissue reconstruction. Statement of Significance In this study we combined the functionalities of a synthetic polymer with those of an engineered and subsequently devitalized extracellular matrix (ECM) to generate a hybrid material for adipose tissue regeneration. The developed hybrid ECM-OPAAF was demonstrated to regulate human adipose stromal cells adipogenic commitment in vitro and adipose tissue infiltration in vivo. Our findings demonstrate that the hybrid ECM-OPAAF provide proper mechanical support and adipoinductive stimuli and represents a promising off-the-shelf material for adipose tissue reconstruction. We believe that our approach could offer an alternative strategy for adipose tissue reconstruction in case of mastectomy or congenital abnormalities, overcoming the current limitations of autologous fat based strategies such as volume resorption and donor site morbidity.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.039
      Issue No: Vol. 73 (2018)
       
  • A microfluidic oxygen sink to create a targeted cellular hypoxic
           microenvironment under ambient atmospheric conditions
    • Authors: Samineh Barmaki; Ville Jokinen; Daniela Obermaier; Daria Blokhina; Matti Korhonen; Robin H.A. Ras; Jyrki Vuola; Sami Franssila; Esko Kankuri
      Pages: 167 - 179
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Samineh Barmaki, Ville Jokinen, Daniela Obermaier, Daria Blokhina, Matti Korhonen, Robin H.A. Ras, Jyrki Vuola, Sami Franssila, Esko Kankuri
      Physiological oxygen levels within the tissue microenvironment are usually lower than 14%, in stem cell niches these levels can be as low as 0–1%. In cell cultures, such low oxygen levels are usually mimicked by altering the global culture environment either by O2 removal (vacuum or oxygen absorption) or by N2 supplementation for O2 replacement. To generate a targeted cellular hypoxic microenvironment under ambient atmospheric conditions, we characterised the ability of the dissolved oxygen-depleting sodium sulfite to generate an in-liquid oxygen sink. We utilised a microfluidic design to place the cultured cells in the vertical oxygen gradient and to physically separate the cells from the liquid. We demonstrate generation of a chemical in-liquid oxygen sink that modifies the surrounding O2 concentrations. O2 level control in the sink-generated hypoxia gradient is achievable by varying the thickness of the polydimethylsiloxane membrane. We show that intracellular hypoxia and hypoxia response element-dependent signalling is instigated in cells exposed to the microfluidic in-liquid O2 sink-generated hypoxia gradient. Moreover, we show that microfluidic flow controls site-specific microenvironmental kinetics of the chemical O2 sink reaction, which enables generation of intermittent hypoxia/re-oxygenation cycles. The microfluidic O2 sink chip targets hypoxia to the cell culture microenvironment exposed to the microfluidic channel architecture solely by depleting O2 while other sites in the same culture well remain unaffected. Thus, responses of both hypoxic and bystander cells can be characterised. Moreover, control of microfluidic flow enables generation of intermittent hypoxia or hypoxia/re-oxygenation cycles. Statement of Significance Specific manipulation of oxygen concentrations in cultured cells’ microenvironment is important when mimicking low-oxygen tissue conditions and pathologies such as tissue infarction or cancer. We utilised a sodium sulfite-based in-liquid chemical reaction to consume dissolved oxygen. When this liquid was pumped into a microfluidic channel, lowered oxygen levels could be measured outside the channel through a polydimethylsiloxane PDMS membrane allowing only for gaseous exchange. We then utilised this setup to deplete oxygen from the microenvironment of cultured cells, and showed that cells responded to hypoxia on molecular level. Our setup can be used for specifically removing oxygen from the cell culture microenvironment for experimental purposes and for generating a low oxygen environment that better mimics the cells’ original tissue environments.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.007
      Issue No: Vol. 73 (2018)
       
  • The in vivo anti-fibrotic function of calcium sensitive receptor (CaSR)
           modulating poly(p-dioxanone-co-l-phenylalanine) prodrug
    • Authors: Bing Wang; Aiping Wen; Chengmin Feng; Lijing Niu; Xin Xiao; Le Luo; Chengyi Shen; Jiang Zhu; Jun Lei; Xiaoming Zhang
      Pages: 180 - 189
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Bing Wang, Aiping Wen, Chengmin Feng, Lijing Niu, Xin Xiao, Le Luo, Chengyi Shen, Jiang Zhu, Jun Lei, Xiaoming Zhang
      In present study, the apoptosis induction and proliferation suppression effects of l-phenylalanine (l-Phe) on fibroblasts were confirmed. The action sites of l-Phe on fibroblasts suppression were deduced to be calcium sensitive receptor (CaSR) which could cause the release of endoplasmic reticulum (ER) Ca2+ stores; disruption of intracellular Ca2+ homeostasis triggers cell apoptosis via the ER or mitochondrial pathways. The down-regulation of CaSR were observed after the application of l-Phe, and the results those l-Phe triggered the increasing of intracellular Ca2+ concentration and calcineurin expression, and then the apoptosis and increasing G1 fraction of fibroblasts have verified our deduction. Hence, l-Phe could be seen as a kind of anti-fibrotic drugs for the crucial participation of fibroblast in the occurrence of fibrosis. And then, poly(p-dioxanone-co-l-phenylalanine) (PDPA) which could prolong the in-vivo anti-fibrotic effect of l-Phe for the sustained release of l-Phe during its degradation could be treated as anti-fibrotic polymer prodrugs. Based on the above, the in vivo anti-fibrotic function of PDPA was evaluated in rabbit ear scarring, rat peritoneum lipopolysaccharide, and rat sidewall defect/cecum abrasion models. PDPA reduced skin scarring and suppressed peritoneal fibrosis and post operation adhesion as well as secretion of transforming growth factor-β1 in injured tissue. These results indicate that PDPA is an effective agent for preventing fibrosis following tissue injury. Statement of Significance We have previously demonstrated that poly(p-dioxanone-co-l-phenylalanine) (PDPA) could induce apoptosis to fibroblast and deduced that the inhibitory effect comes from l-phenylalanine. In present study, the inhibition mechanism of l-phenylalanine on fibroblast proliferation was demonstrated. The calcium sensitive receptor (CaSR) was found to be the action site. The CaSR was downregulated after the application of l-phenylalanine, and then the ER Ca2+ stores were released. The released Ca2+ can simultaneously activate Ca2+/calcineurin and then trigger apoptosis and G1 arrest of fibroblast. Hence, l-phenylalanine could be seen as anti-fibrosis drug and PDPA which conjugate l-phenylalanine by hydrolytic covalent bonds could be seen as l-phenylalanine polymer prodrug. Based above, the in vivo anti-fibrotic function of PDPA were verified in three different animal models.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.018
      Issue No: Vol. 73 (2018)
       
  • Electrofabrication of functional materials: Chloramine-based antimicrobial
           film for infectious wound treatment
    • Authors: Xue Qu; Huan Liu; Chuchu Zhang; Yu Lei; Miao Lei; Miao Xu; Dawei Jin; Peng Li; Meng Yin; Gregory F. Payne; Changsheng Liu
      Pages: 190 - 203
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Xue Qu, Huan Liu, Chuchu Zhang, Yu Lei, Miao Lei, Miao Xu, Dawei Jin, Peng Li, Meng Yin, Gregory F. Payne, Changsheng Liu
      Electrical signals can be imposed with exquisite spatiotemporal control and provide exciting opportunities to create structure and confer function. Here, we report the use of electrical signals to program the fabrication of a chloramine wound dressing with high antimicrobial activity. This method involves two electrofabrication steps: (i) a cathodic electrodeposition of an aminopolysaccharide chitosan triggered by a localized region of high pH; and (ii) an anodic chlorination of the deposited film in the presence of chloride. This electrofabrication process is completed within several minutes and the chlorinated chitosan can be peeled from the electrode to yield a free-standing film. The presence of active NCl species in this electrofabricated film was confirmed with chlorination occurring first on the amine groups and then on the amide groups when large anodic charges were used. Electrofabrication is quantitatively controllable as the cathodic input controls film growth during deposition and the anodic input controls film chlorination. In vitro studies demonstrate that the chlorinated chitosan film has antimicrobial activities that depend on the chlorination degree. In vivo studies with a MRSA infected wound healing model indicate that the chlorinated chitosan film inhibited bacterial growth, induced less inflammation, developed reorganized epithelial and dermis structures, and thus promoted wound healing compared to a bare wound or wound treated with unmodified chitosan. These results demonstrate the fabrication of advanced functional materials (i.e., antimicrobial wound dressings) using controllable electrical signals to both organize structure through non-covalent interactions (i.e., induce chitosan’s reversible self-assembly) and to initiate function-conferring covalent modifications (i.e., generate chloramine bonds). Potentially, electrofabrication may provide a simple, low cost and sustainable alternative for materials fabrication. Statement of Significance We believe this work is novel because this is the first report (to our knowledge) that electronic signals enable the fabrication of advanced antimicrobial dressings with controlled structure and biological performance. We believe this work is significant because electrofabrication enables rapid, controllable and sustainable materials construction with reduced adverse environmental impacts while generating high performance materials for healthcare applications. More specifically, we report an electrofbrication of antimicrobial film that can promote wound healing.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.02.028
      Issue No: Vol. 73 (2018)
       
  • Versatile effects of magnesium hydroxide nanoparticles in PLGA
           scaffold–mediated chondrogenesis
    • Authors: Kwang-Sook Park; Byoung-Ju Kim; Eugene Lih; Wooram Park; Soo-Hong Lee; Yoon Ki Joung; Dong Keun Han
      Pages: 204 - 216
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Kwang-Sook Park, Byoung-Ju Kim, Eugene Lih, Wooram Park, Soo-Hong Lee, Yoon Ki Joung, Dong Keun Han
      Artificial scaffolds made up of various synthetic biodegradable polymers have been reported to have many advantages including cheap manufacturing, easy scale up, high mechanical strength, convenient manipulation, and molding into an unlimited variety of shapes. However, the synthetic biodegradable polymers still have the insufficiency for cartilage regeneration owing to their acidic degradation products. To reduce acidification by degradation of synthetic polymers, we incorporated magnesium hydroxide (MH) nanoparticles into porous polymer scaffold not only to effectively neutralize the acidic hydrolysate but also to minimize the structural disturbance of scaffolds. The neutralization effect of poly(D,L-lactic-co-glycolic acid; PLGA)/MH scaffold was confirmed with the maintenance of neutral pH, contrary to a PLGA scaffold with low pH. Further, the scaffolds were applied to evaluate the chondrogenic differentiation of the human bone marrow mesenchymal stem cells. In in vitro study, the PLGA/MH scaffold enhanced the chondrogenesis markers and reduced the calcification, compared to the PLGA scaffold. Additionally, the PLGA/MH scaffold reduced the release of inflammatory cytokines, compared to the PLGA scaffold, as the cell death decreased. Moreover, the addition of MH reduced necrotic cell death at the early stage of chondrogenic differentiation. Further, the necrotic cell death by the PLGA scaffold was mediated by cleavage of caspase-1, the so-called interleukin 1-converting enzyme, and MH alleviated it as well as nuclear factor kappa B expression. Furthermore, the PLGA/MH scaffold highly supported chondrogenic healing of rat osteochondral defect sites in in vivo study. Therefore, it was suggested that a synthetic polymer scaffold containing MH could be a novel healing tool to support cartilage regeneration and further treatment of orthopedic patients. Statement of Significance Synthetic polymer scaffolds have been widely utilized for tissue regeneration. However, they have a disadvantage of releasing acidic products through degradation. This paper demonstrated a novel type of synthetic polymer scaffold with pH-neutralizing ceramic nanoparticles composed of magnesium hydroxide for cartilage regeneration. This polymer showed pH-neutralization property during polymer degradation and significant enhancement of chondrogenic differentiation of mesenchymal stem cells. It reduced not only chondrogenic calcification but also release of proinflammatory cytokines. Moreover, it has an inhibitory effect on necrotic cell death, particularly caspase-1-mediated necrotic cell death (pyroptosis). In in vivo study, it showed higher healing rate of the damaged cartilage in a rat osteochondral defect model. We expected that this novel type of scaffold can be effectively applied to support cartilage regeneration and further treatment of orthopedic patients.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.022
      Issue No: Vol. 73 (2018)
       
  • Nanofibrous PLGA electrospun scaffolds modified with type I collagen
           influence hepatocyte function and support viability in vitro
    • Authors: Jessica H. Brown; Prativa Das; Michael D. DiVito; David Ivancic; Lay Poh Tan; Jason A. Wertheim
      Pages: 217 - 227
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Jessica H. Brown, Prativa Das, Michael D. DiVito, David Ivancic, Lay Poh Tan, Jason A. Wertheim
      A major challenge of maintaining primary hepatocytes in vitro is progressive loss of hepatocyte-specific functions, such as protein synthesis and cytochrome P450 (CYP450) catalytic activity. We developed a three-dimensional (3D) nanofibrous scaffold made from poly(l-lactide-co-glycolide) (PLGA) polymer using a newly optimized wet electrospinning technique that resulted in a highly porous structure that accommodated inclusion of primary human hepatocytes. Extracellular matrix (ECM) proteins (type I collagen or fibronectin) at varying concentrations were chemically linked to electrospun PLGA using amine coupling to develop an in vitro culture system containing the minimal essential ECM components of the liver micro-environment that preserve hepatocyte function in vitro. Cell-laden nanofiber scaffolds were tested in vitro to maintain hepatocyte function over a two-week period. Incorporation of type I collagen onto PLGA scaffolds (PLGA-Chigh: 100 µg/mL) led to 10-fold greater albumin secretion, 4-fold higher urea synthesis, and elevated transcription of hepatocyte-specific CYP450 genes (CYP3A4, 3.5-fold increase and CYP2C9, 3-fold increase) in primary human hepatocytes compared to the same cells grown within unmodified PLGA scaffolds over two weeks. These indices, measured using collagen-bonded scaffolds, were also higher than scaffolds coupled to fibronectin or an ECM control sandwich culture composed of type I collagen and Matrigel. Induction of CYP2C9 activity was also higher in these same type I collagen PLGA scaffolds compared to other ECM-modified or unmodified PLGA constructs and was equivalent to the ECM control at 7 days. Together, we demonstrate a minimalist ECM-based 3D synthetic scaffold that accommodates primary human hepatocyte inclusion into the matrix, maintains long-term in vitro survival and stimulates function, which can be attributed to coupling of type I collagen. Statement of Significance Culturing primary hepatocytes within a three-dimensional (3D) structure that mimics the natural liver environment is a promising strategy for extending the function and viability of hepatocytes in vitro. In the present study we generate porous PLGA nanofibers, that are chemically modified with extracellular matrix proteins, to serve as 3D scaffolds for the in vitro culture of primary human hepatocytes. Our findings demonstrate that the use of ECM proteins, especially type I collagen, in a porous 3D environment helps to improve the synthetic function of primary hepatocytes over time. We believe the work presented within will provide insights to readers for drug toxicity and tissue engineering applications.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.02.009
      Issue No: Vol. 73 (2018)
       
  • Effects of upstream shear forces on priming of platelets for downstream
           adhesion and activation
    • Authors: Shekh M. Rahman; Colin D. Eichinger; Vladimir Hlady
      Pages: 228 - 235
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Shekh M. Rahman, Colin D. Eichinger, Vladimir Hlady
      Platelets in flowing blood are sometimes exposed to elevated shear forces caused by anastomotic stenosis at the blood vessel-vascular implant interface. The objective of this study was to determine how effective upstream shear forces are in priming platelets for downstream adhesion and activation. Flow chambers with upstream stenotic regions (shear rates of 400–1000 s−1) were manufactured by relief molding of polydimethylsiloxane. Downstream from the stenotic regions, microcontact printing was used to covalently immobilize three different proteins (fibrinogen, collagen, or von Willebrand factor) to serve as platelet capture agents. Anticoagulated whole blood was perfused through the flow chambers and platelet adhesion to the downstream capture region was quantified. It was found that transient exposure of platelets to increased shear forces resulted in higher platelet adhesion on all three proteins. The duration of the platelet exposure to elevated shear forces was varied by changing the length of the stenotic regions. The results indicated that, in addition to the magnitude of shear forces, the duration of exposure to these forces was also an important factor in priming platelets. The effect of upstream shear forces on platelet activation was assessed by quantifying P-selectin, integrin αIIbβ3, lysosomal glycoprotein, and phosphatidylserine exposure using flow cytometry. The results suggested that increased shear forces were capable of increasing the priming of platelets for downstream activation. This study implicates the anastomotic region(s) of vascular implants as a locus of platelet pre-activation that may lead to thrombus formation downstream. Statement of Significance A synthetic small-diameter vascular graft can often become stenotic due to intimal fibrous hyperplasia, either generally along the inside of the graft or at the anastomotic regions, leading to an increased shear force on flowing platelets. Our lab is studying how the upstream platelet preactivation (aka “priming”) in flowing blood affects their downstream adhesion and activation. This manuscript describes a study in which priming of platelets is achieved by upstream stenotic narrowing in a microfluidic flow chamber. Such experimental design was intended to mimic a vascular implant with stenotic upstream anastomosis and downstream exposed platelet protein agonists. Understanding how the pre-activated platelets respond to imperfect vascular implant surfaces downstream is an important factor in designing better vascular implants.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.002
      Issue No: Vol. 73 (2018)
       
  • Recapitulating spatiotemporal tumor heterogeneity in vitro through
           engineered breast cancer microtissues
    • Authors: Claudia Mazio; Costantino Casale; Giorgia Imparato; Francesco Urciuolo; Paolo Antonio Netti
      Pages: 236 - 249
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Claudia Mazio, Costantino Casale, Giorgia Imparato, Francesco Urciuolo, Paolo Antonio Netti
      Tumor and microenvironmental heterogeneity hinders the study of breast cancer biology and the assessment of therapeutic strategies, being associated with high variability and drug resistance. In this context, it is mandatory to develop three-dimensional breast tumor models able to reproduce this heterogeneity and the dynamic interaction occurring between tumor cells and microenvironment. Here we show a new breast cancer microtissue model (T-µTP) uniquely able to present intra-tumor morphological heterogeneity in a dynamic and responsive endogenous matrix. T-µTP consists of adenocarcinoma cells, endothelial cells and stromal fibroblasts. These three kinds of cells are totally embedded into an endogenous matrix which is rich in collagen and hyaluronic acid and it is directly produced by human fibroblasts. In this highly physiologically relevant environment, tumor cells evolve in different cluster morphologies recapitulating tumor spatiotemporal heterogeneity. Moreover they activate the desmoplastic and vascular reaction with affected collagen content, assembly and organization and the presence of aberrant capillary-like structures (CLS). Thus, T-µTP allows to outline main crucial events involved in breast cancer progression into a single model overcoming the limit of artificial extra cellular matrix surrogates. We strongly believe that T-µTP is a suitable model for the study of breast cancer and for drug screening assays following key parameters of clinical interest. Statement of Significance Tumor and microenvironmental heterogeneity makes very hurdle to find a way to study and treat breast cancer. Here we develop an innovative 3D tumor microtissue model recapitulating in vitro tumor heterogeneity. Tumor microtissues are characterized by the activation of the stromal and vascular reaction too. We underline the importance to mimic different microenvironmental tumor features in the same time and in a single tissue in order to obtain a model of spatiotemporal tumor genesis and progression, suitable for the study of tumor treatment and resistance.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.028
      Issue No: Vol. 73 (2018)
       
  • Biomimetic 3D in vitro model of biofilm triggered osteomyelitis for
           investigating hematopoiesis during bone marrow infections
    • Authors: Annamarija Raic; Sophie Riedel; Elena Kemmling; Karen Bieback; Joerg Overhage; Cornelia Lee-Thedieck
      Pages: 250 - 262
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Annamarija Raic, Sophie Riedel, Elena Kemmling, Karen Bieback, Joerg Overhage, Cornelia Lee-Thedieck
      In this work, we define the requirements for a human cell-based osteomyelitis model which overcomes the limitations of state of the art animal models. Osteomyelitis is a severe and difficult to treat infection of the bone that develops rapidly, making it difficult to study in humans. We have developed a 3D in vitro model of the bone marrow, comprising a macroporous material, human hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). Inclusion of biofilms grown on an implant into the model system allowed us to study the effects of postoperative osteomyelitis-inducing bacteria on the bone marrow. The bacteria influenced the myeloid differentiation of HSPCs as well as MSC cytokine expression and the MSC ability to support HSPC maintenance. In conclusion, we provide a new 3D in vitro model which meets all the requirements for investigating the impact of osteomyelitis. Statement of Significance Implant-associated osteomyelitis is a persistent bacterial infection of the bone which occurs in many implant patients and can result in functional impairments or even entire loss of the extremity. Nevertheless, surprisingly little is known on the triangle interaction between implant material, bacterial biofilm and affected bone tissue. Closing this gap of knowledge would be crucial for the fundamental understanding of the disease and the development of novel treatment strategies. For this purpose, we developed the first biomaterial-based system that is able to mimic implant-associated osteomyelitis outside of the body, thus, opening the avenue to study this fatal disease in the laboratory.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.024
      Issue No: Vol. 73 (2018)
       
  • Protective therapeutic effects of peptide nanofiber and hyaluronic acid
           hybrid membrane in in vivo osteoarthritis model
    • Authors: Elif Arslan; Melis Sardan Ekiz; Cagla Eren Cimenci; Nuray Can; M. Hanifi Gemci; Huseyin Ozkan; Mustafa O. Guler; Ayse B. Tekinay
      Pages: 263 - 274
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Elif Arslan, Melis Sardan Ekiz, Cagla Eren Cimenci, Nuray Can, M. Hanifi Gemci, Huseyin Ozkan, Mustafa O. Guler, Ayse B. Tekinay
      Osteoarthritis (OA) is a condition where tissue function is lost through a combination of secondary inflammation and deterioration in articular cartilage. One of the most common causes of OA is age-related tissue impairment because of wear and tear due to mechanical erosion. Hyaluronic acid-based viscoelastic supplements have been widely used for the treatment of knee injuries. However, the current formulations of hyaluronic acid are unable to provide efficient healing and recovery. Here, a nanofiber-hyaluronic acid membrane system that was prepared by using a quarter of the concentration of commercially available hyaluronic acid supplement, Hyalgan®, was used for the treatment of an osteoarthritis model, and Synvisc®, which is another commercially available hyaluronic acid containing viscoelastic supplement, was used as a control. The results show that this system provides efficient protection of arthritic cartilage tissue through the preservation of cartilage morphology with reduced osteophyte formation, protection of the subchondral region from deterioration, and maintenance of cartilage specific matrix proteins in vivo. In addition, the hybrid nanofiber membrane enabled chondrocyte encapsulation and provided a suitable culturing environment for stem cell growth in vitro. Overall, our results suggest that this hybrid nanofibrous scaffold provides a potential platform the treatment of OA. Statement of Significance Osteoarthritis is a debilitating joint disease affecting millions of people worldwide. It occurs especially in knees due to aging, sport injuries or obesity. Although hyaluronic acid-based viscoelastic supplements are widely used, there is still no effective treatment method for osteoarthritis, which necessitates surgical operation as an only choice for severe cases. Therefore, there is an urgent need for efficient therapeutics. In this study, a nanofiber-HA membrane system was developed for the efficient protection of arthritic cartilage tissue from degeneration. This hybrid nanofiber system provided superior therapeutic activity at a relatively lower concentration of hyaluronic acid than Hyalgan® and Synvisc® gels, which are currently used in clinics. This work demonstrates for the first time that this hybrid nanofiber membrane scaffold can be utilized as a potential candidate for osteoarthritis treatment.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.015
      Issue No: Vol. 73 (2018)
       
  • Glycosylation-enhanced biocompatibility of the supramolecular hydrogel of
           an anti-inflammatory drug for topical suppression of inflammation
    • Authors: Taotao Xiong; Xianglian Li; Yanfang Zhou; Qianqian Song; Renshu Zhang; Lei Lei; Xingyi Li
      Pages: 275 - 284
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Taotao Xiong, Xianglian Li, Yanfang Zhou, Qianqian Song, Renshu Zhang, Lei Lei, Xingyi Li
      Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but it displays a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity). We report here an intravitreally injectable thermosensitive glycosylated TA (TA-SA-Glu) hydrogel, formed by covalently conjugating glucosamine (Glu) with succinate TA (TA-SA), for treating uveitis. The TA-SA-Glu hydrogelator forms a supramolecular hydrogel spontaneously in aqueous solution with a minimal gelation concentration of 0.25 wt%. Structural analysis revealed that hydrogen bonds assisted by hydrophobic interaction resulted in self-assembled nanofibers. Rheology analysis demonstrated that this TA-SA-Glu hydrogel exhibited a typical thixotropic property. Sustained release of both TA-SA-Glu and TA from the hydrogel occurred throughout the 3-day in vitro release study. The obtained TA-SA-Glu hardly caused cytotoxicity against ARPE-19 and RAW264.7 cells after 24 h of incubation at drug concentration up to 600 μM. In particular, TA-SA-Glu exhibited a comparable anti-inflammatory efficacy to TA in terms of inhibiting the production of nitric oxide, tumor necrosis factor-α, and interleukin-6 in activated RAW264.7 macrophages. Following a single intravitreal injection, 69 nmol TA-SA-Glu hydrogel caused minimal apparent retinal toxicity, whereas the TA suspension displayed significant effects in terms of localized retinal toxicity. A single intravitreal injection of TA-SA-Glu hydrogel was more effective in controlling inflammatory response than that of the TA suspension treatment, particularly in down-regulating the pro-inflammatory Th1 and Th17 effector responses for treating experimental autoimmune uveitis. This study strongly indicates that supramolecular TA-SA-Glu hydrogels may represent a new option for posterior uveitis management. Statement of Significance Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but suffers a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity). We generated an injectable glycosylated triamcinolone acetonide hydrogelator (TA-SA-Glu) hydrogel for treating uveitis. Following a single intravitreal injection, the proposed TA-SA-Glu hydrogel hardly caused apparent retinal toxicity at a dosage of 69 nmol per eye. Furthermore, TA-SA-Glu hydrogel was more effective in controlling non-infectious uveitis over than a TA suspension, particularly in terms of down-regulating the pro-inflammatory Th1 and Th17 effector responses for treating experimental autoimmune uveitis (EAU). This study strongly indicates that TA-SA-Glu supramolecular hydrogels may represent a new option for the management of various intraocular inflammations.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.019
      Issue No: Vol. 73 (2018)
       
  • Exploiting natural polysaccharides to enhance in vitro bio-constructs of
           primary neurons and progenitor cells
    • Authors: Manuela Medelin; Davide Porrelli; Emily Rose Aurand; Denis Scaini; Andrea Travan; Massimiliano Antonio Borgogna; Michela Cok; Ivan Donati; Eleonora Marsich; Chiara Scopa; Raffaella Scardigli; Sergio Paoletti; Laura Ballerini
      Pages: 285 - 301
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Manuela Medelin, Davide Porrelli, Emily Rose Aurand, Denis Scaini, Andrea Travan, Massimiliano Antonio Borgogna, Michela Cok, Ivan Donati, Eleonora Marsich, Chiara Scopa, Raffaella Scardigli, Sergio Paoletti, Laura Ballerini
      Current strategies in Central Nervous System (CNS) repair focus on the engineering of artificial scaffolds for guiding and promoting neuronal tissue regrowth. Ideally, one should combine such synthetic structures with stem cell therapies, encapsulating progenitor cells and instructing their differentiation and growth. We used developments in the design, synthesis, and characterization of polysaccharide-based bioactive polymeric materials for testing the ideal composite supporting neuronal network growth, synapse formation and stem cell differentiation into neurons and motor neurons. Moreover, we investigated the feasibility of combining these approaches with engineered mesenchymal stem cells able to release neurotrophic factors. We show here that composite bio-constructs made of Chitlac, a Chitosan derivative, favor hippocampal neuronal growth, synapse formation and the differentiation of progenitors into the proper neuronal lineage, that can be improved by local and continuous delivery of neurotrophins. Statement of Significance In our work, we characterized polysaccharide-based bioactive platforms as biocompatible materials for nerve tissue engineering. We show that Chitlac-thick substrates are able to promote neuronal growth, differentiation, maturation and formation of active synapses. These observations support this new material as a promising candidate for the development of complex bio-constructs promoting central nervous system regeneration. Our novel findings sustain the exploitation of polysaccharide-based scaffolds able to favour neuronal network reconstruction. Our study shows that Chitlac-thick may be an ideal candidate for the design of biomaterial scaffolds enriched with stem cell therapies as an innovative approach for central nervous system repair.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.03.041
      Issue No: Vol. 73 (2018)
       
  • Tissue-engineered spiral nerve guidance conduit for peripheral nerve
           regeneration
    • Authors: Wei Chang; Munish B. Shah; Paul Lee; Xiaojun Yu
      Pages: 302 - 311
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Wei Chang, Munish B. Shah, Paul Lee, Xiaojun Yu
      Recently in peripheral nerve regeneration, preclinical studies have shown that the use of nerve guidance conduits (NGCs) with multiple longitudinally channels and intra-luminal topography enhance the functional outcomes when bridging a nerve gap caused by traumatic injury. These features not only provide guidance cues for regenerating nerve, but also become the essential approaches for developing a novel NGC. In this study, a novel spiral NGC with aligned nanofibers and wrapped with an outer nanofibrous tube was first developed and investigated. Using the common rat sciatic 10-mm nerve defect model, the in vivo study showed that a novel spiral NGC (with and without inner nanofibers) increased the successful rate of nerve regeneration after 6 weeks recovery. Substantial improvements in nerve regeneration were achieved by combining the spiral NGC with inner nanofibers and outer nanofibrous tube, based on the results of walking track analysis, electrophysiology, nerve histological assessment, and gastrocnemius muscle measurement. This demonstrated that the novel spiral NGC with inner aligned nanofibers and wrapped with an outer nanofibrous tube provided a better environment for peripheral nerve regeneration than standard tubular NGCs. Results from this study will benefit for future NGC design to optimize tissue-engineering strategies for peripheral nerve regeneration. Statement of Significance We developed a novel spiral nerve guidance conduit (NGC) with coated aligned nanofibers. The spiral structure increases surface area by 4.5 fold relative to a tubular NGC. Furthermore, the aligned nanofibers was coated on the spiral walls, providing cues for guiding neurite extension. Finally, the outside of spiral NGC was wrapped with randomly nanofibers to enhance mechanical strength that can stabilize the spiral NGC. Our nerve histological data have shown that the spiral NGC had 50% more myelinated axons than a tubular structure for nerve regeneration across a 10 mm gap in a rat sciatic nerve. Results from this study can help further optimize tissue engineering strategies for peripheral nerve repair.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.046
      Issue No: Vol. 73 (2018)
       
  • Enhanced wound healing of tissue-engineered human corneas through altered
           phosphorylation of the CREB and AKT signal transduction pathways
    • Authors: Camille Couture; Pascale Desjardins; Karine Zaniolo; Lucie Germain; Sylvain L. Guérin
      Pages: 312 - 325
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Camille Couture, Pascale Desjardins, Karine Zaniolo, Lucie Germain, Sylvain L. Guérin
      The cornea is a transparent organ, highly specialized and unique that is continually subjected to abrasive forces and occasional mechanical or chemical trauma because of its anatomical localization. Upon injury, the extracellular matrix (ECM) rapidly changes to promote wound healing through integrin-dependent activation of specific signal transduction mediators whose contribution is to favor faster closure of the wound by altering the adhesive and migratory properties of the cells surrounding the damaged area. In this study, we exploited the human tissue-engineered cornea (hTECs) as a model to study the signal transduction pathways that participate to corneal wound healing. By exploiting both gene profiling and activated kinases arrays, we could demonstrate the occurrence of important alterations in the level of expression and activation of a few mediators from the PI3K/Akt and CREB pathways in response to the ECM remodeling taking place during wound healing of damaged hTECs. Pharmacological inhibition of CREB with C646 considerably accelerated wound closure compared to controls. This process was considerably accelerated further when both C646 and SC79, an Akt agonist, were added together to wounded hTECs. Therefore, our study demonstrate that proper corneal wound healing requires the activation of Akt together with the inhibition of CREB and that wound healing in vitro can be altered by the use of pharmacological inhibitors (such as C646) or agonists (such as SC79) of these mediators. Statement of significance Corneal wounds account for a large proportion of all visual disabilities in North America. To our knowledge, this is the first time that a tissue-engineered human cornea (hTEC) entirely produced using normal untransformed human cells is used as a biomaterial to study the signal transduction pathways that are critical to corneal wound healing. Through the use of this biomaterial, we demonstrated that human corneal epithelial cells engaged in wound healing reduce phosphorylation of the signal transduction mediator CREB while, in the mean time, they increase that of AKT. By increasing the activation of AKT together with a decrease in CREB activation, we could considerably reduce wound closure time in our punch-damaged hTECs. Considering the increasing interest given to the reconstruction of different types of tissues, we believe these results will have a strong impact on the field of tissue-engineering and biomaterials. Altering the activation status of the Akt and CREB proteins might prove to be a therapeutically interesting avenue and may also find applications in wound healing of other tissues beside the cornea, such as the skin.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.021
      Issue No: Vol. 73 (2018)
       
  • Hydrogel derived from porcine decellularized nerve tissue as a promising
           biomaterial for repairing peripheral nerve defects
    • Authors: Tao Lin; Sheng Liu; Shihao Chen; Shuai Qiu; Zilong Rao; Jianghui Liu; Shuang Zhu; Liwei Yan; Haiquan Mao; Qingtang Zhu; Daping Quan; Xiaolin Liu
      Pages: 326 - 338
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Tao Lin, Sheng Liu, Shihao Chen, Shuai Qiu, Zilong Rao, Jianghui Liu, Shuang Zhu, Liwei Yan, Haiquan Mao, Qingtang Zhu, Daping Quan, Xiaolin Liu
      Decellularized matrix hydrogels derived from tissues or organs have been used for tissue repair due to their biocompatibility, tunability, and tissue-specific extracellular matrix (ECM) components. However, the preparation of decellularized peripheral nerve matrix hydrogels and their use to repair nerve defects have not been reported. Here, we developed a hydrogel from porcine decellularized nerve matrix (pDNM-G), which was confirmed to have minimal DNA content and retain collagen and glycosaminoglycans content, thereby allowing gelatinization. The pDNM-G exhibited a nanofibrous structure similar to that of natural ECM, and a ∼280-Pa storage modulus at 10 mg/mL similar to that of native neural tissues. Western blot and liquid chromatography tandem mass spectrometry analysis revealed that the pDNM-G consisted mostly of ECM proteins and contained primary ECM-related proteins, including fibronectin and collagen I and IV). In vitro experiments showed that pDNM-G supported Schwann cell proliferation and preserved cell morphology. Additionally, in a 15-mm rat sciatic nerve defect model, pDNM-G was combined with electrospun poly(lactic-acid)-co-poly(trimethylene-carbonate)conduits to bridge the defect, which did not elicit an adverse immune response and promoted the activation of M2 macrophages associated with a constructive remodeling response. Morphological analyses and electrophysiological and functional examinations revealed that the regenerative outcomes achieved by pDNM-G were superior to those by empty conduits and closed to those using rat decellularized nerve matrix allograft scaffolds. These findings indicated that pDNM-G, with its preserved ECM composition and nanofibrous structure, represents a promising biomaterial for peripheral nerve regeneration. Statement of Significance Decellularized nerve allografts have been widely used to treat peripheral nerve injury. However, given their limited availability and lack of bioactive factors, efforts have been made to improve the efficacy of decellularized nerve allograft for nerve regeneration, with limited success. Xenogeneic decellularized tissue matrices or hydrogels have been widely used for surgical applications owing to their ease of harvesting and low immunogenicity. Moreover, decellularized tissue matrix hydrogels show good biocompatibility and are highly tunable. In this study, we prepared a porcine decellularized nerve matrix (pDNM-G) and evaluated its potential for promoting nerve regeneration. Our results demonstrate that pDNM-G can support Schwann cell proliferation and peripheral nerve regeneration by means of residual primary extracellular matrix components and nano-fibrous structure features.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.001
      Issue No: Vol. 73 (2018)
       
  • Perfusion-decellularization of human ear grafts enables ECM-based
           scaffolds for auricular vascularized composite tissue engineering
    • Authors: Jérôme Duisit; Hadrien Amiel; Tsering Wüthrich; Adriano Taddeo; Adeline Dedriche; Vincent Destoop; Thomas Pardoen; Caroline Bouzin; Virginie Joris; Derek Magee; Esther Vögelin; David Harriman; Chantal Dessy; Giuseppe Orlando; Catherine Behets; Robert Rieben; Pierre Gianello; Benoît Lengelé
      Pages: 339 - 354
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Jérôme Duisit, Hadrien Amiel, Tsering Wüthrich, Adriano Taddeo, Adeline Dedriche, Vincent Destoop, Thomas Pardoen, Caroline Bouzin, Virginie Joris, Derek Magee, Esther Vögelin, David Harriman, Chantal Dessy, Giuseppe Orlando, Catherine Behets, Robert Rieben, Pierre Gianello, Benoît Lengelé
      Introduction: Human ear reconstruction is recognized as the emblematic enterprise in tissue engineering. Up to now, it has failed to reach human applications requiring appropriate tissue complexity along with an accessible vascular tree. We hereby propose a new method to process human auricles in order to provide a poorly immunogenic, complex and vascularized ear graft scaffold. Methods: 12 human ears with their vascular pedicles were procured. Perfusion-decellularization was applied using a SDS/polar solvent protocol. Cell and antigen removal was examined by histology and DNA was quantified. Preservation of the extracellular matrix (ECM) was assessed by conventional and 3D-histology, proteins and cytokines quantifications. Biocompatibility was assessed by implantation in rats for up to 60 days. Adipose-derived stem cells seeding was conducted on scaffold samples and with human aortic endothelial cells whole graft seeding in a perfusion-bioreactor. Results: Histology confirmed cell and antigen clearance. DNA reduction was 97.3%. ECM structure and composition were preserved. Implanted scaffolds were tolerated in vivo, with acceptable inflammation, remodeling, and anti-donor antibody formation. Seeding experiments demonstrated cell engraftment and viability. Conclusions: Vascularized and complex auricular scaffolds can be obtained from human source to provide a platform for further functional auricular tissue engineered constructs, hence providing an ideal road to the vascularized composite tissue engineering approach. Statement of Significance The ear is emblematic in the biofabrication of tissues and organs. Current regenerative medicine strategies, with matrix from donor tissues or 3D-printed, didn’t reach any application for reconstruction, because critically missing a vascular tree for perfusion and transplantation. We previously described the production of vascularized and cell-compatible scaffolds, from porcine ear grafts. In this study, we ---- applied findings directly to human auricles harvested from postmortem donors, providing a perfusable matrix that retains the ear’s original complexity and hosts new viable cells after seeding. This approach unlocks the ability to achieve an auricular tissue engineering approach, associated with possible clinical translation.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.009
      Issue No: Vol. 73 (2018)
       
  • A robust spectroscopic method for the determination of protein
           conformational composition – Application to the annealing of silk
    • Authors: David J. Belton; Robyn Plowright; David L. Kaplan; Carole C. Perry
      Pages: 355 - 364
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): David J. Belton, Robyn Plowright, David L. Kaplan, Carole C. Perry
      The physical and mechanical properties of structural proteins such as silk fibroin can be modified by controlled conformational change, which is regularly monitored by Fourier transform infrared spectroscopy by peak fitting of the amide I band envelope. Although many variables affecting peak shape are well established, there is no fixed methodology to compare and follow secondary structural differences without significant operator input especially where low frequency spectral noise is a problem. The aim of this contribution is to establish a method for such analyses to be carried at high levels of autonomy to prevent subjective or erroneous fitting. A range of approaches was trialled with optimal peak parameters selected based on overall goodness of fit and reproducibility of fit of replicate sample spectra. The method was successfully tested against reference proteins having contrasting β content and the rationale for parameter selection is presented. Further, we applied this method to measure the effect of conformational change on the energy of the amide I band of silk fibroin during annealing. Energy changes were ca. 400 kJ mol−1 of fibroin. To confirm that this energy change was a consequence of increased hydrogen bonding we used a Thioflavin T staining method typically used to identify β aggregate type structures in amyloid plaques. We propose that the approach described herein can aid in the development of silk based materials for biomedical applications where tuning of the physical and mechanical properties of the silk are needed to guarantee optimum activity. Statement of Significance The physical and mechanical properties of proteins including silk fibroin can be modified by controlled structural change, which is regularly monitored by Fourier transform infrared spectroscopy (FTIR) by peak fitting of the amide I band. Currently there is no fixed methodology to compare and follow secondary structural differences without significant operator input leading to subjectivity and error. This contribution establishes a method for such analyses to be carried at high levels of autonomy applicable to a wide range of proteins and the conformational changes have been quantified as a single energy change output, which clearly shows the progression of the annealing process used. We propose that the approach can help in the development of silk based materials for biomedical applications where tuning of the physical and mechanical properties of the silk are needed to guarantee optimum activity.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.03.058
      Issue No: Vol. 73 (2018)
       
  • Electrospun silk fibroin fibers for storage and controlled release of
           human platelet lysate
    • Authors: Cataldo Pignatelli; Giovanni Perotto; Marta Nardini; Ranieri Cancedda; Maddalena Mastrogiacomo; Athanassia Athanassiou
      Pages: 365 - 376
      Abstract: Publication date: June 2018
      Source:Acta Biomaterialia, Volume 73
      Author(s): Cataldo Pignatelli, Giovanni Perotto, Marta Nardini, Ranieri Cancedda, Maddalena Mastrogiacomo, Athanassia Athanassiou
      Human platelet lysate (hPL) is a pool of growth factors and cytokines able to induce regeneration of different tissues. Despite its good potentiality as therapeutic tool for regenerative medicine applications, hPL has been only moderately exploited in this field. A more widespread adoption has been limited because of its rapid degradation at room temperature that decreases its functionality. Another limiting factor for its extensive use is the difficulty of handling the hPL gels. In this work, silk fibroin-based patches were developed to address several points: improving the handling of hPL, enabling their delivery in a controlled manner and facilitating their storage by creating a device ready to use with expanded shelf life. Patches of fibroin loaded with hPL were synthesized by electrospinning to take advantage of the fibrous morphology. The release kinetics of the material was characterized and tuned through the control of fibroin crystallinity. Cell viability assays, performed with primary human dermal fibroblasts, demonstrated that fibroin is able to preserve the hPL biological activity and prolong its shelf-life. The strategy of storing and preserving small active molecules within a naturally-derived, protein-based fibrous scaffold was successfully implemented, leading to the design of a biocompatible device, which can potentially simplify the storage and the application of the hPL on a human patient, undergoing medical procedures such as surgery and wound care. Statement of Significance Human platelets lysate (hPL) is a mixture of growth factors and cytokines able to induce the regeneration of damaged tissues. This study aims at enclosing hPL in a silk fibroin electrospun matrix to expand its utilization. Silk fibroin showed the ability to preserve the hPL activity at temperature up to 60 °C and the manipulation of fibroin’s crystallinity provided a tool to modulate the hPL release kinetic. This entails the possibility to fabricate the hPL silk fibroin patches in advance and store them, resulting in an easy and fast accessibility and an expanded use of hPL for wound healing.
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      PubDate: 2018-06-02T11:54:12Z
      DOI: 10.1016/j.actbio.2018.04.025
      Issue No: Vol. 73 (2018)
       
  • Functional reconstruction of critical-sized load-bearing bone defects
           using a Sclerostin-targeting miR-210-3p-based construct to enhance
           osteogenic activity
    • Authors: Bin Hu; Yan li; Mohan Wang; Youming Zhu; Yong Zhou; Baiyan Sui; Yu Tan; Yujie Ning; Jie Wang; Jiacai He; Chi Yang; Duohong Zou
      Abstract: Publication date: Available online 10 June 2018
      Source:Acta Biomaterialia
      Author(s): Bin Hu, Yan li, Mohan Wang, Youming Zhu, Yong Zhou, Baiyan Sui, Yu Tan, Yujie Ning, Jie Wang, Jiacai He, Chi Yang, Duohong Zou
      A considerable amount of research has focused on improving regenerative therapy strategies for repairing defects in load-bearing bones. The enhancement of tissue regeneration with microRNAs (miRNAs) is being developed because miRNAs can simultaneously regulate multiple signaling pathways in an endogenous manner. In this study, we developed a miR-210-based bone repair strategy. We identified a miRNA (miR-210-3p) that can simultaneously up-regulate the expression of multiple key osteogenic genes in vitro. This process resulted in enhanced bone formation in a subcutaneous mouse model with a miR-210-3p/poly-L-lactic acid (PLLA)/bone marrow-derived stem cell (BMSC) construct. Furthermore, we constructed a model of critical-sized load-bearing bone defects and implanted a miR-210-3p/β-tricalcium phosphate (β-TCP)/bone mesenchymal stem cell (BMSC) construct into the defect. We found that the load-bearing defect was almost fully repaired using the miR-210-3p construct. We also identified a new mechanism by which miR-210-3p regulates Sclerostin protein levels. This miRNA-based strategy may yield novel therapeutic methods for the treatment of regenerative defects in vital load-bearing bones by utilizing miRNA therapy for tissue engineering. Statement of Significance The destroyed maxillofacial bone reconstruction is still a real challenge for maxillofacial surgeon, due to that functional bone reconstruction involved load-bearing. Base on the above problem, this paper developed a novel miR-210-3p/β-tricalcium phosphate (TCP)/bone marrow-derived stem cell (BMSC) construct (miR-210-3p/β-TCP/BMSCs), which lead to functional reconstruction of critical-size mandible bone defect. We found that the load-bearing defect was almost fully repaired using the miR-210-3p construct. In addition, we also found the mechanism of how the delivered microRNA activated the signaling pathways of endogenous stem cells, leading to the defect regeneration. This miRNA-based strategy can be used to regenerate defects in vital load-bearing bones, thus addressing a critical challenge in regenerative medicine by utilizing miRNA therapy for tissue engineering.
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      PubDate: 2018-06-11T13:04:43Z
      DOI: 10.1016/j.actbio.2018.06.017
       
  • Hyaluronic acid formulation of near infrared fluorophores optimizes
           surgical imaging in a prostate tumor xenograft
    • Authors: Joshua J. Souchek; Nicholas E. Wojtynek; William M. Payne; Megan B. Holmes; Samikshan Dutta; Bowen Qi; Kaustubh Datta; Chad A. LaGrange; Aaron M. Mohs
      Abstract: Publication date: Available online 8 June 2018
      Source:Acta Biomaterialia
      Author(s): Joshua J. Souchek, Nicholas E. Wojtynek, William M. Payne, Megan B. Holmes, Samikshan Dutta, Bowen Qi, Kaustubh Datta, Chad A. LaGrange, Aaron M. Mohs
      The presence of positive surgical margins confers an increased risk of biochemical relapse and need for salvage therapy in men undergoing radical prostatectomy. Image-guided surgery using near-infrared (NIR) fluorescent contrast agents is a potential method to detect remaining cancerous tissue. The objective of this study was to evaluate three hyaluronic acid (HA) nanoparticle (NP) formulations loaded with NIR fluorophore for their ability to contrast-enhance prostate cancer. HA was modified by conjugation with the hydrophobic ligand, aminopropyl-1-pyrenebutanamide to drive nanoparticle self-assembly. Indocyanine green (ICG) was physicochemically entrapped in the HA-NP, termed NanoICG. Alternatively, Cy7.5 was directly conjugated to amphiphilic HA, termed NanoCy7.5. NanoCy7.5 was synthesized with two HA molecular weights to determine the HA size contribution to delivery to PC3 prostate tumor xenografts. Contrast-enhancement of the tumors and relative biodistribution were assessed by a series of fluorescence imaging, image-guided surgery with spectroscopy, and microscopic techniques. Intravenously administered NanoICG improved tumor signal-to-noise ratio (SNR) at 24 h over ICG by 2.9-fold. NanoCy7.5 with 10 kDa and 100kDa HA improved tumor SNR by 6.6- and 3.1-fold over Cy7.5 alone, respectively. The PC3 xenograft was clearly identified with the image-guided system providing increased contrast enhancement compared to surrounding tissue for NanoICG and NanoCy7.5 with 10 kDa HA. NIR fluorescence microscopy showed that Cy7.5 in NPs with 10 kDa HA were distributed throughout the tumor, while NanoCy7.5 with 100 kDa HA or NanoICG delivered dye mainly to the edge of the tumor. CD31 staining suggested that PC3 tumors are poorly vascularized. These studies demonstrate the efficacy of a panel of HA-derived NPs in identifying prostate tumors in vivo, and suggest that by tuning the structural properties of these NPs, optimized delivery can be achieved to poorly vascularized tumors. Statement of Significance We have demonstrated the potential of a panel of near-infrared fluorescent (NIRF) nanoparticles (NPs) for image-guided surgery in a prostate cancer xenograft model. Image-guided surgery and imaging of organsex vivoshowed greater tumor signal and contrast when mice were administered NIRF dyes that were covalently conjugated to (NanoCy7.510k-PBA) or physicochemically entrapped in (NanoICGPBA) hyaluronic acid (HA) NPs, compared to free dyes. These results show the potential to use these NPs as tools to detect the margins of tumors and to differentiate healthy and tumor tissue intraoperatively. Moreover, this project provides insight into selecting optimal formulation strategies for poorly vascularized tumors.
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      PubDate: 2018-06-11T13:04:43Z
      DOI: 10.1016/j.actbio.2018.06.016
       
  • Preservation of the soft protein corona in distinct flow allows
           identification of weakly bound proteins
    • Authors: C. Weber; J. Simon; V. Mailänder; S. Morsbach; K. Landfester
      Abstract: Publication date: Available online 8 June 2018
      Source:Acta Biomaterialia
      Author(s): C. Weber, J. Simon, V. Mailänder, S. Morsbach, K. Landfester
      Nanocarriers that are used for targeted drug delivery come in contact with biological liquid and proteins will adsorb to the nanocarriers’ surface to form the so called ‘protein corona’. The protein corona defines the biological identity and determines the biological response towards the nanocarriers in the body. To make nanomedicine safe and reliable it is required to get a better insight into this protein corona and, therefore, the adsorbed proteins have to be characterized. Currently, centrifugation is the common method to isolate the protein corona for further investigations. However, with this method it is only possible to investigate the strongly bound proteins, also referred to as ‘hard protein corona’. Therefore, we want to introduce a new separation technique to separate nanoparticles including the soft protein corona containing also loosely bound proteins for further characterizations. The used separation technique is the asymmetric flow filed-flow fractionation (AF4). We were able to separate the nanoparticles with proteins forming the soft protein corona and were able to show that only the hard protein co rona directly influences the cell uptake behavior. Statement of significance Currently, there is an ongoing debate whether only strongly bound proteins (hard corona) or also loosely bound proteins (soft corona) contribute to the biological identity of nanocarriers, because up to now isolation of the soft corona was not possible. Here, asymmetric flow field-flow fractionation was used to isolate nanoparticles with a preserved soft corona from the biological medium. This enabled the characterization of the soft corona composition and to evaluate its influence on cellular uptake. For our system we found that only the strongly bound proteins (hard corona) determined cell internalization. This method can now be used to evaluate the impact of the soft corona further and to characterize nanomaterials that cannot be separated from blood plasma by other means.
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      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.05.057
       
  • RNA interfering molecule delivery from in situ forming biodegradable
           
    • Authors: Minh K. Nguyen; Oju Jeon; Phuong N. Dang; Cong T. Huynh; Davood Varghai; Hooman Riazi; Alexandra McMillan; Samuel Herberg; Eben Alsberg
      Abstract: Publication date: Available online 7 June 2018
      Source:Acta Biomaterialia
      Author(s): Minh K. Nguyen, Oju Jeon, Phuong N. Dang, Cong T. Huynh, Davood Varghai, Hooman Riazi, Alexandra McMillan, Samuel Herberg, Eben Alsberg
      RNA interference (RNAi) may be an effective and valuable tool for promoting the growth of functional tissue, as short interfering RNA (siRNA) and microRNA (miRNA) can block the expression of genes that have negative effects on tissue regeneration. Our group has recently reported that the localized and sustained presentation of siRNA against noggin (siNoggin) and miRNA-20a from in situ forming poly(ethylene glycol) (PEG) hydrogels enhanced osteogenic differentiation of encapsulated human bone marrow-derived mesenchymal stem cells (hMSCs). Here, the capacity of the hydrogel system to accelerate bone formation in a rat calvarial bone defect model is presented. After 12 weeks post-implantation, the hydrogels containing encapsulated hMSCs and miRNA-20a resulted in more bone formation in the defects than the hydrogels containing hMSCs without siRNA or with negative control siRNA. This localized and sustained RNA interfering molecule delivery system may provide an excellent platform for healing bony defects and other tissues. Statement of Significance Delivery of RNAi molecules may be a valuable strategy to guide cell behavior for tissue engineering applications, but to date there have been no reports of a biomaterial system capable of both encapsulation of cells and controlled delivery of incorporated RNA. Here, we present PEG hydrogels that form in situ via Michael type reaction, and that permit encapsulation of hMSCs and the concomitant controlled delivery of siNoggin and/or miRNA-20a. These RNAs were chosen to suppress noggin, a BMP-2 antagonist, and/or PPAR-γ, a negative regulator of BMP-2-mediated osteogenesis, and therefore promote osteogenic differentiation of hMSCs and subsequent bone repair in critical-sized rat calvarial defects. Simultaneous delivery of hMSCs and miRNA-20a enhanced repair of these defects compared to hydrogels containing hMSCs without siRNA or with negative control siRNA. This in situ forming PEG hydrogel system offers an exciting platform for healing critical-sized bone defects by localized, controlled delivery of RNAi molecules to encapsulated hMSCs and surrounding cells.
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      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.007
       
  • Microfiber Drug/Gene Delivery Platform for Study of Myelination
    • Authors: William Ong; Junquan Lin; Marie E. Bechler; Kai Wang; Mingfeng Wang; Charles ffrench-Constant; Sing Yian Chew
      Abstract: Publication date: Available online 7 June 2018
      Source:Acta Biomaterialia
      Author(s): William Ong, Junquan Lin, Marie E. Bechler, Kai Wang, Mingfeng Wang, Charles ffrench-Constant, Sing Yian Chew
      Our ability to rescue functional deficits after demyelinating diseases or spinal cord injuries is limited by our lack of understanding of the complex remyelination process, which is crucial to functional recovery. In this study, we developed an electrospun suspended poly(ε-caprolactone) microfiber platform to enable the screening of therapeutics for remyelination. As a proof of concept, this platform employed scaffold-mediated non-viral delivery of a microRNA (miR) cocktail to promote oligodendrocyte precursor cells (OPCs) differentiation and myelination. We observed enhanced OPCs differentiation when the cells were transfected with miR-219 and miR-338 on the microfiber substrates. Moreover, miRs promoted the formation of MBP+ tubular extensions around the suspended fibers, which was indicative of myelination, instead of flat myelin membranes on 2D substrates. In addition, OPCs that were transfected with the cocktail of miRs formed significantly longer and larger amounts of MBP+ extensions. Taken together, these results demonstrate the efficacy of this functional screening platform for understanding myelination. Statement of Significance The lack of understanding of the complex myelination process has hindered the discovery of effective therapeutic treatments for demyelinating diseases. Hence, in vitro models that enable systematic understanding, visualization and quantification of myelination are valuable. Unfortunately, achieving reproducible in vitro myelination by oligodendrocytes (OLs) remains highly challenging. Here, we engineered a suspended microfiber platform that enables sustained non-viral drug/gene delivery to study OL differentiation and myelination. Sustained drug delivery permits the investigation of OL development, which spans several weeks. We show that promyelinogenic microRNAs promoted OL differentiation and myelination on this platform. Our engineered microfiber substrate could serve as a drug/gene screening platform and facilitate future translation into direct implantable devices for in vivo remyelination purposes.
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      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.011
       
  • Polyion complex hydrogels from chemically modified cellulose nanofibrils:
           Structure-function relationship and potential for controlled and
           pH-responsive release of doxorubicin
    • Authors: Sry D. Hujaya; Gabriela S. Lorite; Seppo J. Vainio; Henrikki Liimatainen
      Abstract: Publication date: Available online 7 June 2018
      Source:Acta Biomaterialia
      Author(s): Sry D. Hujaya, Gabriela S. Lorite, Seppo J. Vainio, Henrikki Liimatainen
      Herein, we report the fabrication of a polyion complex hydrogel from two oppositely charged derivatives of cellulose nanofibrils (CNF). CNF was produced from dissolving pulp through subsequent periodate oxidation, chemical modification, and microfluidization. Three different durations for periodate oxidation (30 min, 120 min, and 180 min) resulted in three different aldehyde contents. Further, two types of chemical modifications were introduced to react with the resulting aldehydes: chlorite oxidation to yield anionic CNF with carboxylic acid groups (DCC) and imination with Girard’s reagent T to yield cationic CNF containing quaternary ammonium groups (CDAC). Functional group contents were assessed using conductometric titration and elemental analysis, while nanofibril morphologies were assessed using atomic force microscopy (AFM). Longer durations of periodate oxidation did not yield different width profile but was found to decrease fibril length. The formation of self-standing hydrogel through mixing of DCC and CDAC dispersions was investigated. Oscillatory rheology was performed to assess the relative strengths of different gels. Self-standing hydrogels were obtained from mixture of DCC180 and CDAC180 dispersions in acetate buffer at pH 4 and 5 at a low concentration of 0.5% w/w that displayed approximately 10-fold increase in storage and loss moduli compared to those of the individual dispersions. Self-standing gels containing doxorubicin (an anticancer drug) displayed pH-responsive release profiles. At physiological pH 7.4, approximately 65% of doxorubicin was retained past a burst release regime, while complete release was observed within 5 days at pH 4. Biocompatibility of DCC180, CDAC180, and their mixture were investigated through quantification of the metabolic activity of NIH3T3 cells in vitro. No significant cytotoxicity was observed at concentrations up to 900 µg/mL. In short, the nanocellulose-based polyion complex hydrogels obtained in this study are promising nature-derived materials for biomedical applications. Statement of Significance We demonstrate that polyion complex can be formed between two cellulose nanofibrils containing complementary charges. To the best of our knowledge, this is the first time that polyion complex formation between complementarily-modified cellulose nanofibers has been reported, and the results may lead to new ideas on applications of the very promising nanocellulosic materials. The polyion complex helps form a self-standing network that is demonstrated to provide controlled and pH-responsive release of doxorubicin. Particularly, the report explores the connection between the physical properties of functionalizable nanocellulosic materials and their potential biomedical applications. Thus, the study encompasses several broad fields of materials science and engineering, chemistry, and biomedical science that we believe is in line with the readers’ interests.
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      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.013
       
  • In vitro efficacy of a gene-activated nerve guidance conduit incorporating
           non-viral PEI-pDNA nanoparticles carrying genes encoding for NGF, GDNF and
           c-Jun
    • Authors: William A. Lackington; Rosanne M. Raftery; Fergal J. O'Brien
      Abstract: Publication date: Available online 7 June 2018
      Source:Acta Biomaterialia
      Author(s): William A. Lackington, Rosanne M. Raftery, Fergal J. O'Brien
      Despite the success of tissue engineered nerve guidance conduits (NGCs) for the treatment of small peripheral nerve injuries, autografts remain the clinical gold standard for larger injuries. The delivery of neurotrophic factors from conduits might enhance repair for more effective treatment of larger injuries but the efficacy of such systems is dependent on a safe, effective platform for controlled and localised therapeutic delivery. Gene therapy might offer an innovative approach to control the timing, release and level of neurotrophic factor production by directing cells to transiently sustain therapeutic protein production in situ. In this study, a gene-activated NGC was developed by incorporating non-viral polyethyleneimine-plasmid DNA (PEI-pDNA) nanoparticles (N/P 7 ratio, 2μg dose) with the pDNA encoding for nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) or the transcription factor c-Jun. The physicochemical properties of PEI-pDNA nanoparticles, morphology, size and charge, were shown to be suitable for gene delivery and demonstrated high Schwann cell transfection efficiency (60±13%) in vitro. While all three genes showed therapeutic potential in terms of enhancing neurotrophic cytokine production while promoting neurite outgrowth, delivery of the gene encoding for c-Jun showed the greatest capacity to enhance regenerative cellular processes in vitro. Ultimately, this gene-activated NGC construct was shown to be capable of transfecting both Schwann cells (S42 cells) and neuronal cells (PC12 and dorsal root ganglia) in vitro, demonstrating potential for future therapeutic applications in vivo. Statement of Significance The basic requirements of biomaterial-based nerve guidance conduits have now been well established and include being able to bridge a nerve injury to support macroscopic guidance between nerve stumps, while being strong enough to withstand longitudinal tension and circumferential compression, in addition to being mechanically sound to facilitate surgical handling and implantation. While meeting these criteria, conduits are still limited to the treatment of small defects clinically and might benefit from additional biochemical stimuli to enhance repair for the effective treatment of larger injuries. In this study, a gene activated conduit was successfully developed by incorporating non-viral nanoparticles capable of efficient Schwann cell and neuronal cell transfection with therapeutic genes in vitro, which showed potential to enhance repair in future applications particularly when taking advantage of the transcription factor c-Jun. This innovative approach may provide an alternative to conduits used as platforms for the delivery neurotrophic factors or genetically modified cells (viral gene therapy), and a potential solution for the unmet clinical need to repair large peripheral nerve injury effectively.
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      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.014
       
  • Glutathione detonated and pH responsive nano-clusters of Au nanorods with
           a high dose of DOX for treatment of multidrug resistant cancer
    • Authors: Yun Wang; Feihu Wang; Ying Liu; Shaohui Xu; Yuanyuan Shen; Nianping Feng; Shengrong Guo
      Abstract: Publication date: Available online 6 June 2018
      Source:Acta Biomaterialia
      Author(s): Yun Wang, Feihu Wang, Ying Liu, Shaohui Xu, Yuanyuan Shen, Nianping Feng, Shengrong Guo
      Effects of nanosized drug delivery systems on cancer are often compromised due to their low drug loadings, premature drug release and multi-drug resistance (MDR). Herein, we reported a glutathione detonated and pH responsive nano-cluster of Au nanorods (AuNRs) with chemotherapeutic doxorubicin (DOX) and pre-chemosensitizer polycurcumin to treat MCF-7/ADR cells. The nano-cluster was prepared by self-assembling of AuNRs conjugated with DOX and amphiphilic poly(curcumin-co-dithiodipropionic acid)-b-biotinylated poly(ethylene glycol) via an emulsion/solvent evaporation technique, termed AuNR Cluster. The AuNR Cluster had a high drug loading (31.5% DOX), presenting much better aqueous solubility and stability at physiological pH than their individual AuNRs. The AuNR Cluster could be detonated to be their individual AuNRs at an intracellular concentration level of glutathione (GSH) (5 mM) and triggered to release DOX at an acidic pH (pH 6.8 or 5.0), which effectively facilitated cellular uptake of DOX (607 vs 356 a.u. for AuNRs at 12 h) and inhibited DOX efflux (471.33 vs 39.17 a.u. for free DOX at 24 h). The IC50 value of DOX against MCF-7/ADR cells for AuNR Cluster was 4.15 µg/mL, much lower than that for free DOX (90.97 µg/mL). The AuNR Cluster took much more photothermal effects than their corresponding AuNRs and presented enhanced anti-tumor effect (IC50: 2.61 µg/mL) under 808 nm laser irradiation. Statement of Significance Nano-sized drug delivery systems for anti-MDR cancer is still a challenging task. Herein, AuNR Cluster is self-assembled by individual AuNRs via emulsion/solvent evaporation technique, having a structure consisting of hydrophobic DOX/PCDA-AuNR core and hydrophilic biotin-PEG chain shell. AuNR Cluster is detonated to disintegrate and yield its individual AuNRs at an intracellular concentration level of glutathione (5 mM) and triggered to release DOX at an acidic pH (6.8 or 5.0). In comparison with its individual AuNRs, AuNR Cluster has better water solubility and stability, greater photothermal effects under NIR irradiation, bigger cytotoxicity against MCF-7/ADR cells. AuNR Cluster is expected to be a potential nanomedicine for treatment of MDR cancer.
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      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.012
       
  • A Multi-Functional Polymeric Carrier for Simultaneous Positron Emission
           Tomography Imaging and Combination Therapy
    • Authors: Jingjing Sun; Lingyi Sun; Jianchun Li; Jieni Xu; Zhuoya Wan; Zubin Ouyang; Lei Liang; Song Li; Dexing Zeng
      Abstract: Publication date: Available online 6 June 2018
      Source:Acta Biomaterialia
      Author(s): Jingjing Sun, Lingyi Sun, Jianchun Li, Jieni Xu, Zhuoya Wan, Zubin Ouyang, Lei Liang, Song Li, Dexing Zeng
      Multifunctional nanoplatforms offering simultaneous imaging and therapeutic functions have been recognized as a highly promising strategy for personalized nanomedicine. In this work, we synthesized a farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) based triblock copolymer POEG-b-PVBA-b-PFTS (POVF) composed of a poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic block, a poly(FTS) hydrophobic block, and a poly(4-vinylbenzyl azide) (PVBA) middle block. The POVF polymer itself was active in inhibiting the tumor growth in vitro and in vivo. Besides, it could serve as a carrier to effectively encapsulate paclitaxel (PTX) to form stable PTX/POVF mixed micelles with a diameter around 100 nm. Meanwhile, POVF polymer provides the active azide group for incorporating a positron emission tomography (PET) imaging modality via a facile strategy based on metal-free click chemistry. This nanocarrier system could not only be used for co-delivery of PTX and FTS, but also for PET imaging guided drug delivery. In the 4T1.2 tumor bearing mice, PET imaging showed rapid uptake and slow clearance of radiolabeled PTX/POVF nanomicelles in the tumor tissues. In addition, the FTS-based multi-functional nanocarrier was able to inhibit tumor growth effectively, and the co-delivery of PTX by the carrier further improved the therapeutic effect. Statement of significance Due to the intrinsic heterogeneity of cancer and variability in individual patient response, personalized nanomedicine based on multi-functional carriers that integrate the functionalities of combination therapy and imaging guidance is highly demanded. Here we developed a multi-functional nanocarrier based on triblock copolymer POEG-b-PVBA-b-PFTS (POVF), which could not only be used for co-delivery of anticancer drugs PTX and Ras inhibitor FTS, but also for PET imaging guided drug delivery. The POVF carrier itself was active in inhibiting the tumor growth in vitro and in vivo. Besides, it was effective in formulating PTX with high drug loading capacity, which further enhanced the tumor inhibition effect. Meanwhile, we developed a simple and universal approach to incorporate a PET radioisotope (Zr-89 and Cu-64) into the azide-containing PTX/POVF micelles via metal-free click chemistry in aqueous solution. The radiolabeled PTX/POVF micelles exhibited excellent serum stability, rapid tumor uptake and slow clearance, which validated the feasibility of the PET image-guided delivery of PTX/POVF micelles.
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      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.010
       
  • Optimizing resin-dentin bond stability using a bioactive adhesive with
           concomitant antibacterial properties and anti-proteolytic activities
    • Authors: Ya-ping Gou; Mohamed M. Meghil; Cesar R. Pucci; Lorenzo Breschi; David H. Pashley; Christopher W. Cutler; Li-na Niu; Ji-yao Li; Franklin R. Tay
      Abstract: Publication date: Available online 6 June 2018
      Source:Acta Biomaterialia
      Author(s): Ya-ping Gou, Mohamed M. Meghil, Cesar R. Pucci, Lorenzo Breschi, David H. Pashley, Christopher W. Cutler, Li-na Niu, Ji-yao Li, Franklin R. Tay
      Secondary caries and hybrid layer degradation are two major challenges encountered in long-term resin-dentin bond stability. As a link between resin and dentin, adhesives that possess both antimicrobial and anti-proteolytic activities are in demand for eliminating bacteria-induced secondary caries and preventing hybrid layers from degradation. In the present study, a new quaternary ammonium methacryloxy silane (QAMS) prepared from sol-gel chemistry was incorporated into experimental adhesives to examine their antimicrobial effect and anti-proteolytic potential. This functional methacrylate resin monomer contains polymerizable methacryloxy functionalities as well as a positively-charged quaternary ammonium functionality with a long, lipophilic -C18H37 alkyl chain for puncturing the cell wall/membrane of surface-colonizing organisms. Antibacterial testing performed using agar diffusion test, live/dead bacterial staining and colony-forming unit counts all indicated that the QAMS-containing adhesives killed Streptococcus mutans and Actinomyces naeslundii in a dose-dependent manner via a predominant contact-killing mechanism. Gelatinolytic activity within the hybrid layers created by these adhesives was examined using in-situ zymography. Hybrid layers created with 0% QAMS-containing adhesive exhibited intense green fluorescence emitted by the hydrolyzed fluorescein-conjugated gelatin, with 4-fold increase in enzymatic activity compared with an experimental adhesive containing 5% QAMS. Taken together, incorporation of 5% QAMS in the experimental adhesive provides simultaneous antimicrobial and anti-proteolytic activities that are crucial for the maintenance of long-term resin-dentin bond integrity. Statement of Significance Durability of resin-dentin interfacial bond remains a clinically-significant challenge. Secondary caries caused by bacteria and the degradation of hybrid layers via endogenous dentin proteases are two important contributors to the poor resin-dentin bond durability. The present study developed a new 5% QAMS-containing adhesive that provides simultaneous antimicrobial and dentin protease inhibition functions to extend the longevity of resin-dentin bonds.
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      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.008
       
  • Solvent-free preparation of porous poly(l-lactide) microcarriers for cell
           culture
    • Authors: Mirasbek Kuterbekov; Paul Machillot; Pierre Lhuissier; Catherine Picart; Alain M. Jonas; Karine Glinel
      Abstract: Publication date: Available online 6 June 2018
      Source:Acta Biomaterialia
      Author(s): Mirasbek Kuterbekov, Paul Machillot, Pierre Lhuissier, Catherine Picart, Alain M. Jonas, Karine Glinel
      Porous polymeric microcarriers are a versatile class of biomaterial constructs with extensive use in drug delivery, cell culture and tissue engineering. Currently, most methods for their production require potentially toxic organic solvents with complex setups which limit their suitability for biomedical applications and their large-scale production. Herein, we report an organic, solvent-free method for the fabrication of porous poly(l-lactide) (PLLA) microcarriers. The method is based on the spherulitic crystallization of PLLA in its miscible blends with poly(ethylene glycol) (PEG). It is shown that the PLLA spherulites are easily recovered as microcarriers from the blends by a water-based process. Independent control over microcarrier size and porosity is demonstrated, with a higher crystallization temperature leading to a larger size, and a higher PLLA content in the starting blend resulting in a lower microcarrier porosity. Microcarriers are shown to be biocompatible for the culture of murine myoblasts and human adipose stromal/stem cells (hASC). Moreover, they support not only the long-term proliferation of both cell types but also hASC differentiation toward osseous tissues. Furthermore, while no significant differences are observed during cell proliferation on microcarriers of two different porosities, microcarriers of lower porosity induce a stronger hASC osteogenic differentiation, as evidenced by higher ALP enzymatic activity and matrix mineralization. Consequently, the proposed organic-solvent-free method for the fabrication of biocompatible porous PLLA microcarriers represents an innovative methodology for ex vivo cell expansion and its application in stem cell therapy and tissue engineering. Statement of Significance We report a new solvent-free method for the preparation of porous polymeric microcarriers for cell culture, based on biocompatible poly(l-lactide), with independently controllable size and porosity. This approach, based on the spherulitic crystallization in polymer blends, offers the advantages of simple implementation, biological and environmental safety, easy adaptability and up-scalablility. The suitability of these microcarriers is demonstrated for long-term culture of both murine myoblasts and human adipose stromal/stem cells (hASCs). We show that prepared microcarriers support the osteogenic differentiation of hASCs, provided microcarriers of properly-tuned porosity are used. Hence, this new method is an important addition to the arsenal of microcarrier fabrication techniques, which will contribute to the adoption, regulatory approval and eventually clinical availability of microcarrier-based treatments and therapies.
      Graphical abstract image

      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.009
       
  • Polymeric microsphere-facilitated site-specific delivery of quercetin
           prevents senescence of pancreatic islets in vivo and improves
           transplantation outcomes in mouse model of diabetes
    • Authors: Shiva Pathak; Shobha Regmi; Tiep Tien Nguyen; Biki Gupta; Milan Gautam; Chul Soon Yong; Jong Oh Kim; Youlim Son; Jae-Ryong Kim; Min Hui Park; Young Kyung Bae; So Young Park; Daewon Jeong; Simmyung Yook; Jee-Heon Jeong
      Abstract: Publication date: Available online 5 June 2018
      Source:Acta Biomaterialia
      Author(s): Shiva Pathak, Shobha Regmi, Tiep Tien Nguyen, Biki Gupta, Milan Gautam, Chul Soon Yong, Jong Oh Kim, Youlim Son, Jae-Ryong Kim, Min Hui Park, Young Kyung Bae, So Young Park, Daewon Jeong, Simmyung Yook, Jee-Heon Jeong
      Attenuation of senescence progression may be attractive way to preserve the functionality of pancreatic islets (PI) after transplantation. In this study, we developed a model for in vitro induction of premature senescence in rat PI and showed the effectiveness of quercetin (QU) to prevent the senescence. To provide targeted-delivery of QU to the PI after transplantation, we prepared the hybrid clusters (HC) of islet single cells (ISC) and QU-loaded polymeric microspheres (QU; ∼7.55 ng HC-1). Long-term culture of the HC revealed reduced levels of reactive oxygen species and decreased expression of senescence-associated beta galactosidase, Rb, p53, p16, and p21 compared to that of the control islets. Transplantation of HC into subcutaneous space of the immune-deficient mice produced better glycemic control compared to the control islets or the ICC-transplanted mice. SA-β-Gal staining of the in vivo transplanted HC sample showed lower intensity compared to that of the control islets or the islet cell clusters. Thus, in situ delivery of therapeutic agent may be a promising approach to improve therapeutic outcomes in cell therapy. Statement of Significance In this study, we aimed to improve outcomes in islet transplantation using in situ delivery of quercetin to pancreatic islets, using polymeric microspheres. We prepared prolonged release-type microspheres and constructed hybrid clusters of pancreatic islets and the microspheres using hanging drop method. The presence of quercetin in the cellular microenvironment attenuated the progression of senescence in the pancreatic islets in a long-term in vitro culture. Moreover, transplantation of the hybrid clusters in the diabetic mice produced better glycemic control compared to that of the control islets. In addition, quercetin delayed the progression of senescence in the pancreatic islets after in vivo transplantation. Thus, local delivery of antioxidants like quercetin may be an attractive way to improve outcomes in cell therapy.
      Graphical abstract image

      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.006
       
  • Cell-Laden and Orthogonal-Multilayer Tissue-Engineered Corneal Stroma
           Induced by a Mechanical Collagen Microenvironment and Transplantation in a
           Rabbit Model
    • Authors: Zekai Cui; Qiaolang Zeng; Shiwei Liu; Yanan Zhang; Deliang Zhu; Yonglong Guo; Mengyuan Xie; Sanjana Mathew; Dongqing Cai; Jun Zhang; Jiansu Chen
      Abstract: Publication date: Available online 5 June 2018
      Source:Acta Biomaterialia
      Author(s): Zekai Cui, Qiaolang Zeng, Shiwei Liu, Yanan Zhang, Deliang Zhu, Yonglong Guo, Mengyuan Xie, Sanjana Mathew, Dongqing Cai, Jun Zhang, Jiansu Chen
      The development of functional therapies for corneal repair and regeneration is a pressing issue. Corneal stroma provides the principal functions of the cornea. However, because of the highly organized nature of the stromal matrix, the attempts to reproduce corneal stroma might follow a scar model. Here, we have developed a protocol for the efficient generation of a cell-laden and orthogonal-multilayer tissue-engineered (TE) corneal stroma, which is induced by the mechanical effects of compressed collagen (CC) or stretched compressed collagen (SCC). Within SCC, with applied compression and force extension, collagen microfibres and corneal stromal cells (CSCs) are arranged orderly, while collagen fibres and CSCs in CC are randomly arranged. Dehydrated SCC has higher tensile strength than dehydrated CC. Hydrated SCC has similar transparency with hydrated native corneal stroma. Compared with those cultured on tissue culture plates (TCP), down-regulation of the genes and proteins of cytoskeleton, activation, proliferation, collagen and TRPV4, up-regulation of proteoglycans, gap junction proteins and TRPA1 are in CSCs of CC and SCC. Moreover, SCC and CC grafts displayed biocompatibility and integration with host corneal tissue after rabbit intra-corneal stromal transplantation by wk 6 under slit lamp microscopy, in vivo confocal microscopy and histological examination. The SCC model facilitates the construction of physiological feature TE corneal stroma, which serves as a foundation for physiological TE construction of other tissues. Statement of significance The development of functional therapies for corneal repair and regeneration is a pressing issue. Corneal stroma provides the principal functions of the cornea. Here, we have developed a protocol for the efficient generation of a cell-laden and orthogonal-multilayer tissue-engineered (TE) corneal stroma, which is induced by the mechanical effects of compressed collagen (CC) or stretched compressed collagen (SCC). These models facilitate the construction of physiological feature TE corneal stroma, which serves as a foundation for physiological TE construction of other tissues and helps to reverse fibrosis pathologies in general.
      Graphical abstract image

      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.005
       
  • Additive manufacturing of hierarchical injectable scaffolds for tissue
           engineering
    • Authors: A. Béduer; N. Piacentini; L. Aeberli; A. Da Silva; C.A. Verheyen; F. Bonini; A. Rochat; A. Filippova; L. Serex; P. Renaud; T. Braschler
      Abstract: Publication date: Available online 5 June 2018
      Source:Acta Biomaterialia
      Author(s): A. Béduer, N. Piacentini, L. Aeberli, A. Da Silva, C.A. Verheyen, F. Bonini, A. Rochat, A. Filippova, L. Serex, P. Renaud, T. Braschler
      We present a 3D-printing technology allowing free-form fabrication of centimetre-scale injectable structures for minimally invasive delivery. They result from the combination of 3D printing onto a cryogenic substrate and optimisation of carboxymethylcellulose-based cryogel inks. The resulting highly porous and elastic cryogels are biocompatible, and allow for protection of cell viability during compression for injection. Implanted into the murine subcutaneous space, they are colonized with a loose fibrovascular tissue with minimal signs of inflammation and remain encapsulation-free at three months. Finally, we vary local pore size through control of the substrate temperature during cryogenic printing. This enables control over local cell seeding density in-vitro and over vascularization density in cell-free scaffolds in-vivo. In sum, we address the need for 3D-bioprinting of large, yet injectable and highly biocompatible scaffolds and show modulation of the local response through control over local pore size. Statement of significance This work combines the power of 3D additive manufacturing with clinically advantageous minimally invasive delivery. We obtain porous, highly compressible and mechanically rugged structures by optimizing a cryogenic 3D printing process. Only a basic commercial 3D printer and elementary control over reaction rate and freezing are required. The porous hydrogels obtained are capable of withstanding delivery through capillaries up to 50 times smaller than their largest linear dimension, an as yet unprecedented compression ratio. Cells seeded onto the hydrogels are protected during compression. The hydrogel structures further exhibit excellent biocompatibility 3 months after subcutaneous injection into mice. We finally demonstrate that local modulation of pore size grants control over vascularization density in vivo. This provides proof-of-principle that meaningful biological information can be encoded during the 3D printing process, deploying its effect after minimally invasive implantation.
      Graphical abstract image

      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.05.056
       
  • Comparative analysis of two porcine kidney decellularization methods for
           maintenance of functional vascular architectures
    • Authors: Joao Paulo Zambon; In Kap Ko; Mehran Abolbashari; Jennifer Huling; Cara Clouse; Tae Hyoung Kim; Charesa Smith; Anthony Atala; James J. Yoo
      Abstract: Publication date: Available online 5 June 2018
      Source:Acta Biomaterialia
      Author(s): Joao Paulo Zambon, In Kap Ko, Mehran Abolbashari, Jennifer Huling, Cara Clouse, Tae Hyoung Kim, Charesa Smith, Anthony Atala, James J. Yoo
      Kidney transplantation is currently the only definitive solution for the treatment of end-stage renal disease (ESRD), however transplantation is severely limited by the shortage of available donor kidneys. Recent progress in whole organ engineering based on decellularization/recellularization techniques has enabled pre-clinical in vivo studies using small animal models; however, these in vivo studies have been limited to short-term assessments. We previously developed a decellularization system that effectively removes cellular components from porcine kidneys. While functional re-endothelialization on the porcine whole kidney scaffold was able to improve vascular patency, as compared to the kidney scaffold only, the duration of patency lasted only a few hours. In this study, we hypothesized that significant damage in the microvasculatures within the kidney scaffold resulted in the cessation of blood flow, and that thorough investigation is necessary to accurately evaluate the vascular integrity of the kidney scaffolds. Two decellularization protocols [sodium dodecyl sulfate (SDS) with DNase (SDS + DNase) or Triton X-100 with SDS (TRX + SDS)] were used to evaluate and optimize the levels of vascular integrity within the kidney scaffold. Results from vascular analysis studies using vascular corrosion casting and angiograms demonstrated that the TRX + SDS method was able to better maintain intact and functional microvascular architectures such as glomeruli within the acellular matrices than that by the SDS + DNase treatment. Importantly, in vitro blood perfusion of the re-endothelialized kidney construct revealed improved vascular function of the scaffold by TRX + SDS treatment compared with the SDS + DNase. Our results suggest that the optimized TRX + SDS decellularization method preserves kidney-specific microvasculatures and may contribute to long-term vascular patency following implantation. Statement of Significance Kidney transplantation is the only curative therapy for patients with end-stage renal disease (ESRD). However, in the United States, the supply of donor kidneys meets less than one-fifth of the demand; and those patients that receive a donor kidney need life-long immunosuppressive therapy to avoid organ rejection. In the last two decades, regenerative medicine and tissue engineering have emerged as an attractive alternative to overcome these limitations. In 2013, Song et al. published the first experimental orthotopic transplantation of a bioengineering kidney in rodents. In this study, they demonstrated evidences of kidney tissue regeneration and partial function restoration. Despite these initial promising results, there are still many challenges to achieve long-term blood perfusion without graft thrombosis. In this paper, we demonstrated that perfusion of detergents through the renal artery of porcine kidneys damages the glomeruli microarchitecture as well as peritubular capillaries. Modifying dynamic parameters such as flow rate, detergent concentration, and decellularization time, we were able to establish an optimized decellularization protocol with no evidences of disruption of glomeruli microarchitecture. As a proof of concept, we recellularized the kidney scaffolds with endothelial cells and in vitro perfused whole porcine blood successfully for 24 h with no evidences of thrombosis.
      Graphical abstract image

      PubDate: 2018-06-08T13:03:40Z
      DOI: 10.1016/j.actbio.2018.06.004
       
  • Hybrid Collagen Alginate Hydrogel as a Platform for 3D Tumor Spheroid
           Invasion
    • Authors: Chun Liu; Daniela Lewin Mejia; Benjamin Chiang; Kathryn E Luker; Gary D Luker
      Abstract: Publication date: Available online 5 June 2018
      Source:Acta Biomaterialia
      Author(s): Chun Liu, Daniela Lewin Mejia, Benjamin Chiang, Kathryn E Luker, Gary D Luker
      Extracellular matrix regulates hallmark features of cancer through biochemical and mechanical signals, although mechanistic understanding of these processes remains limited by lack of models that recreate physiology of tumors. To tissue-engineer models that recapitulate three-dimensional architecture and signaling in tumors, there is a pressing need for new materials permitting flexible control of mechanical and biophysical features. We developed a hybrid hydrogel system composed of collagen and alginate to model tumor environments in breast cancer and other malignancies. Material properties of the hydrogel, including stiffness, microstructure and porosimetry, encompass parameters present in normal organs and tumors. The hydrogel possesses a well-organized, homogenous microstructure with adjustable mechanical stiffness and excellent permeability. Upon embedding multicellular tumor spheroids, we constructed a 3D tumor invasion model showing follow-the-leader migration with fibroblasts leading invasion of cancer cells similar to in vivo. We also demonstrated effects of CXCL12-CXCR4 signaling, a pathway implicated in tumor progression and metastasis, in a dual-tumor spheroid invasion model in 3D hydrogels. These studies establish a new hydrogel platform with material properties that can be tuned to investigate effects of environmental conditions on tumor progression, which will advance future studies of cancer cell invasion and response to therapy. Statement of Significance Our manuscript describes a novel design of hybrid hydrogel system composed of collagen and alginate modeling 3D tumor environments in breast cancer. The hydrogel possesses a well-organized, homogenous microstructure with adjustable mechanical stiffness. Upon embedding tumor spheroids, we successfully showed a 3D tumor invasion model showing follow-the-leader migration with fibroblasts leading invasion of cancer cells similar to in vivo. To the best of our knowledge, this is the first study showing two spheroids invade simultaneously and forming bridge-like connection and effects of chemical gradients in 3D hydrogel environment. This research provides a new model for tumor-stromal interactions in cancer cell migration and establishes a novel hydrogel system for analyzing physical and biochemical signals regulating cancer progression and response to therapy.
      Graphical abstract image

      PubDate: 2018-06-05T11:55:19Z
      DOI: 10.1016/j.actbio.2018.06.003
       
  • Accelerated Neural Differentiation of Mouse Embryonic Stem Cells on
           Aligned GYIGSR-functionalized Nanofibers
    • Authors: Elena A. Silantyeva; Wafaa Nasir; Jacqueline Carpenter; Olivia Manahan; Matthew L. Becker; Rebecca K. Willits
      Abstract: Publication date: Available online 5 June 2018
      Source:Acta Biomaterialia
      Author(s): Elena A. Silantyeva, Wafaa Nasir, Jacqueline Carpenter, Olivia Manahan, Matthew L. Becker, Rebecca K. Willits
      Substrates for embryonic stem cell culture are typified by poorly defined xenogenic, whole proteins or cellular components that are difficult and expensive to generate, characterize, and recapitulate. Herein, the generation of well-defined scaffolds of Gly-Tyr-Ile-Gly-Ser-Arg (GYIGSR) peptide-functionalized poly(ε-caprolactone) (PCL) aligned nanofibers are used to accelerate the neural lineage commitment and differentiation of D3 mouse embryonic stem cells (mESCs). Gene expression trends and immunocytochemistry analysis were similar to laminin-coated glass, and indicated an earlier differentiation progression than D3 mESCs on laminin. Further, GYIGSR-functionalized nanofiber substrates yielded an increased gene expression of Sox1, a neural progenitor cell marker, and Tubb3, Cdh2, Syp, neuronal cell markers, at early time points. In addition, guidance of neurites was found to parallel the fiber direction. Herein, we demonstrate the fabrication of a well-defined, xeno-free functional nanofiber scaffold and demonstrates its use as a surrogate for xenogenic and complex matrixes currently used for the neural differentiation of stem cells ex vivo Statement of Significance In this paper, we report the use of GYIGSR-functionalized poly(ε-caprolactone) aligned nanofibers as a tool to accelerate the neural lineage commitment and differentiation of D3 mouse embryonic stem cells. The results indicate that functional nanofiber substrates promote faster differentiation than laminin coated substrates. The data suggest that aligned nanofibers and post-electrospinning surface modification with bioactive species can be combined to produce translationally relevant xeno-free substrates for stem cell therapy. Future development efforts are focused on additional bioactive species that are able to function as surrogates for other xenogenic factors found in differentiation media.
      Graphical abstract image

      PubDate: 2018-06-05T11:55:19Z
      DOI: 10.1016/j.actbio.2018.05.052
       
  • Structure-function study of Poly(sulfobetaine 3,4-ethylenedioxythiophene)
           (PSBEDOT) and its derivatives
    • Authors: Chen-Jung Lee; Huifang Wang; Megan Young; Shengxi Li; Fang Cheng; Hongbo Cong; Gang Cheng
      Abstract: Publication date: Available online 4 June 2018
      Source:Acta Biomaterialia
      Author(s): Chen-Jung Lee, Huifang Wang, Megan Young, Shengxi Li, Fang Cheng, Hongbo Cong, Gang Cheng
      Poly(3,4-ethylenedioxythiophene) (PEDOT) has been widely studied in recent decades due to its high stability, biocompatibility, low redox potential, moderate band gap, and optical transparency in its conducting state. However, for its long-term in vivo applications, the biocompatibility of PEDOT still need to be improved. To address this challenge, zwitterionic Poly(sulfobetaine 3,4-ethylenedioxythiophene) (PSBEDOT) that contains EDOT backbone with sulfobetaine functional side chains were developed in our previous study. Although PSBEDOT showed great resistance to proteins, cells, and bacteria, it is still not clear how the zwitterionic sulfobetaine side chain affects the electrochemical properties of the polymer and reactivity of the monomer. To have better understanding on the structure-function relationship of zwitterionic conducting polymer, we synthesized two derivatives of PSBEDOT, PSBEDOT-4 and PSBEDOT-5, by introducing the alkoxyl spacer between EDOT and sulfobetaine. The interfacial impedance of PSBEDOT-4 and PSBEDOT-5 was examined by electrochemical impedance spectroscopy and showed significant improvement which is about 20 times lower than PSBEDOT on both gold and indium tin oxide substrates at 1 Hz. In the protein adsorption test, PSBEDOT, PSBEDOT-4 and PSBEDOT-5 exhibited comparable resistance to the fibrinogen solution. All three polymers had low protein adsorption around 3%-5% comparing to the control sample, PEDOT, which was normalized to 100%. Additionally, the morphology of PSBEDOT, PSBEDOT-4 and PSBEDOT-5 with different synthesis parameter have been investigated by scanning electron microscope. We believe that these stable and biocompatible materials can be good candidates for developing long-term bioelectronics devices. Statement of significance To address the challenges associated existing conducting materials for bioelectronics, we developed a versatile and high performance zwitterionic conducting material platform with excellent stability, electrochemical, antifouling and controllable antimicrobial/antifouling properties. In this work, we developed two high-performance conducting polymers and systematically investigated how its structure affect their properties. Our study shows we can accurately tune the molecular structure of the monomer to dramatically improve the performance of zwitterionic conducting polymer. This zwitterionic conducting polymer platform may dramatically increase the performance and service life of electrochemical devices for many long-term applications, such as implantable biosensing, tissue engineering, wound healing, robotic prostheses, biofuel cell etc., which all require high performance conducting materials with excellent antifouling/biocompatibility at complex biointerfaces.
      Graphical abstract image

      PubDate: 2018-06-05T11:55:19Z
      DOI: 10.1016/j.actbio.2018.06.002
       
  • Dentin horn angle and enamel thickness interactively control tooth
           resilience and bite force
    • Authors: Herzl Chai
      Abstract: Publication date: Available online 3 June 2018
      Source:Acta Biomaterialia
      Author(s): Herzl Chai
      Fossil teeth are a primary source for inferring species development via evolutionary adaptation due to their linkage to feeding ecology and well perseverance. The main working tools in such studies are bite force analysis derived from jaw musculature and lever arms and morphogenetic based on enamel thickness and occlusal surface area. Despite progress made, quantitative correlation between predictions and behavior is still lacking. We studied histological sections in varieties of extracted premolar and molar human teeth. Sections corresponding to planes intersecting tips of primary cusps as well as more random planes were considered. The results revealed a unique, conclusive link between cuspal enamel thickness d c and dentin horn angle φ, a developmental parameter which contribution to tooth functioning has been overlooked. Naturally led by design principles of corbel arches, we examined the bending stress at the horn apex due to axial cuspal loading. The results show that this d c vs. φ relationship produces a constant force causing cusp fracture P F, making the latter a viable measure of tooth resilience. A preliminary study on published sections of extinct hominin teeth showed that their d c vs. φ behavior is consistent with modern humans albeit with varying P F. Scaling BF with P F enables direct estimate of bite force from measures of d c and φ in fossil teeth, achievable nondestructively from micro-computed tomography scans. Statement of Significance The correspondence between cuspal enamel thickness and dentin horn angle in the postcanine is a natural design here revealed for the first time. This correspondence yields constant force causing fracture at the horn apex, P F, making the latter a viable measure of tooth resilience. Scaling bite force (BF) with P F enables direct estimate of BF. The proposed mechanistic link between bite force and anatomical parameters d c and φ, expressed in a simple analytic form, offers direct, development-based expectation for examining evolutionary processes in hominins.
      Graphical abstract image

      PubDate: 2018-06-05T11:55:19Z
      DOI: 10.1016/j.actbio.2018.06.001
       
  • A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic
           drugs as a tool to reverse multidrug resistance in breast cancer
    • Authors: Fengchun Tian; Fatima Zohra Dahmani; Jianan Qiao; Jiang Ni; Hui Xiong; Tengfei Liu; Jianping Zhou; Jing Yao
      Abstract: Publication date: Available online 3 June 2018
      Source:Acta Biomaterialia
      Author(s): Fengchun Tian, Fatima Zohra Dahmani, Jianan Qiao, Jiang Ni, Hui Xiong, Tengfei Liu, Jianping Zhou, Jing Yao
      Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-molecular-weight heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in subcutaneous Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-positive tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis. Immunohistochemistry and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, respectively. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer. Statement of Significance Herein, we successfully developed a novel amphiphilic nanomaterial, LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]–reversing drug) inner core, and a hydrophilic low-molecular-weight heparin (an antiangiogenic agent) outer shell for encapsulating and delivering a hydrophobic chemotherapeutic agent (gambogic acid). This versatile nanoplatform with multiple targeted features, i.e., dual chemo/angiostatic effects, destruction ability of the peritumoral lymphatic vessels, and reversal of MDR, resulted in a significantly stronger antitumor efficacy and lower toxic side effect than those of nontargeted nanoparticles and the free drug solution. Therefore, this versatile nanosystem might provide a novel insight for the treatment and palliation of breast cancer by targeted co-delivery of chemo/antiangiogenic agents and reversing MDR and metastasis.
      Graphical abstract image

      PubDate: 2018-06-05T11:55:19Z
      DOI: 10.1016/j.actbio.2018.05.050
       
 
 
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